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Acta Tropica 176 (2017) 206–223

Contents lists available at ScienceDirect

Acta Tropica
journal homepage: www.elsevier.com/locate/actatropica

Review

Leptospirosis: Molecular trial path and immunopathogenesis correlated with MARK


dengue, malaria and mimetic hemorrhagic infections
Sivan Padma Priyaa, S. Sakinaha, K. Sharmilaha, Rukman A. Hamata, Zamberi Sekawia,

Akon Higuchib,c,d, Mok Pooi Linge, Syafinaz Amin Nordina, Giovanni Benellif, S. Suresh Kumara,g,
a
Department of Medical Microbiology and Parasitology, Universiti Putra Malaysia, 43400 UPM Serdang Selangor, Malaysia
b
Department of Chemical and Materials Engineering, National Central University, Jhong-li, Taoyuan, Taiwan
c
Department of Botany and Microbiology, King Saud University, Riyadh, Saudi Arabia
d
Department of Reproduction, National Research Institute for Child Health and Development, Tokyo, Japan
e
Department of Biomedical Science, Faculty of Medicine and Health Science Universiti Putra Malaysia, 43400, UPM, Serdang, Selangor, Malaysia
f
Department of Agriculture, Food and Environment, University of Pisa, Via del Borghetto 80, 56124 Pisa, Italy
g
Genetics and Regenerative Medicine Research Centre, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia

A R T I C L E I N F O A B S T R A C T

Keywords: Immuno-pathogenesis of leptospirosis can be recounted well by following its trail path from entry to exit, while
Leptospira inducing disastrous damages in various tissues of the host. Dysregulated, inappropriate and excessive immune
Leptospirosis responses are unanimously blamed in fatal leptospirosis. The inherent abilities of the pathogen and inabilities of
Arbovirus the host were debated targeting the severity of the disease. Hemorrhagic manifestation through various me-
Co-infection
chanisms leading to a fatal end is observed when this disease is unattended. The similar vascular destructions
Cytokines
and hemorrhage manifestations are noted in infections with different microbes in endemic areas. The simulta-
Dengue
Malaria neous infection in a host with more than one pathogen or parasite is referred as the coinfection. Notably,
Chikungunya common endemic infections such as leptospirosis, dengue, chikungunya, and malaria, harbor favorable en-
Hemorrhagic fever vironments to flourish in similar climates, which is aggregated with stagnated water and aggravated with the
poor personal and environmental hygiene of the inhabitants. These factors aid the spread of pathogens and
parasites to humans and potential vectors, eventually leading to outbreaks of public health relevance. Malaria,
dengue and chikungunya need mosquitoes as vectors, in contrast with leptospirosis, which directly invades
human, although the environmental bacterial load is maintained through other mammals, such as rodents. The
more complicating issue is that infections by different pathogens exhibiting similar symptoms but require dif-
ferent treatment management. The current review explores different pathogens expressing specific surface
proteins and their ability to bind with array of host proteins with or without immune response to enter into the
host tissues and their ability to evade the host immune responses to invade and their affinity to certain tissues
leading to the common squeal of hemorrhage. Furthermore, at the host level, the increased susceptibility and
inability of the host to arrest the pathogens’ and parasites’ spread in different tissues, various cytokines accu-
mulated to eradicate the microorganisms and their cellular interactions, the antibody dependent defense and the
susceptibility of individual organs bringing the manifestation of the diseases were explored. Lastly, we provided
a discussion on the immune trail path of pathogenesis from entry to exit to narrate the similarities and dis-
similarities among various hemorrhagic fevers mentioned above, in order to outline future possibilities of pre-
vention, diagnosis, and treatment of coinfections, with special reference to endemic areas.

1. Introduction Mitsani, 2011). Leptospira interrogans, the causative organism of this


disease, is an aerobic, gram negative bacterium belongs to genus Lep-
Leptospirosis is a zoonotic disease that claims nearly thousands of tospira, (Phylum- Spirochaetes: Family-Leptospiraceae). It is evolutio-
lives annually worldwide. Farmers, fishing industry workers, veter- narily primitive eubacteria having strong survival potential in soil and
inarians, slaughterhouse employees, agricultural workers and sewage water as saprophyte and facultative parasite. BLAST analysis comparing
workers are more at risk of leptospirosis infections (Forouhar and the protein homologues reveals that the structural similarity with


Corresponding author at: Department of Medical Microbiology and Parasitology, Universiti Putra Malaysia, UPM Serdang 43400, Selangor, Malaysia.
E-mail address: sureshkudsc@gmail.com (S.S. Kumar).

http://dx.doi.org/10.1016/j.actatropica.2017.08.007
Received 7 July 2017; Received in revised form 3 August 2017; Accepted 4 August 2017
Available online 16 August 2017
0001-706X/ © 2017 Elsevier B.V. All rights reserved.
S.P. Priya et al. Acta Tropica 176 (2017) 206–223

Fig. 1. This schematic diagram explains the trans-


mission cycle of Leptospira in the environment.
Rodents and wild animal act as reservoirs for
Leptospira, contaminating the water, vegetation, and
soil through their urine. Human with skin abrasions
and exposed mucosal surfaces get infected through
direct contact with Leptospira and disseminate the
pathogens throughout the body via the circulatory
system.

archaeal and eukaryal proteins raising the possibility of the emergence they do influence homeostasis, hematopoiesis and nervous system due
of this pathogenic bacterium from non-pathogenic one, possibly by to their complicated mechanisms with overlapping functions. Recent
lateral gene transfer for better survival (Ren et al., 2003). This micro- studies conducted within the last two decades have focused on large
organism is typically excreted in urine from reservoir hosts, such as variations in laboratory diagnostics, case reports and epidemiological
rats, rodents, dogs, cattle, and others. It can enter into the body via procedures concerning the identification of leptospirosis and other
intact mucosa and/or abraded skin (Fig. 1). In the case of severe hemorrhagic fevers (Wiwanitkit and Wiwanitkit, 2013; Musso and La
flooding, individuals are at greater risk of coming in contact with lep- Scola, 2013). However, only a few studies have described a systematic
tospira in endemic areas. The incubation period for infected individuals approach to differentiate coinfections with leptospirosis (Dircio Montes
is 7–10 days on average, resulting in clinical manifestations in two Sergio et al., 2012; Mishra et al., 2013; Levett et al., 2000; Flannery
stages: the initial leptospiremic stage and the subsequent immune stage et al., 2001).
involving multiple organs. The initial leptospiremic phase reflects the
multiplication of the organism in the blood and tissues upon entry. 2. Invading the surface barriers/breaching the epidermal barriers
Leptospira binds to capillary endothelium, resulting in vasculitis, a
major cause of multisystem involvement (Evangelista et al., 2014b) or The surface defense such as physical (skin and mucosa), chemical
Weil’s syndrome extends to liver, heart, kidney and nervous system (antimicrobial secretions) and biological (commensals) barriers of the
resulting in cardiac and renal failure. Brain involvement and neurolo- body needs to be breached to activate the next level of defenses, the
gical manifestations are not common in leptospirosis (Mathew et al., innate and adaptive immune responses. The fundamentals of immune
2006). interactions in leptospirosis are yet poorly described, in spite of millions
Simultaneous infection of a host with more than one pathogen or of researches and projects have completed and running (Cassadou et al.,
parasite is referred as the coinfection. Coinfection of leptospirosis with 2016).
dengue (Dircio Montes Sergio et al., 2012; Wijesinghe et al., 2015;
Perez Rodriguez et al., 2014; Singh et al., 2013; Zaki and Shanbag,
2010; Nunez-Garbin et al., 2015), chikungunya (Nhan et al., 2016) and 2.1. Physical barriers
malaria (Lindo et al., 2013; Costa Ade et al., 2010; Magalhaes et al.,
2014) incidences are increasing, especially in pacific regions where Human body surfaces and cavities are covered with intact epithe-
these diseases are endemic (Victoriano et al., 2009; Cao-Lormeau and lium, which is an effective barrier against microbes. Any breach in the
Musso, 2014). Hemorrhagic manifestation through different microbes integrity of epithelial junctions, such as injured skin or through the
with a fatal end is observed when these diseases were unattended and mucous membranes, generates an entry route for many microbes, in-
share similar endothelial destruction through different routes. The cluding Leptospira species (Adler and de la Pena Moctezuma, 2010)
bioactive molecules are similar but driven through different pathways. (Fig. 1). The epithelium covering skin and mucous membrane or-
The maximum spread and establishment of lesions are typically ob- opharyngeal and ocular region is stratified with multiple layers, and the
served by the first week of infection. During this crucial time, if timely thickness of this barrier varies according to the toughness of the in-
control over biomolecules can be exerted to stop the progress of the tended function (Junqueira and Mescher, 2010). Either complete injury
microbe initiated damages, then the host-induced damages can be re- (ulcer) or partial injury (erosion) to the epithelium with or without
duced. Coinfections in endemic areas and during outbreaks can be exposure of the connective tissue components enhances the entry of
handled together by understanding the similarities and dissimilarities Leptospira species (Haake and Levett, 2015). Epithelial thickness in skin
in immuno-pathogenesis to uniquely designed diagnosis, treatment, and varies from thick palm (1.5 mm) to thin eyelid (0.05 mm), the corneal
preventive modalities. mucosa having 52 μm (Hogan et al., 1971) and in oral mucosa varies
Immune response of a host to any pathogen or parasite either innate from 294 μm (buccal mucosa) to 99 μm (floor of the mouth) (Prestin
or adaptive at cellular level involves interaction of molecules, which are et al., 2012). The thick epithelial layers of the skin are maintained tight
dynamic and complex in function, integrated with tissue damages, re- by keratin and fillagrin bond and physiologically desquamating epi-
pair, and resolution. During their signal inducing effector functions, thelial cells releasing amino acids, lactic acids, urea' and salts, act as a
repellent coat (named as the natural moisturizing factor) to preserve the

