Académique Documents
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Virology
Parasitology
Mycology
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General properties Forms of viruses
• vegetative virus:
• Composition
– intracellular
- nucleic acid (DNA or RNA)
– replicating viral genome
- proteins
• virion (viral particle):
- lipids, carbohydrates
– extracellular
– the entire infectious unit
• Cultivation in receptive, living cells – inert in extracellular environment (no
(parasites at the genetic level) replication)
– infective
7 8
Herpes viruses
• subfamilies (subfamilia):
-virinae (Betaherpesvirinae) Alpha-
herpesvirinae
Beta-
herpesvirinae
Gamma-
herpesvirinae
subfamily
• genera (genus):
-virus (Cytomegalovirus) Herpes Varicella-zoster Epstein Barr Kaposi sarcoma
Cytomegalovirus HHV7 HHV6
simplex virus1, 2 virus virus virus
11
2
DNA viruses RNA viruses
Adenoviridae Arenaviridae The structure of the virion
Hepadnaviridae Bunyaviridae
Herpesviridae Caliciviridae
Coronaviridae
Polyomaviridae
Filoviridae
Nucleic acid
Papillomaviridae
Flaviviridae
Parvoviridae Orthomyxoviridae
Poxviridae Paramyxoviridae Capsid
Picornaviridae
Reoviridae
Retroviridae Envelope
Rhabdoviridae
Togaviridae
13 14
15
3
Types of nucleocapsid symmetry Helical symmetry
• capsomeres are individually bound to the viral
• based on the arrangement of morphologic nucleic acid, winding it into a helix → close
subunits interaction between the nucleic acid and
– cubic (icosahedral) symmetry proteins
– helical symmetry • filamentous nucleocapsid
– rod shape: tobacco mosaic virus, rhabdovirus
– complex structures – spherical: due to secondary coiling of
nucleocapsid
• regular (Orthomyxovirus)
• irregular (Paramyxovirus)
20
LL 21 22
24
4
Influenzavirus (EM)
25 26
27 28
• icosahedral pattern
• 20 faces, 12 vertices, 30 edges
• capsomeres: pentons, hexons
• number of capsomeres is characteristic for
a given species
30
5
31 32
Icosahedral
Build your own capsid
virus
Packing of subunits in
picornaviruses
36
6
Adenovirus
37 38
LL 39 40
Papillomavirus (electron
microscopy)
41 42
7
Poliovirus
46
47 48
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HIV
Chemical composition of
viruses
LL 49 50
Nucleic acid
51 52
Proteins Lipids
• capsid proteins
• in the envelope
– resistant to proteolytic enzymes – protect the
genome • origin: cellular membranes in which viral
– attach to cellular receptors proteins have been integrated
– determine the symmetry type • enveloped viruses are susceptible to ether
– antigenic properties and organic solvents
• core proteins
– enzymes
53 54
9
Carbohydrates
• Envelope: glycopeptides
• encoded by the viral genome
Viral replication
• Role:
– attachment to receptors
– antigens
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10
Penetration or engulfment Attachment - penetration
• the virus is taken up inside the cell by:
– endocytosis – uptake of virus particles within
endosomes
– direct penetration across the plasma membrane
– fusion of the virion envelope with the plasma
membrane - coreceptor
11
Uncoating Eclipse period
• a period between uncoating – appearance of
new viral particles
• synthetic phase
• essential processes:
– specific, functional mRNA transcribed from the viral
nucleic acid
– translation of mRNA
– replication of the genome
• virus-specific proteins are synthesized in a
highly organized sequence
12
Release Release
Release - budding
HIV
13
HIV replication
Cultivation of viruses
Cell cultures
Cultivation of viruses: only in
• Origin:
viable, receptive cells – human or animal
– fetal or adult
• cell cultures
– normal or tumor tissue
• embryonated egg
• primary cell cultures - monolayer
• experimental animals
• tumor cell lines
• diploid cell lines
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Experimental animals
Viral genetics
15
Possible phenotypic consequences
Mutation
of mutation
• conditional lethal mutants
nucleic – temperature sensitive mutants do not grow at higher
acid temperatures
• host range mutants
substitution – do not grow in all types of cells that the wild-type virus does
• drug resistance
• enzyme deficient mutants
insertion • hot mutants (better growth at higher temperatures) – less
susceptible to host fever response
• attenuated mutants – mild disease (or no symptoms at
deletion all)
– vaccine development
– pathogenesis
inversion
Recombination Recombination
classic recombination
• exchange of genes between two genomes DNA viruses
• homologous recombination
• In:
– viruses with ds DNA
– positive strand RNA
– viruses with segmented RNA genome (reassortment)
+ strand
Vaccinia virus –
vaccine against rabies
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Copy choice recombination Reassortment
Influenza virus
PB2 PB2
PB1
PA
X PB1
PA
HA
HA
NA NA
NP NP
M M
NS NS
PB2
PB1
Attenuated donor PA New virulent