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S.P. Priya et al. Acta Tropica 176 (2017) 206–223

skin pliable and water repellent. The epithelium is an avascular struc- not been explored in Leptospira species. The role of micronutrients and
ture with lack of blood vessels delivered defense cells, but themselves the risk and severity of leptospirosis has been documented (Herman
secret cholesterol, free fatty acids and sphingolipids (especially cer- et al., 2016) and for dengue (Ahmed et al., 2014). The importance of
amides) to stack the surface and intercellular areas to prevent water and malnutrition in underdeveloped countries especially those belong to
microbe movement (Coderch et al., 2003). Other than wounded skin endemic areas are to be seriously taken for further researches to prevent
and mucosal area, systematic histopathological and histochemical stu- the leptospirosis, because malnutrition is one of the common cause of
dies needed to explore whether and how Leptospira invade into the immunodeficient state (Keusch, 2003).
intact skin of different thickness and soiled skin of vulnerable profes- Dengue virus (DENV), chikungunya virus (CHIKV) and malarial
sionals. parasites escape surface barriers with the help of mosquito vectors,
Leptospira penetrates the undamaged mucosal layer but not the skin. which deliver them directly to connective tissue or dermal region by
The differences in preventive barriers are thickness and the moisture their biting mouthparts (proboscis) (Cox et al., 2012; Pingen et al.,
content between them, but the distinguished secretions of skin epithe- 2016). The inability of all these pathogens or parasites to breach the
lium preventing their entry need to be explored to initiate the invention surface barriers needs to be strongly highlighted and included in pri-
of topical applications to enrich the preventive ability especially for mary prevention plan. Leptospira species do show their best way of
travelers to the endemic area. Epithelium also secrets eicosanoids escaping from all these barriers by different mechanisms. Therefore,
(Brock and Peters-Golden, 2007), an inflammatory mediator and do key prevention at this level is highly encouraging to prevent all these
possess non-keratinocytes like Langerhans cells (well known as antigen diseases together, if proper personal and environmental hygiene could
presenting cells (APC) or dendritic cells (DC) in the basal layer), which be educated to the public.
senses the antigens and present it to regional lymph nodes for specific
defense (Junqueira and Mescher, 2010). There are specialized in- 3. Driving beyond the dermal layer
traepithelial γd T cells initiates a rapid defense by recognizing self-
antigens expressed on damaged or stressed cells and maintains tissue Stakeholders do rise to understand more about the entry of
homeostasis (Jameson et al., 2002). Broken skin and thin mucosa lack Leptospira species. However, the researchers are trying to find out the
theses protection shields render susceptible to leptospiral invasion. Nil mechanisms of immunity after the Leptospira breaches the dermal layer
reports about entry through the intact skin strongly recommend the of the host system. Innate immunity readily recognizes trespassers once
need for educating personal hygiene awareness in endemic areas as a they clear the obstacle of surface barriers, by identifying pathogen
crucial factor for primary prevention. (non-self) related immuno-stimulants like formyl methionine con-
taining peptides, surface molecules like LPS, short sequence bacterial
2.2. Chemical barriers DNA and CpG motifs, all of them including Leptospiras’, attract the
neutrophils (PMN) (Mandal et al., 2005) The innate immune network
The chemical barrier other than mentioned above secretions in- consists of cell population resident to the local tissue including DC
cludes lysozyme in sweat, saliva, and tear which is an enzyme that can (APC), PMN, mast cells, T- cells and natural killer cells and their cell
break down peptidoglycans present on the microbial cell wall (Asoh secretions namely cytokines. The pattern recognition receptors (PRR)
et al., 2014). RNase (Simanski et al., 2012) and DNase secreted by skin distributed on these cells recognize the Leptospira specific receptors and
are more powerful that, they might interfere the laboratory procedures other microbe specific receptors on the pathogens to initiate the pha-
of molecular biology if gloves not worn. There are few research works gocytosis and to trigger the genes of the immune response. The PRR can
explaining the production of chemicals barriers in the presence of be soluble as in complement system or attached on to the host cell
Leptospira species, however, a clear understanding is still needed for membrane (Alberts, 2008). PRRs on the cells are strewn as membrane-
each virulent strain. Defensins (Wu et al., 1992) and cathelicidin bound receptors including Toll-like receptors (TLRs) (Akira, 2009) and
(Sambri et al., 2002) are antimicrobial peptides (AMP), the small ca- C-type lectin receptors (CLRs) (Hoving et al., 2014; Geijtenbeek and
tionic peptides secreted by a variety of cells (Ganz, 1994) including Gringhuis, 2009) or unbound in the cytosol like NOD-like receptors
neutrophils and epithelial cells against many microbes, including Lep- (NLRs) (Proell et al., 2008) and RIG-I-like receptors (RLRs) (Loo and
tospira. AMPs’ secreted by surface barrier cells are effective chemical Gale, 2011). The specificity shown by different PPRs for different pa-
barriers at surface level. thogen necessitates reconsidering new concept that the PPR in innate
immunity cannot be considered as a non-specific response, but a pa-
2.3. Biological barriers thogen specific immediate response.

The biological barrier is by the non-pathogenic microbes on the skin 3.1. Complement system
named as commensals, which are always defending their territory by
fighting with other invading pathogens. The revised ratio of the bac- The complement system consists of about 30 interacting proteins
terial and human cells is 1:1 according to current report (Sender et al., elicit a cascade of reactions to recruit PMNs to the site of pathogens,
2016) and the difference in the microbiome in each human, each opsonizes the pathogen for better engulfing of PMNs, initiates cell lysis
community and each ethnic group (Hospodsky et al., 2014) is well by membrane attack complexes, regulating antibody effector mechan-
versed. The commensals improving resistance to local and systemic isms and modulating T cell function (Stoermer and Morrison, 2011).
infections in different aspects is a never ending research interest (Zhang Complements are readily available proteins secreted by the liver in the
and He, 2015). The need for exploring individual genetic susceptibility inactive form and widely distributed extra (ECM) and intravascularly
in endemic areas and the difference in susceptibility among the en- (plasma). The Leptospira species interact with few of the complement
demic and non-endemic areas are to be strengthened regarding lep- proteins of both classical and alternative pathways to evade the im-
tospirosis (Esteves et al., 2014). Interestingly prophylactic and ther- munity. This is achieved by the blocking action of the surface proteins
apeutic aspects of topical probiotics have been reviewed (Volz and of Leptospira Lig binding protein with factor H (FH), factor H-like 1
Biedermann, 2009). (FHL-1), factor H-related 1 (FHR-1), LigB with C3b and C4b, Lsa30 with
The increased susceptibility resulting from polymorphisms asso- C4 bp regulator, Lsa33 with C4 bp and LcpA (leptospiral complement
ciated with the human leukocyte antigen (HLA DQ6) has also been regulator-acquiring protein A) with C4 binding protein (C4 bp) (da
reported (Lingappa et al., 2004). Individual susceptibility due to de- Silva et al., 2015; Barbosa et al., 2010; Fraga et al., 2014; Domingos
fective surface barrier function or due to genetic defects in the barrier et al., 2012; Choy, 2012; Castiblanco-Valencia et al., 2012; Souza et al.,
or nutritional imbalance targeting the surface barrier dysfunction has 2012).

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Table 1
Correlation and common clinical features of leptospirosis with dengue, malaria and chikungunya.

Leptospirosis Dengue Malaria Chikungunya


S.P. Priya et al.