virus HA strain
NA (epidemic,
NP
Resulting attenuated M pandemic)
vaccine strain: NS
Ag of the virulent strain
Virulence of the
attenuated strain
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Interference Complementation
• infection with 2 viruses can lead to an • interaction at functional level, not the
inhibition of multiplication of one of the nucleic acid
viruses – one virus provides a gene product in which
– one virus may inhibit the ability of the second the second is defective, allowing the second
to adsorb to the cell to growth
– competition for components of replication
apparatus
– the first virus may induce the poduction of an
inhibitor
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Phenotypic mixing Phenotypic mixing
Genome: unchanged
Altered host range
pseudotype – enveloped viruses
transcapsidation (phenotypic masking) – naked capsid viruses
Resistance to neutralizing antibodies
Genetic
Genotypic mixing active-active yes no paramyxovirus
Recombination active-active yes yes influenzavirus,
poliovirus
Marker rescue active-inactive yes yes influenzavirus Complementation active-inactive no yes poxvirus
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Bacteriophages with tail
Bacterial viruses
- head: icosahedral Head
Bacteriophages symmetry
- tube: contractile sheath
- base plate and fibers:
role in binding to Contractile tail
sheath
bacterial cell surface
tail fibers
Base plate
• Attachment
– tail fibers (LPS)
• Irreversible binding
through the base plate
• Penetration, uncoating
sheath contraction
nucleic acid injection
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Bacteriophages Lysogenic conversion
• lytic (virulent) phages: • extra genes carried on the phage get
– phages multiply within the bacterial cell
– released through cell lysis
expressed in the cell
• lysogenic (temperate) phages
–genome integrates into the host genome • modify O antigens in Salmonella
– phage genome in repressed state = prophage, it is
replicated along the bacterial chromosome • toxin production in Corynebacterium
– cells carrying a prophage: lysogenic state diphtheriae
– lysogenic state can be terminated: induction → lytic cycle
Bacteriophages
• Have specific host range
– one phage – one bacterial species
– different phage susceptibility among strains of the same
species – phage typing of bacteria (Staphylococcus
aureus)
• Prophage
– when the prophage is released, bacterial DNA might be
captured in the phage genome and this can be
transferred to new bacterial cells (transduction)
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Viroids
– have no proteins, only nucleic acid
- infect plants
- single stranded circular RNA molecules,
intracellularly can form double stranded Prions
structures
- no virion phase
- transmitted by direct contact
- no genes, no translation
- pathogenesis not known
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Formation of PrP Prion diseases
Creutzfeld-Jakob disease
• Forms
– Sporadic
– Yatrogen / acquired Pathogenesis of viral diseases
• injection, transplantation, contact with
contaminated medical devices
– Familial (hereditary)
– New variant (vCJD)
• high incidence of CJD in younger people in UK –
association with BSE epidemic?
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Range of virus-cell interactions 1 Range of virus-cell interactions 2
• cytolytic, productive infection • abortive (non-productive infection)
– host cells are termed: permissive – the viruses do not complete the replication
cycle
• non-cytolytic, productive infection • viruses that cannot adsorb to cell – resistant cells
– e.g. viruses released by budding or
• cells are infected but the viruses are not produced
– may lead to persistent infection (the cell and by the cell – the cells are termed non-permissive
viruses co-exist for a longer period of time)
Transformation
• viral DNA integrated in cellular DNA or
non-integrated or both states
• the properties of the cells are changed –
Virus – Host Interactions
tumour cells INFECTION
• DNA viruses: adenoviruses,
herpesviruses, hepadnaviruses,
papillomaviruses, poxviruses
• RNA viruses: retroviruses
• transformation: rare event (1 in 105 cells)
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Type of infections
Type of infections
• acute infection: short duration infection (several
days)
• latent infection: the patient recovers from the • According to the presence of symptoms
initial infection but the virus persist (in a hidden – symptomatic
or cryptic form) and the infection may recur
• chronic infection – the virus remains detectable – asymptomatic infections
for a long period of time (asymptomatic carrier
state or result in chronic illness)
• slow virus infections: prolonged period between
the initial infection and appearance of disease