Type of microbe Gram-negative, aerobic bacteria, Single stranded- positive sense RNA virus, Plasmodium falciparum, Plasmodium vivax; Single stranded-positive sense RNA virus
Unicellular Parasites
Family: Leptospiraceae Family: Flaviviridae Family: Plasmodiidae Family: Togoviridae
Genus: Leptospira Genus: Flavivirus Genus: Plasmodium Genus: Alphavirus
Transmission to host Direct mucosal entry; Reservoir mammals Via Aedes mosquito vectors (commonly Aedes Via Culex mosquito vectors Via Aedes mosquito vectors
are rats, dogs and pigs (Adler and de la aegypti)
Pena Moctezuma, 2010; Andre-Fontaine,
2006)
Incubation 2–30 days (Adler and de la Pena 4–6 days (Guzman and Kouri, 2004) 7–30 days (Bartoloni and Zammarchi, 2012) 4–7 days (Lum and Ng, 2015)
Moctezuma, 2010)
Mode of Living, Target cells and Extracellular and Facultative intracellular Obligate intracellular Intra and extra cellular stages during their Obligate intracellular
organs complex life cycle, Hepatocytes, red blood
cells, endothelial cells (Bousema et al., 2008)
All these hemorrhagic fevers, Cells: endothelial, hepatocytes and Cells: macrophages, Langerhans cells, Cells: endothelial, epithelial and fibroblastic primary
unanimously alter epithelial cells monocytes, T cells, dendritic cells, cells (Wikan et al., 2012), muscle satellite cells (Ozden
microcirculation of entire body. hepatocytes, endothelial cells, mast cells et al., 2007), dermal macrophages (Sourisseau et al.,
2007) and PBMC (Sourisseau et al., 2007)
Organs: liver, lung, kidney, eye and brain Organs: damages primarily in liver, blood Organs, muscle joints, connective tissue, spleen, lymph
cells and blood vessels, but lung, eye, heart, node, brain, and skin (Sourisseau et al., 2007)
pancreas and brain are secondary to bleeding.
(Adler and de la Pena Moctezuma, 2010) (Simmons et al., 2012)
Cytokines associated with IL-1b,2, 4,6, 8, 10,17A, and TNF α (Goris IL-2, 4, 5, 6, 8, 10, 12, 17AIFN α, γ, TNF α, TNF α, IL4, IL10, IL6, IFN- gamma, TNF α, IFN γ, IFN α, IL2, 6,7,15,17,18 (Teng et al.,
pathogenesis et al., 2011; Reis et al., 2013) (Chaturvedi et al., 1999; Diamond et al., lymphotoxin 2015)
2000; Arias et al., 2015; Arias et al., 2014)
Common clinical features for the infections discussed here are fever, myalgia, headache, abdominal pain vomiting, anemia, thrombocytopenia

209
Rash + + ± ±
Jaundice + ± +
Leukocytosis + ± – ±
Leukopenia ± + ± ±
Hyperbilirubinemia + ± + +
BUN (Blood Urea Nitrogen) elevated + ± – –
Tourniquet test positive + + – –
Hepato-splenomegaly ± ± + +
Common treatment for all the microbial infections under discussion are supportive or symptomatic treatment like fluid replacement and adequate rest
Specific treatment 1. Antibiotics: oral or intravenous for mild No specific antiviral treatment (Chawla et al., Antimalarial drugs (e.g. chloroquine and No specific antiviral treatment.
and severe cases respectively (Brett-Major 2014, 2009). artemisinin). However, many drug-resistant
and Coldren, 2012). Plasmodium strains currently reported.
2. Whole blood or platelet transfusion for Patients are advised to get isolated with Patients are advised to get isolated with Patients are advised to get isolated with treated net to
Weil’s syndrome (Wiwanitkit, 2006). treated net to prevent viral spread especially treated net to prevent of spread the protozoa prevent viral spread especially during febrile illness
during febrile illness especially during febrile illness (Biamonte
et al., 2013)
3. Usefulness of steroid to prevent Treatment with corticosteroids is under Corticosteroids contraindicated (Bettadapura et al.,
pulmonary and ocular damages reported controversy (Rajapakse et al., 2014; Chawla 2013)
(Trivedi et al., 2001; Martins et al., 1998) et al., 2014)
Immune evasion 1. Resists complement mediated killing 1. Antibody dependent enhancement (ADE) 1. Antigen diversity/polymorphism, 1. ADE (Stapleford et al., 2014),
(Fraga et al., 2014) (Halstead 2007),
2. Reduced expression of antigenic proteins 2. Inadequate immune response “Original 2. Antigen variation (Scherf et al., 2008) 2. Utilizing apoptotic machinery (Krejbich-Trotot et al.,
(Monahan et al., 2008) antigenic sin” (Mongkolsapaya et al., 2003) 2011),
3. Higher expression of O antigen (Nally 3. Apoptotic mimicry (Amara and Mercer 3. Total immune suppression (Craig and 3. Evade antibody dependent neutralization (Lee et al.,
et al., 2005) Biofilm formation (Ristow 2015) Scherf 2001) 2011)
et al., 2008)
4. Inhibiting IFN signal (Green et al., 2014) 4. Resists complement mediated killing
(Schmidt et al., 2015)
Alters host lipid synthesis (Heaton and
Randall 2010)
Acta Tropica 176 (2017) 206–223
S.P. Priya et al. Acta Tropica 176 (2017) 206–223

Complement system as one of the controlling factor of diseases se- responses to vaccines. TLR based molecular level studies need to be
verity (Yamanaka et al., 2013) as well as contributing factor to en- simulated in larger units among the different ethnic group to validate
dothelial damage in DENV infections which were discussed by several the findings with independent approaches to aim for novel therapeutic
researchers (Martina et al., 2009; Dalrymple and Mackow, 2012). An- intervention strategies (Buonaguro and Pulendran, 2011).
tibodies of the NS1 protein of DENV triggers several complement pro-
teins and contribute to endothelial damage and vascular leakage 3.3. Cytokines
leading to hemorrhage (Avirutnan et al., 2006).
CHIKV infection is less reported with the role of complement (Reddy Cytokines are potent chemicals in very minute quantity, fastening
et al., 2017). Both the classical and the alternative pathways of the changes at the molecular level in many target cells and influencing all
complement system are strongly activated in malaria (Wenisch et al., systems of the body. Immune responses and its related cytokine storm
1997) and causing the depletion of complement proteins which chal- as chemical war has been immensely discussed by research works with
lenges the host's innate defense (Korir et al., 2014). Malarial parasites, a special focus on leptospirosis and dengue (Rizvi et al., 2011;
when exposed to human serum actively recruit FH and its alternative Alvarado-Esquivel et al., 2016; Rathakrishnan et al., 2012) as well as in
spliced form FH-like protein 1 to its surface to protect from complement CHIKV (Lum and Ng, 2015; Chaaitanya et al., 2011) and malaria
activation and uses the same during sexual forms to evade complement- (Angulo and Fresno, 2002), yet the clear pathway of Leptospira patho-
mediated killing in the mosquito host (Schmidt et al., 2015). genesis never been unanimously concluded. The cytokines involved in
The complements’ pathogenic roles in a variety of autoimmune, Leptospira, DENV, CHIKV and malaria pathogenesis are summarized in
ischemic and inflammatory diseases have been documented (Thurman Table 1. The individual and synergistic effect of cytokines on the vas-
and Holers, 2006; Holers, 2014). The post infection follow-up records cular endothelial cells increases capillary permeability resulted in
monitoring the complements’ level and the associated cytokines and the leakage, endothelial dysfunction and hemorrhagic episodes (Burke-
symptoms of documented complications have never been recounted for Gaffney and Keenan, 1993; Mathew and Rothman, 2008). Many con-
all the mentioned hemorrhagic fevers. Systematic studies to be initiated flicting results have been blamed for the lack of standardization in
to record proper follow-up of the infected patients to analyze the im- many aspects like less number of samples, lack of independent variables
muno-pathogenesis for prevention. like diseases with mild and severe (Reis et al., 2013), a large panel of
cytokines released during the different period of illness confusing due to
3.2. Toll like receptors associated diseases. Pro-inflammatory cytokines IL1, IL2, IL6, and TNFα
and the anti-inflammatory cytokines IL10 and IL4 were associated with
TLR is about 10 in humans (Pandey and Agrawal, 2006) distributed all these infections of discussion (Reis et al., 2013; Angulo and Fresno,
abundantly on epithelial cells, macrophages, and neutrophils and re- 2002; Rathakrishnan et al., 2012; Chaaitanya et al., 2011), but the
cognizes non-self-structures including all microbes and synthetic in- majority of the reports have agreed with the association of IL10 in-
vaders (Kawai and Akira, 2005). They activate nuclear factor (NF)-κB, crease and severity of disease (Reis et al., 2013; Venugopalan et al.,
AP (Activator protein)-1 and IFN (interferon) regulatory factor for the 2014; Zhang et al., 2012; Ferreira et al., 2015; Perez et al., 2004).
effective immune response (Kawai and Akira, 2006) by inducing cyto- Systematic retrospective studies and prospective animal studies
kines and chemokines and also aiding DCs. By upregulating the costi- about the common cytokines of endemic diseases at different stages
mulatory molecules of DC they initiate the adaptive response which is might bring a simple common solution by intervening cytokine actions
the top level of the immune defense. Cell surfaces express TLRs 1, 2, 4, to control the disease process as well for early prediction of damages.
5, and 6 and the TLRs 3, 7, 8, and 9 are present within the cell inside The high serum level of IL6 noticed during post infection period and in
endosomes (Pandey and Agrawal, 2006). TLR10, a modulatory PRR infected joints is correlated with persistent arthralgia (Noret et al.,
with inhibitory properties (Oosting et al., 2014). 2012; Hoarau et al., 2010). Interestingly, the IL6 has the ability to drive
TLR 2 and TLR 4 mediated responses can clear the pathogen ef- osteoclastogenesis (Hofbauer et al., 1999) and responsible for rheu-
fectively through B cells (Chassin et al., 2009), but the leptospiral LPS is matic symptoms, which are prevented in IL6 neutralized mice (Chen
less endotoxic because of the different lipid A moiety than other gram et al., 2014). This raises the possibility of the modulating the post in-
negative bacteria and stimulate TLR2 instead of TLR4, which weakens fection complications by directing inhibitory action on uncontrolled or
the clearance. Since TLR4-MD2 pathway is not activated in humans, the over expressed cytokines. More cautious to mention is that there are
Leptospira is located in the cytosol of macrophages, but in murine almost nil reports about the recovered patients’ follow-up investigations
macrophages where the pathway is activated, the organism is located like blood profiles of mentioned diseases to find the subclinical da-
inside the phagosome, which explains the question of human suscept- mages during post infection period similar to arthralgia of CHIKV.
ibility (Nahori et al., 2005). The interferon (IFN) are antiviral cytokines include IFN-I, IFN-II,
TLR 3 is mainly linked in controlling the cytopathic effect induced and IFN-III classes. The IFN-I class involves IFN-α and IFN-β, the IFN-II
by DENV infections by mediating IFN α/β release to inhibit viral re- includes IFN-γ and the IFN-III includes IFNλ1, IFNλ2, IFNλ3 and IFNλ4
plication (Tsai et al., 2009). Also in CHIKV TLR 3 regulates host im- (de Weerd and Nguyen, 2012; Palma-Ocampo et al., 2015). IFN α and β
munity in human and mice by mediating production of type I IFN (Her are secreted by epithelial cells and fibroblasts, both upregulate the MHC
et al., 2015). TLR 2 and TLR6 were also found to be associated with I receptors and inhibits the viral proliferation. Lymphocytes also secrete
DENV infection and play a potential role in the immunopathogenesis IFN α. NK cells secrete IFN γ which is another potent antiviral protein
(Chen et al., 2015). Malaria parasites are recognized by TLR4, a het- upregulates MHC I and II. Since the intracellular phase is very transient,
erodimer of TLR2/TLR1 or TLR2/TLR6 and TLR 9 (Coban et al., 2007; IFN response is very mild in Leptospirosis. It is believed with current
Gun et al., 2014). reports that the DENV might have evolved to reduce the IFN action on
Ability of the microbes to evade the effects of immune system by them with the help of nonstructural proteins NS2A and NS4 B by
modulating the TLR system (Yokota, Okabayashi and Fujii 2010) and blocking the IFN receptor- Janus kinase/signal transducer pathway and
the TLR polymorphism leading to increased individual susceptibility to activation of transcription signaling pathway in the infected cell (Gun
infections have been reported and asserts the importance of alternative et al., 2014; Dalrymple et al., 2015; Hsu et al., 2016). IFN-α, IFN-β, and
approach in treatment modalities (Mockenhaupt et al., 2006; Misch and IFN-γ modulate the course of malarial progression and are associated
Hawn, 2008; Yokota et al., 2010; Pulendran, 2009; Ferwerda et al., with the severity of the infection (Gun et al., 2014).
2008). Moreover, the vaccines arbitrate their efficacy by activating The pre-existing and/or co-existing systemic conditions including
specific innate immune receptors (Platt and Wetzler, 2013), especially co-infections do alter the cytokines level. We hypothesize that while the
the TLR, which alarms the importance of validating the immune skin or mucosa at the site of entry of a microbe in in need of pro-