(years) – e.g. SSPE, diseases caused by
unconventional agents (prions)
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Infections in a population
Stages of a typical viral infection
• Sporadic – few cases, no relation betweens cases
• Incubation period: asymptomatic • Endemic – infections occurring at a constant rate in a
• prodromal period: nonspecific symptoms defined geographical area
• Epidemic: the number of infections increases above a
• specific-illness period: specific symptoms baseline
and signs • Pandemia – spread across continents
• Morbidity – the frequency of a disease in a population
• recovery period: the illness resolves and • Incidence – new cases in 100000 inhabitants
the patient regains good health • Prevalence – all cases reported to 100000 inhabitants
• Mortality – frequency of fatal cases due to a certain
• in some cases: the infection persists, disease
carrier state or latent infection occurs
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25
Virulence Pathogenesis involves:
• transmission of the virus and its entry into
• ability to cause disease
the host
• property of a viral strain, measurable
• replication of the virus and damage to cells
• may increase or decrease
• spread of the virus
• viruses that have lost their ability to cause
• immune response as
a disease: attenuated viruses
– host defense
(vaccinology)
– cause of damage in certain viral infections
• persistence of the virus in some cases
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155 156
26
Systematic infections Tropism
• spread through:
– bloodstream (viraemia), lymphatic system • range of host cells that can be infected by
– nerves a virus
– epithelial cells
• receptors
• role of macrophages
– inactivate the virus
• coreceptors
or
– the virus can multiply inside the macrophage and the
infected macrophages may distribute the viruses in the
body (HIV)
157 158
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Interferons (IFN) Biological effect of IFN
• factors produced by cells in response to viral • interact with cell surface receptors
infections that protect other cells of the same • after binding: up-regulation of some genes, down-
species from from attack by a wide range of regulation of others →
viruses – inhibit viral replication
• types: • inhibit attachment and uncoating
– α - 20 subtypes – produced by periferal blood • early viral transcription
mononuclear cells as a response to the presence of • viral translation
viruses (used also as therapeutic agent) • protein synthesis
– β - produced by fibrobalsts and epithelial cells as a • budding
response to the presence of viruses – activate host defense mechanisms
– γ - produced by T-lymphocytes, NK cells in response • enhancement of MHC-encoded molecules
• control of B cell response
to a specific antigen – (immune interferon)
• enhancement of cytotoxicity of immune effector cells (macrophages,
neutrophils, T cells, NK cells)
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165 166
INTERFERON INTERFERON
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INTERFERON Natural killer (NK) cells
• distinct functional population of lymphocytes
• “natural”: active without prior exposure to the
antiviral state
virus, are not enhanced by exposure and are not
specific for any virus
• recognize and destroy cells infected by viruses
• they can kill without antibody, but antibodies
antiviral state antiviral state enhance their effectiveness (ADCC – antibody-
dependent cellular cytotoxicity)
antiviral state
169 170
NK cells Macrophages
• Functions:
– phagocytosis – role in limiting viraemia
– antigen presentation (limited role for viruses)
– cytokine production (IL1, TNF)
• Some viruses can replicate in
macrophages (cytomegalovirus, HIV)
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Efficiency of humoral immunity
• depends on whether the virus passes through
the bloodstream to reach its target organ
– polio:
• intestinal wall – blood – spinal cord
• small amount of Ab: neutralize virions in the bloodstream
– influenzavirus:
• target organ: at the portal of entry
• large amounts of circulating antibodies relatively inefficient
• antibody must be present in the mucous secretions
• implications in vaccine strategy: live attenuated vaccines
(intranasal application) – efficient immune response
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180
30
Inhibitors of viral nucleic acid
Inhibition of early events
synthesis
• Inhibitors of herpesviruses
• amantadine – Acyclovir
• Herpes simplex virus 1,2,
– prevents replication of influenza A virus by • Varicella-zoster virus
– Ganciclovir
inhibiting uncoating • cytomegalovirus
• Inhibitors of HIV
– Azidothymidine (AZT)
• effective against DNA synthesis by reverse transcriptase
– Dideoxyinosine
– Stavudine
– Lamivudine
– etc.