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inflammatory cytokines, any pre-existing pathological conditions and and also the importance of NK cells in for better cytokine signals for
co-infections might have already loaded the anti-inflammatory cyto- viral clearance (Chaix et al., 2008). The efficient innate immune re-
kines in blood and the protein inventory, liver might be in stress of sponse against malarial protection and modulating adaptive immune
delivering proteins to build cytokines for diseases progression at dif- responses need to be utilized by careful intervention during treatment
ferent phases. Unfortunately, due to the dual circulation in an organ (Stevenson and Riley, 2004). NK cells have a prominent role in CHIKV
like liver, cytokines with synergetic and antagonistic actions are loaded infections (Teo et al., 2015). Early clearance and less post infection
(cytokine storm) and shatter their function. Since the liver is the complaints of arthralgia have ameliorating role of NK cells in children
common organ of damage in all these diseases, the hypothesis regarding (Simarmata et al., 2016).
cytokine storm needs to be explored. The usefulness of cytokine ad- Innate immunity elicited on the recognition of pathogen specific
juvant and anti-cytokine therapies and techniques like cytokine dialysis surface molecules. Leptospira have express proteins/biomolecules on the
in different infections in different stages of the disease can be studied outer membrane for adhesion with multifarious structures of the con-
systematically (Uchino et al., 2002; Rathakrishnan et al., 2012). nective tissue (Fig. 2). Because the connective tissue is widely dis-
tributed through the entire body as a binding structure, bacterial
3.4. Innate defence cells binding ability improves host tissue occupancy. Approximately, 260
membrane-associated proteins have been identified through genomic
Transient or short living first defence phagocytes include the most studies (Nascimento et al., 2004). Only a few of these proteins have
common PMN along with basophils, eosinophils and mast cells. The been well-studied with respect to adhesion, transmission, and viru-
long living patrolling phagocytes or scavenger cells are the macro- lence. These proteins include: OMPL (outer membrane protein Leptos-
phages. These cells are attracted to the local area within no time by pira proteins) 1 (Oliveira et al., 2013), 36 (Pinne et al., 2010), 37 (Pinne
chemicals released by the pathogens, activated macrophages, and et al., 2010), 47 (Pinne et al., 2010), 67 and 54; Lig (Leptospira im-
complements. PMN attack the pathogenic and non-pathogenic strains of munoglobulin-like proteins) A (Choy et al., 2007; Lin et al., 2009), B
Leptospira, but the pathogenic strains resist by mechanisms including (Lin et al., 2009) and C; Len (Leptospira endostatin-like proteins)
catalase expression (Murgia et al., 2002). Neutrophilic extra cellular A,B,C,D,E and F (Stevenson et al., 2007); Lsa (Leptospira surface adhe-
trap mechanism is mentioned for the prevention of initial dissemination sion proteins) 20 (Mendes et al., 2011), 21 (Atzingen et al., 2012), 23
(Scharrig et al., 2015). Direct involvement of phagocytes is less re- (Siqueira et al., 2013), 25 (Domingos et al., 2012), 26 (Siqueira et al.,
ported with DENV infection, but they assist the activation of the com- 2013), 27 (Longhi et al., 2009), 30 (Oliveira et al., 2013), 33 (Domingos
plements, coagulation, and fibrinolytic mechanisms and that might lead et al., 2012), 36 (Siqueira et al., 2013), 63 (Barbosa et al., 2006) and 66
to pathogenesis like endothelial damage (Butthep et al., 1993). Acti- (Atzingen et al., 2012); Loa (Leptospira outer membrane protein A-like
vated PMNs are blamed for the pathogenesis of severe malaria in- protein) 22 (Koizumi and Watanabe, 2003); MFn (Pinne et al., 2012)
cluding cerebral malaria (Pukrittayakamee et al., 1992; Feintuch et al., (Microarray/membrane Fibronectin-binding proteins) 1,2,6,7 and 9;
2016). and LipL (OM Lipoproteins) 32 (Murray, 2015), 41 (Lin et al., 2013), 46
The surface barriers efficiently prepared not only for local defence (Matsunaga et al., 2006), 53 (Oliveira et al., 2010) (Fig. 3). The range of
but to initiate the adaptive immune response with the help of secret bacterial adhesive proteins attaching with human tissues is described in
squads, the Langerhans cells (dendritic cell) present in the basal layer of Fig. 3. Among these proteins, only Loa22 fulfills Koch’s postulates
epithelium, which take the antigens from the invaders including (Ristow et al., 2007; Zhang et al., 2010). These proteins exhibit dif-
Leptospira and migrates from epithelium towards regional lymph node ferent binding affinities with connective tissue molecules, namely la-
to present the antigen to T-helper cells to proceed with antibody for- minin, fibronectin, collagen, tropoelastin, elastin, heparin and other
mation by B-cells or to stimulate memory cell, if infection is secondary blood-related molecules, such as plasmin, plasminogen, Factor H and
(Liu, 2001; Collin et al., 2013). These deeds take almost two to four complement (Vieira et al., 2014). Previous studies have identified
days to receive a response from the lymphocytes or more specifically multiple adhesion molecules (Barbosa et al., 2006) in Leptospira species,
the action of acquired immunity. Therefore, at this stage, the demon- which exhibit good adhesion with cells and the extracellular matrix
stration of Leptospira from the patient either by PCR, Immuno-histo- (ECM), as shown in Figs. 2 & 3. Investigations about the cellular and
chemical and simple microscopic technique including blood and urine extracellular binding proteins and its genetic study might help to design
smears is the best way of confirming the diagnosis. Furthermore, DCs acellular vaccine (contains only fragments of the cell) to protect and
are regulators of adaptive immunity in lymphoid and non-lymphoid treat leptospirosis (Vieira et al., 2014; Oliveira et al., 2015).
tissues. They do activate the Natural Killer (NK) cells and other resident The ability to invade and survive intracellularly in phagocytic and
immune and non-immune cells for the immediate control of the in- non-phagocytic cells with the help of receptor mediated endocytosis has
vaders by their cytokine release (Cooper et al., 2004; Nakayama et al., been correlated with its virulence, but since it is rarely demonstrated
2011; Albert, 2008). They deliver strong signals to arouse the cells of with the characteristics of intracellular pathogens such as cell to cell
innate and acquired immunity. spread and intracellular multiplication, the suggestion of transcytosis
Zuerner et al. (2011) suggested that the quick response from NK (Barocchi et al., 2002) is widely supported and the Leptospira is reported
cells to act against Leptospira is important to develop immunity as extracellular organism.
(Zuerner et al., 2011; Sun et al., 2009). NK cells of the human are a Unlike leptospiral infections, viral infections strictly survive in-
special type of bone-marrow derived lymphocytes working in innate tracellularly, but they do elicit an innate response because of the lib-
immunity with ability to kill virally infected and tumor cells with no eration of their specific proteins. Although DENV produces the same
prior sensitization and also without MHC 1 expression (O’Leary et al., clinical manifestations as leptospirosis, the entry of this virus is through
2006; Vivier et al., 2011). They kill them by secretion of cytotoxic the bite of infected Aedes mosquitoes (Benelli and Mehlhorn, 2016).
chemokines and inducing lysis of the cell by antibody dependent cell After the bite from an infected mosquito, DENV is initially internalized
mediated cytotoxicity (Robertson, 2002). DCs release chemokines to inside human cells through receptor mechanisms, including clathrin-
recruit NK cells by extravasation of NK (Della Chiesa et al., 2005). mediated endocytosis (Ang et al., 2010) or clathrin-independent en-
Immunological memory demonstrated in NK cells opens the way for docytic pathways (Acosta et al., 2009), and then the single-stranded
programming them with the vaccine. The DENV evade their action by positive sense RNA viral genome is introduced into the host cell ma-
upregulating the MHC I receptors and reduces the susceptibility of the chinery to produce viral proteins (Seema and Jain, 2005). The specific
NK cell induced lysis because the KIR is stimulated which prevents surface proteins for the DENV have not yet been identified, but once
cytotoxic effect (Yossef et al., 2012). Strong innate immune response these viruses enter humans, many molecules are employed to gain ac-
with early clearance in children is reported (Simarmata et al., 2016) cess to different types of tissues (Cruz-Oliveira et al., 2015). These