• Inhibitors of other viruses
– Ribavirin
• respiratory syncitial virus infections
• influenza B
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31
Live vaccines Inactive vaccines (killed viruses)
• attenuated viruses • shorter duration of immunity, lower
• greater and longer-lasting response compared effectiveness compared to live vaccines
to inactivated viral vaccines
• the virus multiplies in the host, prolonged • IgG, weak or no cellular immune response
antigenic stimulus
• production of IgA and IgG + cellular immunity
• reversion to virulent form is not possible
• contraindicated in case of immune deficiency, • excretion of vaccine virus and
pregnant women transmission to non-immune contact is not
• possibility to reverse to virulent form possible
• excretion of vaccine virus and transmission to
non-immune contact is possible
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Immune globulins against: Herd immunity
• Rabies • sufficiently large percentage of the
– administered at the bite site + intramuscularly population is immunized so that an
• HBV unimmunized person is protected
– for those exposed to infection by needle-stick
• prevention of transmission
– neonates born from HBV carrier mother
• Varicella-zoster
– for immunecompromised persons
• Hepatitis A virus
• measles
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33
DNA viruses RNA viruses
• ds DNa • ss DNA • positive ss RNA • negative ss RNA
– enveloped – enveloped – enveloped – enveloped
– Herpesviridae – Parvoviridae • Togaviridae • Ortho-, Paramyxoviridae
– Hepadnaviridae • Flaviviridae • Rhabdoviridae
– unenveloped • Coronaviridae • Bunyaviridae
• circular DNA • Retroviridae • Arenaviridae
– Papovaviridae – unenveloped • Filoviridae
• linear DNA • Picornaviridae • ds RNA
– Adenoviridae • Caliciviridae
– unenveloped
– Poxviridae
• Reoviridae
Adenoviruses Adenovirus
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Classification
• Alphaherpesvirinae
– Simplexvirus
• Herpes simplex virus 1,2 (HHV1,2)
– Herpes B virus (simiae)
Human herpesviruses (HHV) – Varicellovirus
• Varicella-zoster virus (VZV/ HHV3)
• Betaherpesvirinae
– Cytomegalovirus
• Human cytomegalovirus (CMV/ HHV5)
– Roseolovirus
• Human herpesvirus 6,7 (HHV6,7)
• Gammaherpesvirinae
• Epstein-Barr virus (EBV / HHV4)
• Human herpesvirus 8 (KSHV / HHV8)
Structure Replication
• herpesviruses are indistinguishable by electron microscopy • Penetration by fusion with plasma
• genome: DNA, double stranded, linear, 120-230 kbp, 70-
200 proteins are encoded, reiterated sequences membrane
• capsid: 162 capsomeres, cubic symmetry • Nuclear site of replication
• envelope: derived from the nuclear membrane, contains
viral glycoprotein spikes • Capsids assemble in nucleus and bud
• tegument: an amorphous structure between the capsid and through nuclear membrane
envelope
• size: with envelope – 150-200 nm, without envelope: 100
nm
Herpesvirus - capside
35
Genome Overview of herpesvirus diseases
• Latent infections
– primary infection (with or without symptoms)
– latency
– reactivation
• Malignancies
– Epstein-Barr virus
– Kaposi sarcoma virus
• Tropism
– epithelial cells
– neurons
– lymphocytes
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Herpetic gingivostomatitis Cold sore, herpes labialis
Keratoconjunctivitis Keratoconjunctivitis
• HSV1
• corneal lesions
• lesions of the conjunctival epithelium
• recurrent keratitis: visual impairment,
blindness
37
Genital herpes Skin infections
• infection through cuts or abrasions
• herpetic whitlow – on fingers
– dentists, hospital personnel, thumb-sucking
children
• herpes gladiatorum (wrestling, rugby)
38
HHV3, Varicella-Zoster Virus (VZV) Pathogenesis
• Initial replication: respiratory tract
– epithelial cells (VZV can spread cell-to-cell)
• Primary infection: varicella (chickenpox) – the virus is spread by viremia to skin → lesions in
successive crops
• Latency: dorsal root or cranial nerve
• latency
ganglia
• recurrence: in case of depression of cell-
• Reactivation: herpes zoster (shingle) mediated immunity and other mechanisms of
viral activation;
– the virus replicates and is released along the neural
pathways to the skin, causing a vescular rash along
the dermatome
Zoster Zoster
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HHV4 (Epstein-Barr Virus, EBV) EBV antigens
• “B-lymphocyte parasite” • different groups or proteins are expressed for
the different types of infections
– permissive cells: early genes are activated + lytic
• Outcomes of EBV infections: cycle
• viral proteins: viral capsid antigen (VCA), membrane antigen
– replication in B cells and epithelial cells (MA), early antigen (EA)
permissive for infection – nonpermissive infection: some early antigens are
expressed