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Fig. 2. This schematic figure shows Leptospira having the double plasma membrane, typical of gram negative bacteria, with the endoflagellum between them; the endo-flagella helps their
spiral structure and movement. The array of surface binding proteins has been symbolized.

viruses have three structural proteins, core (C), envelope (E) and initial replication and entry into lymph nodes or direct entry into blood
membrane (M) proteins, and seven non-structural proteins (NS 1, 2a, circulation to reach the target tissues or cells. The N-linked glycosylated
2b, 3, 4a, 4b, 5) (Rothman 2004; Modis et al., 2004; Kapoor et al., 1995; transmembrane glycoprotein on CHIKV interacts with C-type lectin
Innis et al., 1989). Host proteins play an important role during viral receptors in mammalian-like dendritic cell immune receptors (DCIR)
entry and subsequent virion and envelope assembly. The main attach- expressed on monocytes, macrophages, dendritic cells, B-cells and
ment factor depends on glycosaminoglycan (Chen et al., 1997), den- neutrophils (Bates et al., 1999). Target cell entry occurs via clathrin-
dritic cell adhesion molecules (Tassaneetrithep et al., 2003), macro- independent, Eps15-dependent endocytosis (Bernard et al., 2010). Even
phage mannose receptors (Miller et al., 2008), lipopolysaccharide though the classical clinical manifestations of CHIKV is not typical with
receptor CD14 (Chen et al., 1999) and stress-induced proteins, such as other hemorrhagic fevers, the initial symptoms and considerable
heat shock proteins 90 and 70 (Reyes-Del Valle et al., 2005; Navarro- emerging reports about the co-infections with leptospirosis applies to
Sanchez et al., 2003). DENV enters a cell via direct membrane trans- include in this discussion.
location, mediated through C protein (Freire et al., 2013) or receptor- Plasmodium falciparum is the most common malaria parasite among
mediated endocytosis (Acosta et al., 2009). DENV targets monocytes, the five human-infecting species identified and is responsible for
macrophages, and dendritic cells (Wu et al., 2000). These cells have a 600,000 deaths annually (Nilsson et al., 2015). The malarial parasite
mannose-specific C-type lectin receptor DC-SIGN (dendritic cell specific enters humans through mosquito bites, and the surface proteins of these
ICAM3-grabbing non-integrin receptor), which mediates the viral entry parasites, including the P. falciparum erythrocyte binding protein
into the cell (Navarro-Sanchez et al., 2003), and subsequently, these (EBV)-175, interact with the surface membrane protein (glycophorin A)
cells transfer the virus to T-cells in regional lymph nodes. Although T of human erythrocytes for entry. Furthermore, these parasites induce
cell transferring the invaders to lymph node is part of immune clear- the infected erythrocytes to express receptors for adherence with en-
ance mechanism for adaptive or cell mediated immunity, these cells dothelial cells, progressing to the erythrocytic phase of the parasite life-
unfortunately become accidental culprits for spreading and damaging cycle (White et al., 2013). This phase clinically manifests as hemor-
the tissues because the intracellular virus evade the immune system, rhage, reflecting the sequestration of infected erythrocytes within blood
resulting in widespread tissue damage, which manifests as hemorrhagic vessels (White et al., 2013) and endothelial damage (Brown et al.,
disease (Courageot et al., 2003; Marianneau et al., 1998; An et al., 2013).
2004). Since viruses are in need of intracellular environments for Leptospira are typically extracellular organisms moving along in-
multiplication, the extracellular matrix attachment of these particles is tercellular junctions (Haake and Levett, 2015), although intracellular
not well-studied, unlike leptospira. survival has been reported (Merien et al., 1997; Thomas and Higbie,
Chikungunya (CHIKV) is an enveloped, single-stranded, positive 1990). The motility (Fontana et al., 2016) of the corkscrew shaped
sense RNA virus, also transmitted to humans by the bite of Aedes organism is considered as one of the virulent factors at this level, which
mosquitoes, similar to DENV and Zika virus. CHIKV comprises four non- enhances their locomotion along the cleaved planes created with their
structural proteins (nsP1, nsP2, nsP3, and nsP4) and five structural ability to secrete collagenase (Janwitthayanan et al., 2013). Leptos-
proteins (C–E3–E2–6K–E1). E1 and E2 are associated with viral at- piremia (Leptospira in the blood) reflects the ability of these organisms
tachment and entry into the specific cell of interest (Schwartz and to swim effectively along tissues and reach blood vessels by evading the
Albert, 2010; Voss et al., 2010). Following the bite of an infected Aedes immune system to survive extra- and intravascular sites within minutes
vector, CHIKV locally infects epidermal epithelial and dendritic cells for after surface entry. The entry is achieved through associated surface

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Fig. 3. Leptospira binding proteins with extracellular matrix molecules. The extensive array of binding proteins helps them early spread and extensive involvement of many organs. The
proteins with the broad spectrum of binding ability with many types of tissue are marked in the center of the figure (brown box). The groups of proteins having the affinity for particular
host proteins are marked around.

proteins, particularly on the outer membrane, which improves contact et al., 2014; Viratyosin et al., 2008). Once the Leptospira species enters
with host tissue and promotes the mobility of these organisms (Adler and creates adhesions, locally available neutrophils are initiated with
and de la Pena Moctezuma, 2010). The ability of the pathogen to phagocytosis and the complement system enhances the action of these
trespass the surface level of defense within minutes without eliciting cells through opsonization (Fraga et al., 2011) (Fig. 4).
any local immune reaction unlike other pathogenic spirochetes is less Leptospira can be effectively controlled by specific antibody medi-
interrogated. The receptors expressed to bind the host plasminogen can ated immunity. The invading leptospiral antigens are collected and
lead to activation of proteases as well as the degradation of ECM and processed by DCs and presented to helper T cells to process and present
intercellular junctions. This can be connected to the leptospiral mobility it to B-cells, which then matures into plasma cells for specific anti-
even after binding with ECM, the transcytosis and transmigration along bodies. The antibodies are specific to the antigen expressed by the
the intercellular junctional cleavage, especially in epithelial and en- serovar and so antigenic shift in the same serovar or different serovar
dothelial tissues (Barocchi et al., 2002; Vieira et al., 2013; Vieira et al., cannot be embattled. The complication in vaccine preparation and
2012; Vieira et al., 2014). Also, the ability to bind with cadherins (i.e. passive immunity has never prevailed. Diagnostic techniques used IgG
adhesive proteins made up of the extra cellular domain and a cyto- and IgM antibodies for the highly accepted MAT test. The intracellular
plasmic tail to link with the intracellular cytoskeleton, belong to the phase should initiate the T cell response but it depends on the TLR2,
family of calcium-dependent transmembrane adhesion proteins) TLR4 and IFN γ production, which is an acquired immune response or
(Evangelista et al., 2014a) can mutually aid them to reach the blood cell-mediated immune war start with the formation of antibodies
circulation within few minutes. against the Leptospira, which is poorly, reported both in animal and
human studies. The γδ T cells may play an important role in immunity
against bacterial, viral, and parasitic infections including Leptospira
3.5. Acquired immunity
(Truccolo et al., 2001; Johnson et al., 2005). The role of acquired im-
munity on Leptospira in human is less explained. The γδ T cells are
As explained under innate immunity section, the surface barriers
distributed near the epithelial structures and guard against the non-self-
initiate the adaptive immunity at the entry level of pathogens. The
invaders and recognizes distressed epithelial cells without the need of
evidence of acquired immunity in leptospirosis was demonstrated with
antigen processing (by DC) and MHC (Major Histocompatibility Com-
the antibodies to LPS in animal serum since it was thought that the
plex) intervention, an empathetic prompt play which is not accom-
humoral immunity alone work against leptospirosis (Adler, 2015). The
plished by αβ T cells and NK cells (Hsu et al., 2015; Pang et al., 2012)
leptospiral virulence factors responsible for disease severity and anti-
Absence of similar action in human adds the answer to conundrum on
body formation are associated with lipopolysaccharide (Patra et al.,
human susceptibility. The known combinatorial function of γδ T cells
2015), haem oxygenase (Murray et al., 2009), flagellar protein
among immune repertoire strengthens the need to study their effect on
(Fontana et al., 2016) and outer membrane/surface proteins (Vieira

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Leptospira and to discuss the aspects like inducing immunotherapy The predicted sphingomyelinases (Narayanavari et al., 2012a) and
(Yuri, 1993). phospholipases have crucial roles not limited to cracking the host cells
Antibody mediated defense is extensively studied in DENV, espe- for nutrition but facilitates escape from phagosomes, aids for coloni-
cially their transient autoimmunity contributing the disease severity. zation, immune evasion and persistence (Flores-Diaz et al., 2016). Re-
Anti NSI antibodies cross react with host hepatocytes, endothelial cells searches to nullify this tissue drilling bacterial enzymes might lead to
and platelets aggravating the disease by cellular functional alteration, new prospective in primary prevention. Initial leptospiremia might be
cellular damage and triggering apoptosis eventually resulting in in- effectively removed through the defense action of immune cells, but the
creased EC damage, platelet depletion and cytokine storm preventing ability of the Leptospira to evade the immune system prevails the per-
clotting and repair (Avirutnan et al., 2007). There are several hy- sistence of these organisms and subsequent tissue damage in selective
potheses explained including antigen-antibody-complement-mediated organs with different mechanisms adapt by these organisms in different
vascular permeability, antibody-dependent enhancement, mimetic an- tissues (Haake and Levett, 2015).
tibodies, cross-reactive T-cell response, original antigenic sin, directly Leptospiral organisms have been identified in multiple organs by
infecting cells responsible for vascular leakage myeloid cells and en- three days post-infection (Segura et al., 2005) and immune reaction-
dothelial cells (Halstead, 2015). Strikingly, the NS1 interaction with provoked inflammatory cytokines are the major culprits underlying the
TLR4 similar to LPS of gram negative bacteria has been observed on the pathogenesis of all organ damage (Vernel-Pauillac and Merien, 2006)
surface of endothelial cells, macrophages and monocytes and their as- (Fig. 4). Liver autopsy specimens of leptospirosis demonstrated a large
sociation with the release of cytokines (Modhiran et al., 2015). TLR4 number of Leptospira in hepatocytes with disturbed intercellular junc-
antagonist LPS- Rhodobactersphaeroides, inhibits this interaction and tions, congested sinusoids and hepatocyte apoptosis (Merien et al.,
prevents the cytokine related damages opens new therapeutic modality 1997). The intercellular junctional disturbance between hepatocytes,
to control the similar interactions (Modhiran et al., 2015). Since the hepatocyte damage and elevated bilirubin results in jaundice. The
viral load in blood is very low during the manifestation of DHF, the elevated bilirubin proposed with leptospirosis induces hemolysis
viral protein toxicity is the acceptable concept needs to be emphasized (Avdeeva et al., 2002). The kidney is the target tissue for the persistence
during prevention and treatment of DSS/DHF. The γδ T cells do con- of the infection. The systemic load of an organism can effectively be
tribute to the immune protection against DENV infection by providing eliminated through the immune system, but the immune-privileged
an initial source of IFN-γ for antiviral effect and by killing DENV-in- kidney tissue is utilized by Leptospira for survival, multiplication, and
fected cells (Tsai et al., 2015). shedding. These organisms escape through the surface of the epithelial
The role of regulatory T cells (Tregs) and the B cell on persistence cells of proximal convoluted tubules and colonize the brush border
arthralgia and their mechanism of action in pathogenesis are under area, shedding as leptospiruria. Transcytosis, enhanced through a pro-
discussion (Lum et al., 2013; Lee et al., 2015; Teo et al., 2013) for teolytic mechanism, has been suggested as a mechanism for crossing the
prevention. The role γδ T cells on regulating inflammatory responses of epithelial cell membrane (Vieira et al., 2014; Kassegne et al., 2014).
CHIKV during the acute stages especially on joint tissues (Long et al., Transcytosis has been observed in hamsters and sheep, showing that the
2015) is narrated. Leptospira living in the proximal tubule with close association with the
Both the cellular and humoral supports of the adaptive immune microvilli of the epithelial surface does not exhibit any cellular pa-
system are vital for malarial elimination, but the memory is transient thology and might present a commensal relationship (Haake and Levett,
(Rowe et al., 2009). The γδ T cells play an essential role from the be- 2015). Leptospira survives in the renal tissues by presenting various
ginning of the infection (Inoue et al., 2013). Evidence on naturally mechanisms, such as biofilm formation (Ristow et al., 2008), reduced
acquired immunity for surface proteins supported the use of P. falci- antigenic protein expression (Monahan et al., 2008) and increased LPS
parum erythrocyte membrane protein 1 (PfEMP1), a variant surface O antigen (O antigen is a polysaccharide, hydrophilic in nature and an
antigens of the parasite suggested for the vaccine development (Chan immunodominant domain present in the outermost end of LPS), asso-
et al., 2012). Autoantibodies induced by the malarial parasite reacting ciated with complement resistance (Clay et al., 2008). The pathogenesis
on host cytoskeletal network have been discussed (Mattei et al., 1989), of severe pulmonary hemorrhage syndrome (SPHS) is associated with
but yet to be investigated since an extensive sequence homology be- vascular damage, the immune complex deposition on the alveolar
tween human and the parasite is reported (Faya et al., 2015). membrane and coagulation abnormalities (Silva et al., 2002; Wagenaar
et al., 2007). The pulmonary pathology worsens the patient’s condition
4. Nutritional acquisition, organ invasion and immune evasion for because of these added effects, which reduce oxygen delivery to the
persistence tissues. The hemorrhagic episodes deplete the red blood cells needed to
carry sufficient oxygen to the tissues, and this pulmonary insufficiency
Initial leptospiremia manifests within minutes of infection, with aggravates the situation, leading to central nervous system (CNS)
organism counts of 106 to 107 per ml of blood (Truccolo et al., 2001) manifestations (neurological symptoms) such as confusion because the
and the presence of microbe persists up to 2 weeks. DENV reaches its CNS is highly sensitive to hypoxia.
maximum load in blood by 103 RNA particles/ml in primary DENV A severe headache with leptospirosis should be considered a neu-
infections and > 106 RNA particles/ml in secondary DENV infections rological symptom, particularly meningitis, which challenges the di-
from 5 to 8 days (Johnson, Russell and Lanciotti 2005), and malarial agnosis because this disease can manifest as septic and aseptic forms
parasite level in the blood reaches up to 2500 parasites per 200 white (Silva et al., 2002). In addition, altered mental status and confusion
cell (Goncalves et al., 2014). were reported during severe stages of the disease (Ko et al., 1999).
The necessity for Leptospira to swim rapidly towards the blood vessel During the recovery phase, the ocular manifestation with uveitis is
is their craving for iron, B vitamins, ammonium, fatty acids and β common in either mild or severe form, with self-limiting capabilities.
oxidation for energy. The nutrition acquisition from RBCs urges them to The ability to demonstrate bacterial DNA in the aqueous humor of the
reach the nearby blood vessels from the site of entry. The RBCs are the eye at this stage using PCR has been reported (Chu et al., 1998;
best source even though many cells of the host can satisfy all but the Rathinam, 2005). Leptospira have evolved various mechanisms to evade
rich iron. The RBCs are the chemoattractant for the Leptospira (Yuri immune reactions. Reportedly, the less reactive LPS of Leptospira trig-
et al., 1993) and to reach them the layers of blood vessels need to be gers Toll-like Receptor 2 (TLR2) instead of TLR4, unlike other more
penetrated by binding with various surface proteins of the host. Pa- potent LPS (i.e., Escherichia coli), which reduces the effectiveness of
thogenic Leptospira identified with 12 of the TonB- dependent receptors defensive action (Werts et al., 2001; Werts, 2010). Innate immunity can
important for active nutrient import, which is more in number than the be effectively initiated against the LPS and peptidoglycan membranes
saprophytic ones (Nascimento et al., 2004; Narayanavari et al., 2012b). only when both (TLR4 and TLR2) receptors are stimulated for these