– latent infection of B cells • Epstein-Barr nuclear antigens (EBNA), latent proteins (LP) –
essential for maintaining the infection and immortalization
– stimulation and immortalization of B cells
• latent membrane proteins (LMP) – oncogene-like activity,
stimulate the growth of and immortalize B cells
• latency in memory B cells
Immunity Pathogenesis
• first antibodies: anti-VCA, anti-MA antibodies • overactive immune response: infectious
• later: anti-EA antibodies
mononucleosis
• after resolution of infection: anti-EBNA
antibodies • lack of effective immune response:
• T-cells: essential for limiting the infection lymphoma
• infectious mononucleosis: results from a “war”
between infected B cells and protective T cells • B-cell mitogen: B cell proliferation
– lymphocytosis (atypical mononuclear cells) results
from the activation and proliferation of T cells
– swelling of lymph glands, spleen, liver (T cell
proliferation)
40
Diseases Heterophile Antibody
• Infectious mononucleosis • EBV induces polyclonal proliferation of B
– heterophile antibody positive cells
• EBV induced lymphoproliferative diseases • One of the antibodies produced (heterophil
• people lacking T cell immunity
• transplant recipients antibody) is able to agglutinate sheep red
• AIDS blood cells – Paul-Bunnell test
– Burkitt – lymphoma: B cell lymphoma of the jaw and
face
• children living in malarial regions of Africa – EBV monucleosis is heterophile antibody
– Hodgkin’s lymphoma positive
– Nasopharyngeal carcinoma (epithelial cells) – CMV mono is heterophile antibody negative
41
Diseases Microcephaly
• Heterophile antibody negative infectious
mononucleosis
• immun ocompromised patients: - pneumonia,
encephalitis, colitis, disseminated disease
• congenital infections – risk is especially high for
infants born to mothers who underwent primary
infection during their pregnancy
– cytomegalic inclusion disease (microcephaly,
hepatosplenomegaly, rash), hearing loss
• perinatal infections – no clinically evident
infection in full-term infants
– pre-term infants: hepatitis, pneumonia
HHV6 Roseola
• Exanthema subitum (roseola)
• Viral replication: CD4+ lymphocytes
• Receptor: other than CD4
42
Human papillomavirus (HPV) Viral replication
• more than 100 serotypes • steps in viral replication are in parallel with the
• genome: DNA differentiation of the epithelium
• cubical symmetry – infection of cells in the basal layer
• no envelope – early genes: stimulate cell growth – thickening of the
• E1-7 regulatory (early) basal and the prickle cell layer (stratum spinosum)
proteins – as the basal cells differentiate – transcription of viral
• L1-2 – structural (late) genes
capsid proteins – terminally differentiated upper layer cells: expression
of late genes
– the virus is shed with the dead cells of the outer layer
HPV Diseases
• Narrow host range
• Oncogenic virus
• Tropism: • warts - benign proliferation of the skin
– squamous epithelial cells of the skin (cutaneous HPV - warts)
– mucous membranes (mucosal HPV - genital, oral, conjunctival
• benign head and neck tumours (HPV6, 11)
papillomas) – oral papillomas
– laryngeal papillomas
• Transmission
– direct contact • anogenital warts
– sexual intercourse
– during birth
– condylomata acuminata (HPV6, 11)
43
Anogenital warts Cervical dysplasia and cancer
• HPV 16, 18 – 70%
• in most cases (90 %): HPV infection is cleared in 1-2
years;
• cytological changes – koilocytes (detected by
Papanicolau smears)
• first changes detected by microscopy: dysplasia (regress
in 40-70%)
• cervical cancer develops through progressive cellular
changes: mild - CIN I (cervical intraepithelial neoplasia),
moderate - CIN II to severe lesions – CIN III, carcinoma
in situ (1-4 years)
• untreated CIN II/III can progress in invasive cancer
Cervical cancer
44
Development of cervical cancer • Co-factors in the development of cervical cancer
– genetic background
– smoking
– immune status
• Risk factors:
– sexual activity
– age at first intercourse
– oral contraceptive use
– occurrence of other sexually transmitted diseases
Poxviridae Variola
• the largest and most complex viruses
• diseases are characterized by: rash,
proliferative lesions
• Variola virus: smallpox
• Molluscipoxvirus: molluscum
contagiosum – benign epidermal
tumour
– spread by direct and indirect contact
– sexually transmitted disease
45
Molluscum contagiosum Viral morphology
• complex structure
Parvoviruses
• Parvovirus B19 causes
– erythema infectiosum (slapped cheek syndrome)
– aplastic anemia
– fetal infections
• Viral morphology:
– very small (22 nm)
– single-stranded DNA genome
– icosahedral symmetry
– nonenveloped virus
46
Orthomyxoviridae
RNA viruses
• Influenza viruses
• associated with respiratory tract diseases
of humans and animals (mammals and