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Fig. 4. This schematic figure focuses on the pathogenesis of dengue, leptospirosis, and malaria, showing common aspects of invasion and cellular events leading to diagnostic confusion.
Dengue: During primary dengue virus infection, the immune cells release cytokines and other factors which lead to viremia and loosen the endothelial layer. Later, the virus activates
memory T cell, in addition to the viral infecting endothelial cells, which finally lead to endothelial damage and inflammation at surrounding area. Leptospirosis: during Leptospira
infection, the immune cells release pro-inflammatory cytokines and chemokines which contribute to inflammation and damage of the endothelial layer. Malaria: In malaria, Plasmodium
parasites invade the blood cells. Infected red blood cells express the surface marker that binds to the receptors of endothelial cells activating them. Later, cytokines are released and fibrin
is deposited into the blood vessel causing obstruction, plasma leakage, and inflammation.

Gram-positive and Gram-negative components (Chassin et al., 2009). A proteome based analysis on viral adaptation reported that the viral
Leptospira species bind and evade or down regulate the action of com- structural proteins exhibit similarity to the host-preferred codon (Lobo
plement regulatory proteins Factor H and C4b binding Protein (C4BP) et al., 2009). The probable explanations may be related to the devel-
(Meri et al., 2005), thereby preventing the opsonization and formation opment of humans and the co-evolution of the viruses or may be due to
of the membrane attack complex on the bacterial surface and increasing the hypothesis that major portions of the human genome are actually of
the persistence of these microbes. The less virulent LPS and evasion of viral origin. DENV has tropism for the immune system, liver and en-
the complement system promote infection by rejecting the effective dothelial cell (EC) linings of blood vessels. A review based on autopsy
elimination of these components (Chassin et al., 2009). specimens of 160 cases revealed demonstration of DENV in liver,
The success of any viral infection is accomplished by the capability spleen, lymph node, lungs, kidney, thymus, and brain (Martina et al.,
of entering the host cell and taking over cellular functions to direct 2009).
them toward the effectual production of new virus (Bahir et al., 2009). The ability of DENV to attach to an array of molecules has been

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associated with the susceptibility of the vectors and vertebrates. The reflecting similar climatic affinities. These infections might simulta-
DENV C-protein has been implicated in the transport of the viral neously present in different patients or in the same patient exhibiting
genome directly from one cell to another without requiring complete coinfection with both diseases. The treatments for viral infections are
assembly (Zhong et al., 2013; Cruz-Oliveira et al., 2015). Following the primarily associated with symptomatic support and the prevention of
incubation of the virus, the clinical presentation is presented as three further damage. However, for Leptospira, or any bacterial infection, the
phases: febrile, critical and recovery. The febrile phase is manifested treatment primarily involves antibiotics and symptomatic support. The
from mild petechial bleeding in the mucous membrane of the oral and precocious administration of antibiotics for all hemorrhagic fevers in
nasal cavities to massive bleeding in the gastrointestinal tract. Liver endemic areas with leptospirosis is not advisable because the over-
enlargement and blood count abnormalities are subsequently initiated loading of antibiotics might lead to hepatic insufficiency. The early
(Kalayanarooj et al., 1997). The critical phase is manifested with diagnosis/separation of specific infections during the acute phase
plasma leakage, reflecting extensive endothelial injury and depleted would promote therapeutic success. Fever is initiated through a body
blood constituents, leading to hemorrhage and clotting, metabolic mechanism that defends against any microbe. The affinity of hemor-
acidosis and disseminated intravascular coagulation, which is pre- rhagic infections towards the endothelium and the resulting damage
carious (Martinez Torres, 2006). The recovery phase is complicated lead to rashes, reflecting capillary damage and bleeding. The liver
when the administration of intravenous fluid as a treatment during the controls body metabolism. The cascade of events and reactions during
early phases is overzealous, leading to circulatory overload or hy- any infection are continuously increasing microbial load, cell damages
pervolemia (Malavige et al., 2004). The pathogenesis is primarily as- (of both bacterial and host), cell injury-released materials and loaded
sociated with the damage and consequences of viral-infected cells and immune cell clearance and their secretions, and the host’s reaction to
targeted immune responses. Neurological complications associated these burdens the liver. The acute phase proteins are released from the
with DENV have been reported in up to 6.2% of cases (Hendarto and liver, suggesting that increased production indirectly increases work-
Hadinegoro, 1992) and are categorized into three groups according to load. The direct pathogenic action and liver burden lead to abdominal
the severity as mild with less specific manifestations, such as headache pain. Multiple small hemorrhages result in the depletion of thrombo-
and dizziness, moderately severe with seizures, encephalitis and pa- cytes, leading to thrombocytopenia, bleeding disorders, and a reduction
ralysis, and extremely severe with seizures, memory impairment and in circulating red blood cells (RBCs), which leads to anemia. The active
psychiatric symptoms (Garcia-Rivera and Rigau-Perez, 2002). immune defense leads to leukocytosis and subsequently results in the
The Plasmodium life cycle is complex, with different stages in hu- loss of leukocytes, leading to leukopenia. Taken together, these effects
mans and mosquitoes. These parasites have sexual and asexual forms lead to hypoproteinemia and aggravated endothelial damage with
requiring both humans and mosquitoes to complete the cycle. The leaking capillaries and the consequent loss of volume inside the blood
asexual stage in humans is highly pathogenic compared with sexual vessels. Liver damage leads to protein deficiency and jaundice (with
gamete formation, which is primarily important for the mosquito in- hyperbilirubinemia), and the spleen is under stress for the removal of
fected by humans. The initial step of gametogenesis is completed in the damaged RBCs, which leads to hepatosplenomegaly. Ineffective or
humans and transmitted to mosquitoes during blood meals, and the unnecessary antibiotic load can worsen these conditions in any un-
sexual cycle is completed with zygote formation and sporozoites, which trained medical setup. Pulmonary damage adds to hypoxic cell injury,
infect the next human through a bite. The complicated developmental particularly to vulnerable CNS tissues. Thus, these signs and symptoms
processes and non-correlation of the gametocyte density with para- are common for all hemorrhagic fever-inducing diseases under discus-
sitemia end with poorly explained parasite load and infectiveness sion, but some symptoms are more common and more prominent for
(Orjih, 2014), thereby complicating intervention through elimination particular diseases. Leptospirosis and DENV have nearly similar clinical
based on the infectiveness detected, even after several advanced studies presentations, but myalgia is more prominent in CHIKV and rigor is
have been conducted. Therefore, this disease is still confused with many more prominent in malaria.
other diseases widely spread and tropical and subtropical endemic
areas (Nilsson et al., 2015). 5. Genetic susceptibility
Viral infections are managed differently by the body system com-
pared with bacterial infections, once these particles are internalized Genetic influence on long time protection for reinfection and ge-
inside the target cells. In vertebrate hosts, CHIKV virion are produced netic susceptibility related genes likeIL1b, IL12RB1 and CISH have been
through replication from the infected cells within 8 h post-infection reported for Leptospira (Esteves et al., 2014). The association of human
(Sourisseau et al., 2007). The target tissues, such as the joints, muscles, leukocyte-like antigen DQ-6 (HLA-DQ6) (Lingappa et al., 2004) and
liver, spleen, bone, and brain, and related clinical manifestations are alleles from HLA-A (*24 and *31) and HLA-B*08, interleukin 4 (IL-4)
widespread. CHIKV-infected osteoblasts stimulate interleukin 6 (IL6) and IL-4Ra genes (Fialho et al., 2009) towards the risk of leptospirosis
and receptor activator of the nuclear factor kappa-B ligand (RANKL),- has been also reported.
thereby promoting further osteoclast activity, resulting in rheumatic Human HLA class I and II alleles associated with the development of
symptoms (Noret et al., 2012). Monocyte chemotactic protein (MCP)-1, DHF have been summarized by Matina et al. (Martina et al., 2009).
−2, and −3 are chemo-attractants for the signaling of monocytes/ They reviewed the polymorphism in genes of TNF-α, vitamin D re-
macrophages to the target area, and the expression of these molecules ceptor, TGF β, FcγRIIa receptor, CTLA-4,DC-SIGN,HLA class I alleles
increases during CHIKV infection. The virus uses these recruited cells as A*01, A*0207, A*24, B*07, B*46, B*51 HLA class II alleles DQ*1,
transport vehicles and reservoirs (Labadie et al., 2010). The relative DR*1, DR*4 having association with development of DHF/DSS
increase in dendritic cells (Colonna et al., 2004), CD4+ T cells (Hoarau (Martina et al., 2009). Malarial infection susceptibility and resistance
et al., 2010) and B cells (Poo et al., 2014), has also been reported, and have been highly probed with genome wide linkage (GWL) and asso-
the pathogenesis, particularly associated with the joints, has been dis- ciation studies (GWAS) and various controlling pathways and genetic
cussed. The type of cells and the increase in associated inflammatory origins of diseases suggested among different populations (Driss et al.,
cytokines has been associated with the pathogenesis. 2011). CHIKV has been also reported with genetic predisposition in a
Notably, as outlined above, most hemorrhagic fevers of different study among 100 families showing that no Rh negative blood group was
pathogens share common mechanisms, particularly endothelial da- affected (Lokireddy et al., 2009). Recent advances in genetic studies
mage, immune responses and blood cell loss resulting from hemorrhage have urged many publishers to discuss on genetic susceptibility to many
and other related events. However, the treatment is not always the diseases. However, sample size and methodology and their specificity
same. The confusion in diagnosis is more complicated, particularly and sensitivity for wide populations, genetic diversity even among the
when the endemic area has an outbreak of the same types of infections, small population, co-infections and pre-existing underlying pathologies

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of relevant pathologies, have not been corroborated. increased load of immune cells might lead to the hemophagocytosis of
most of the blood cells. The early administration of appropriate anti-
6. Clinical presentation of leptospirosis and co-infections biotics, distinguishing different organisms through proper diagnosis,
and the faultless evaluation of patients are key strategies to reduce the
The reductions in morbidity and mortality are dependent on the mortality rate of individuals co-infected with leptospirosis and other
early diagnosis of single, co- or mixed infections. Previous evidence microbial agents (Biggs et al., 2013). Patients with co-infections are
suggests that the pathogens that colonize a human body infected with highly loaded with different pathogens and need to be handled care-
leptospirosis are human immunodeficiency virus (HIV) (Biggs et al., fully. Early and rapid diagnosis and proper interventions should be
2013; Ganoza et al., 2005) Malaria (Baliga et al., 2011; Gurjar et al., quantified (Yang et al., 2012). Leptospirosis being misidentified as
2011; Srinivas et al., 2007; Wongsrichanalai et al., 2003), hepatitis A DENV and presenting together as co-infections are increasingly re-
(Alves et al., 2011), melioidosis (Hin et al., 2012; Sapian et al., 2012), ported which require early and proper treatment. If any one of the in-
scrub typhus (Mahajan et al., 2012), Orientia tsutsugamushi fections is wrongly diagnosed, then the patient falls into immense death
(Sonthayanon et al., 2013b), and DENV (Sharp et al., 2012; Mohammad conditions. To avoid this type of burden during co-infection, improve-
et al., 2008). Multiple co-infections with viruses, such as Hantaviruses, ments in the diagnostics and proper treatment of multiple coinfections
Leptospira spp., and Babesia spp., have also been observed in rodents are mandatory (Yang et al., 2012).
(Tadin et al., 2012). During the incubation period, almost all pathogens establish
The coinfection of other infectious agents with Leptospira con- themselves through multiplication and dissemination into the different
tributes to the confusion in the diagnosis and treatment of this disease parts of the body using various methods. These processes are achieved
due to many similarities in early signs and symptoms (Table 1). The through the ability of the pathogen to invade tissues by succeeding and
virulence properties of different pathogens indirectly alter or increases evading the human immune system (Table 1), particularly the initial
host immunity (Behera et al., 2010). During co-infections with Leptos- humoral response (Finlay and McFadden, 2006). The extended estab-
pira, significantly increased immune cell proliferation and damages lishment in different organs results in extensively damaged clinical
multiple organs primarily liver, kidneys, lung, heart, and brain (Lokida presentations. Also, during coinfection different pathogens in different
et al., 2016; Zaki and Shanbag, 2010; Romero et al., 2010). stages might provoke untoward effects for the initiated treatment. The
Patients with co-infections are highly loaded with different patho- high microbial count in the body tissues from the initial stage of the
gens and need to be handled carefully. Early and rapid diagnosis and infection is an important factor for treatment. During the high leptos-
proper interventions should be quantified (Yang et al., 2012). The piremic phase, antimicrobial treatment might result in a Jarisch-Herx-
majority of leptospirosis cases (90%) are noticed during anicteric phase, heimer reaction, as broken organisms suddenly release their contents,
which presents as acute influenza or dengue like symptoms, such as particularly endotoxins that elevate cytokine levels through normal
fever, headache and myalgia in the thighs and calf. The important di- responses in the immune system (Friedland and Warrell, 1991). This
agnostic clues during this acute stage are conjunctival congestion and effect is fatal, particularly in young or old patients, pregnant women,
sub conjunctival bleeding (Gupta et al., 2007). In the first 5–7 days of and patients with preexisting diseases, such as diabetics. Dengue and
anicteric, the organism is isolated from all tissues where the leptos- Chikungunya are airborne viral infections with similar clinical pre-
piremic stage occurred. Typically, the patient becomes asymptomatic sentations to leptospirosis, and confusion exists worldwide (Behera
after this phase, and the symptoms will reappear with a mild fever and et al., 2009). All of these diseases have common initial symptoms and
myalgia after 3 days if it progresses to icteric phase, which can be fatal are also endemic in nature. Local practitioners should note early clinical
(Wysocki et al., 2014). The effects of hepatic involvement include in- presentations with similar signs and symptoms, endemic presentation,
trahepatic cholestasis, centrilobular necrosis and Kupffer cell hyper- and common vectors (such as mosquitoes or common environmental
plasia, lung tissue manifest with pulmonary hemorrhage and acute re- risks). Any diagnostic procedure that can identify the disease during the
spiratory distress syndrome (ARDS) and cardiac involvement result as incubation period is particularly useful in the endemic areas with an
myocarditis (Sondergaard et al., 2016; Wysocki et al., 2014; outbreak and might be the best strategy to overcome these microbes
Pushpakumara et al., 2015). In most patients, the immune phase is not and prevent extensive damage in infected individuals. Molecular deli-
manifested, while for other patients, a few neurological symptoms, such neations of the pathogenesis, from attachment to immune evasion,
as meningitis, iridocyclitis, and choroid, manifest (Rathinam, 2005; might shed light on the prevention and control of these diseases.
Romero et al., 2010; Wang et al., 2016). For approximately 15% of Discussions on the pathogenesis of the mentioned hemorrhagic
anicteric forms, the neurological manifestations are described as diseases made evident that it is complicated by excessive immune ac-
symptomatic meningitis, while many patients experience asymptomatic tivation and the cytokines involved are summarized in Table 1. As
pleocytosis (abnormal, large number of lymphocytes in cerebrospinal mentioned earlier, the association of IL10 and the severity of disease in
fluid) (Wang et al., 2016). Neurological involvement is purely an im- fatal outcome is well documented. IL 10, the master regulator of im-
munological reaction, as meningism corresponds to the appearance of munity to almost all pathogenic infections (Table 1) and regulates both
antibodies in the serum and cerebrospinal fluid (CSF), which regularly cell mediated and humoral response (Couper et al., 2008). The ex-
manifest aseptic meningitis, myelitis, meningoencephalitis, poly- cessive, prolonged and untimed release of this cytokine may influence
radiculoneuritis and seizures (Panicker et al., 2001; Olmer et al., 1950). the persistence of the immunopathogenesis by allowing the pathogen to
By days 2 and 3, the CSF abnormality slowly resolves, and the signs of escape the immunity by its potent inhibition of pro-inflammatory action
meningism disappear. In a study involving 100 consecutive patients and anti-inflammatory effects. The natural process is actually aimed to
with meningoencephalitis, 5 patients had high levels of IgM antibodies help the host to reduce the tissue damages and fibrosis, but the pa-
for leptospirosis, suggesting that the leptospiral infection is an un- thogens are also benefited to escape the immune surveillance. It is
noticed cause of meningoencephalitis in endemic areas (Watt et al., worth mentioning that the wide array of cells having the ability to se-
1989). Another prospective study involving more than 1000 cases of cret IL10 including non-immune cells and their wide range of action
CNS infections reported 33% of conventional bacterial infections in- and control complicates the issue (Couper et al., 2008). Added to that
cluding Leptospira (Dittrich et al., 2015). Hence, it has been suggested the multiple organs invading pathogens involve them at different stages
that leptospirosis should be measured when diagnosing the cause of and the immune reactions vary as mentioned. This is to be considered
meningoencephalitis in a susceptible person in an endemic area during the designing of IL10 blocking therapy and other im-
(Dittrich et al., 2015; Romero et al., 2010). The co-infection of leptos- munomodulation therapies (Schulte et al., 2013). The careful analysis
pirosis and scrub typhus significantly amplifies macrophage activation of individual cases added with antimicrobials and/or vaccine to control
syndrome (Sonthayanon et al., 2013a). The sudden activation and the escaping pathogens and untoward effects.

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as by International Scientific Partnership Program ISPP at King Saud Broor, S., Aggarwal, P., 2010. Co-infections due to leptospira, dengue and hepatitis E:
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