birds)
• myxovirus: these viruses interact with
mucins, glycoproteins on the surface of the
cells (myxa=mucous)
Orthomyxoviridae Structure
influenzavirus A, B, C • genome: 8 segments,
negative polarity ssRNA
• type A: • Proteins PB1, PB2, PA:
– humans, swine, aquatic birds, chickens, ducks, horses, polymerase components
seals
• nucleoproteins (NP) –
• type B:
– only humans
attached to the genome
• type C: • M – matrix protein (M1, M2)
– humans (swine) – associated with the
envelope
• 100 nm, helical symmetry • envelope: glycoproteins
• spherical/oval hemagglutinin (HA) and
neuraminidase (NA)
47
Antigenic structure Hemagglutinin (HA)
• core antigens: • spike-shaped – elongated stalk capped by a
– nucleoproteins (A, B, C), RNA dependent RNA large globule
polymerase • binds the virion to the surface of the
– stable
susceptible cells
• outer antigens: glycoproteins (HA, NA)
• major antigen – antibodies directed against
H, N antigens
– H: 1-15
HA are neutralizing (protective)
– N: 1-9 • variability – continuous evolution of new
– subtypes: H1N1, H3N2, H5N1 strains
– changing structure
48
Pathogenesis Disease
Antibody
Antibody Future
protection
T-cellT-cell • Influenza – respiratory tract infection
response
response
– self-limited in persons with intact immunity
Interferon
– most frequent complication: pneumonia
• elderly
• infants
Desquamation
Infection Replication of epithelial Influenza • chronic underlying diseases
cells – other complications: myocarditis, pericarditis,
encephalitis
Bacterial pneumonia secondary bacterial infection
– Reye’s syndrome mainly in children, adolescents:
primary viral pneumonia acute encephalopathy + hepatic disorders (salicylate
use)
CNS, muscle involvement
Epidemiology Pandemics
• annual outbreaks caused by
– influenza A: 1-3 yearly
• 1890: H2N2
– influenza B: 3-6 yearly • 1900: H3N8
• 3-5 million cases of severe illness, 250000-
500000 deaths worldwide • 1918-19: Spanish flu (H1N1 swine-like)
• Northern Hemisphere: January – April • 1957-58: Asian flu (H2N2)
• epidemics developed across continents:
pandemics (exclusively influenza A) • 1968-69: Hong Kong flu (H3N2)
• the size and the extent of an outbreak depends • 1977: H3N2 and H1N1
on the virulence of the new subtype/type and the
immunity in the population • 1990: H3N2 and H1N1
49
Spanish flu Transmission
• Airborn respiratory droplets
• Contagion precedes symptomes
• human-to-human, animal-to-human
• reservoir: birds (in birds the infection is
usually asymptomatic)
• wild birds – domestic birds, animals –
humans
Transmission
50
2009 seasonal influenza vaccine Vaccines
• Both TIV (Trivalent Inactivated Vaccine) • TIV (trivalent inactivated vaccine)
– Fluzone – Sanofi Pasteur
and LAIV (live attenuated influenza • regular
vaccine) • high dose (>65 year old) – contains four times the amount of
antigen, provides stronger immune response
– A/Brisbane/59/2007 – H1N1-like • intradermal (18-64 years old) – requires less antigen,
provides the same immune response as the regular one
– A/Brisbane/10/2007 – H3N2 – since 2011-2012 season
– Fluvirin – Novartis
– B/Brisbane/60/2008 – Fluarix – GSK
– Fluluval – GSK
• LAIV – live attenuated influenza vaccine
– FluMist - MedImmune
51
H1N1 in post-pandemic period
2009 influenza
• WHO - Director-General's opening statement at
virtual press conference (10 August 2010): • 4572 deaths related to laboratory-
„The world is no longer in phase 6 of influenza confirmed influenza in the WHO/Europe
pandemic alert. We are now moving into the post- region (5,1 deaths/1000000 population)
pandemic period. The new H1N1 virus has largely run • Clinical consultation and influenza
its course.”
positivity rates observed during 2009/2010
„As we enter the post-pandemic period, this does not
mean that the H1N1 virus has gone away. Based on
pandemic have been comparable with
experience with past pandemics, we expect the H1N1 recent influenza seasons.
virus to take on the behaviour of a seasonal influenza • The age profile of persons at risk for worse
virus and continue to circulate for some years to outcome differed (younger age group)
come.”
CDC
H5N1 Paramyxoviridae
• Human illness • Paramyxovirus
– 335 cases, 206 deaths – Parainfluenza
– Mumps
– 2007: 72 cases, 48 deaths
• Morbillivirus
• Pneumovirus –
Respiratory Syncytial
Virus
52
Morphology
53
Measles Measles
• Complications
– pneumonia, otitis media
– bacterial infections
– encephalitis
– SSPE (subacute sclerosing panencephalitis)
• Prevention
– attenuated viral vaccine
• monovalent vaccine
• trivaccine: MMR (measles, mumps, rubella)
Pathogenesis Rubella
• postnatal infection:
– 12-21 days incubation
– upper respiratory tract – local lymph nodes -
The lesions are less intense and
lymphadenopathy have not coalesced, as usually occurs in
measles.
– viraemia
– rash: maculopapular: face – body
54
• Congenital infection
– the virus can pass the placenta and replicate Prevention:
in the fetus Vaccine - MMR
– malformation
• heart
• eyes
• brain (deafness, mental retardation)
Picornaviruses causing
Picornaviridae human disease
• smallest viruses of vertebrates (28 nm) GENUS Virus
• + ss RNA Enterovirus poliovirus
Coxsackie A, B virus
• icosahedral symmetry
echovirus
• no envelope (naked virion) enterovirus (68-71)
Hepatovirus Hepatitis-A-virus
Rhinovirus rhinovirus
Cardiovirus encephalomyocarditis-virus
Aphtovirus Foot-and-mouth disease virus
Poliovirus Poliovirus 1, 2, 3
• types1, 2, 3
– portal of entry – digestive tract
– disseminated infection (90% of infections:
asymptomatic)
– poliomyelitis – most severe outcome of the
infection
• CNS - anterior horn cells of the spinal cord and
the motor cortex of the brain
55
Polio
• Epidemiology
– fecal-oral transmission
– before vaccination: outbreaks
– 2002: wild type polio-free Europe
• Prevention: vaccination
– IPV – Salk – inactivated virus (parenteral)
– OPV – Sabin – attenuated virus (oral)
Coxsackie A, B viruses
56
Rhinoviruses Caliciviridae
Coronaviridae Coronavirus
• + ss RNA
• helical symmetry
• envelope – glycoproteins (E1-3)
• E2 spikes – solar corona-like
appearance
57
Disease Reoviridae
• ds RNA, segmented
• common cold
• cubical symmetry
• SARS (severe acute respiratory
• double-layered capsid
syndrome)
• no envelope
• gastroenteritis
• common agents
of infantile
diarrhea
Pathogenesis Epidemiology
– portal of entry: digestive tract • ubiquitous
– target cells: enterocytes • only infants and small children have
– shortening and blunting of of the microvilli symptomatic disease
– diarrhea
– lactose intolerance
– viremia: respiratory tract
58
Arboviruses Roboviruses
Arthropode borne Rodent borne
• Bunyaviridae
– Togaviridae – Alphaviruses – encephalitis Hantavirus genus
– Flaviviridae – yellow fever, tick encephalitis, nephritis, hemorrhagic fever
Dengue- fever
– Bunyaviridae – encephalitis, haemorrhagic
fever
Filoviridae
• Arenaviridae: arena = sand • filamentous
• haemorrhagic fever
Haemorrhagic fever • transmitted from human-
– Lassa - Nigéria to-human
– Junin – Argentina • Marburg, 1967
– Machupo –Bolívia • Ebola, 1976 Zair,
2003 Congo
Morphology Replication
– helical symmetry
– negative, ss RNA
– size: 900 nm/80 nm
– proteins, polymerase, glycoprotein
– envelope
59
Haemorrhagic fever Rhabdoviridae
• Lyssa virus – agent of rabies
• sudden onset with high fever, malaise, – negative ss RNA
myalgia, sore throat – helical symmetry
• diarrhea, vomiting, rash – polymerase
• liver and kidney dysfunction, hemorrhages – envelope - spikes
– appearance: bullet
Rhabdovirus Pathogenesis
• bite of an animal
• the virus infects the nerve endings
• days to months – progress to the central
nervous system, then disseminates to
highly innervated sites: skin, salivary
glands, retina, cornea, renal parenchyma,
etc.
• fatal disease
Hepatitis viruses
60
Hepatitis A Virus (HAV)
Hepatitis viruses
Fecal-
Fecal-oral
A E transmssion
B D C
Parenteral
F, G, transmission
? others
61
Disease HAV infection
• Incubation: 3-4 weeks Symptoms
• acute disease HAV antibodies
Titer
• spontaneous resolution in 2-4 weeks HAV
in feces
• symptomatic/asymptomatic form:
HAV IgM
– children: 1/12
– adults: 1/3
• letality: 0,1%
0 1 2 3
Months 4 5 6 1 2
2 4
Immunity Epidemiology
• neutralizing antibodies (IgM, IgG) • worldwide occurrence
• IgM titer: peak level during the sixth week
• outbreaks (summer and autumn peaks)
of infection
• IgG antibodies persist lifelong – protection • source of infection: the infected person (most often:
asymptomatic)
against reinfection
• IgA: saliva, gastrointestinal mucosa - not • Common route of spread: fecal-oral
• Also possible through blood, saliva
neutralizing • Rarely: by sexual activity (anal, oral contact)
• cellular immunity
Seroprevalence
High
Medium
Low
Very low
62
Diagnosis Hepatitis B Virus (HBV)
• Serology - ELISA
– IgM – acute infection
– IgG – lifelong persistence
63
HBV genome
HBV proteins
64
HBV
HBeAg anti-HBe
anti-HBc
• chronic hepatitis (5-10%)
Titer
• cirrhosis
HBsAg anti-HBc IgM anti-HBs
• hepatocellular carcinoma (HCC)
0 4 8 12 16 20 24 28 32 36 52 100
Weeks
(6 months) (years)
Symptomatic infection (%)
80 80
HBeAg anti-HBe
HBsAg
60 60
anti-HBc Chronic infection
Titer
40 40
20 20
anti-HBc IgM
Symptomatic infection
0 0
1-6 months 7-12 months 1-4 years adults
0 4 8 12 16 20 24 28 32 36 52 Years
Weeks
Age at the infection
65
Geographic distribution of HBV infection HBV
• 300.000.000 infected people
• 2.000.000 deaths/year due to HBV
infections
• 700.000 deaths due to hepatocellular
carcinoma
HBsAg prevalence
≥8% - high
2-7% - medium
<2 - low
Transmission
• Parenteral spread
Romania – Blood, blood products (transfusion, needle
sharing, acupuncture, piercing, tattooing) –
- HBsAg prevalence: medium 0.0001 ml plasma
- carrier state - 7% of the population – Sexual contact (semen, saliva, vaginal
secretions) – more efficient transmission than in
case of HIV – 30%
– Perinatal route
66
HCV HCV genome
• Extrahepatic manifestations 0 1 2 3 4 5 6 1 2 3 4
Months Years
• Vasculitis, renal impairment
ALT – alanin aminotransferase
67
Epidemiology HCV in Romania
• HCV incidence in Romania is the highest
in European Union
• 44.5 mortalities per 10 000 inhabitants
related to HCV
• 1 058 000 estimated cases (2007)
RNA
• Deltavirus
• envelope (HBsAg)
• genome: circular negative sense ss RNA –
very small
68
HBV - HDV coinfection
HDV infection Symptoms
ALT
• Transmission: parenteral
anti-
• Coinfection HBs
Titer
anti-HDV IgM
–Severe acute disease
• Superinfection HDV RNA
–Chronic disease
HBsAg
–Unfavorable prognosis anti-HDV
Symptoms
anti-HDV
ALT
Titer
Taiwan
Pacific Islands
Hepatitis E virus
Prevention
• HBV-HDV coinfection
- Prevention of HBV infection by
vaccination
• HBV-HDV superinfection
- Education, standard precautions
69
Hepatitis E virus (HEV) HEV infection
HEV infection
Geographical distribution of HEV
Symptoms
ALT
anti-HEV IgG
anti-HEV IgM
Titer
Virus in feces
0 1 2 3 4 5 6 7 8 9 1 1 1 1
0 1 2 3
Weeks
Weeks
HIV
Human immunodeficiency virus • Retroviridae
• Lentivirus
– slow viruses associated with neurologic and
immunosuppressive diseases
(HIV) – life-long infections
– cannot be eliminated from the organism
• HIV-1 – discovered in 1983/1984
– groups, subtypes (Ro. group M, subtype F)
• HIV-2 – 1986 (40% homology with HIV-1)
– Less transmittable, mostly confined to West Afria
70
HIV structure HIV
• Size: 100 nm
• complex symmetry
• Capsid – polipeptidic antigens
• Envelope - glycoproteins, lipids
• Genome – 2 copies of positive, single
stranded, linear RNA molecules
Structural genes
HIV genome
• gag (group specific antigen)
– CA (capsid) – p24
– MA (matrix)
– 3 groups of genes
– NC (nucleocapsid)
• structural genes • pol (polymerase)
• transcriptional activator genes – RT (reverse transcriptase)
• accessory genes – IN (integrase)
– PR (protease)
• env (envelope)
– SU (surface) – gp120
– TM (transmembrane) – gp41
71
HIV genome Target cells, tropism
• Receptor: CD4+ T-lymphocytes, monocytes,
macrophages
• Co-receptor: chemokine receptor: CCR5 or CXCR4
• Receptors: adhesion
• Coreceptors: fusion
72
CD4 antigen CD4 antigen
Co-receptor Co-receptor
gp4 CD4
1 antigen
gp120
Reverse
transcriptase
Protease
Integrase
tRNA
Conformational change
gp41 embeds into the cells membrane
73
Fusion
Fusion
Nuclear
membrane
74
RT
protease
integrase
RNA
HIV components enter
the nucleus
tRNA
Pathogenesis
Pathogenesis 2
• major determinant in pathogenesis:
tropism for CD4 + cells • the virus can be detected in the blood and
• infection – viruses reach the lymph nodes circulating lymphocytes by 5 days
(within 2 days) – CD4+ T lymphocytes are • as the immune system responds: p24 and
infected viral RNA decreases
• macrophages: major reservoir and means – by 6-12 months:
of distribution of HIV • p24 becomes undetectable
• RNA level stabilizes (temporary increases in RNA
• continuous replication of the virus – levels during intercurrent infections, immunizations
release of the virus and infected T cells and pregnancy)
into the blood
75
Pathogenesis 3 Pathogenesis 4
• only a small fraction of CD4+ cells are • reduction of the number of CD4+ T cells
productively infected – direct cytolysis – the ability of HIV to kill the cell
• many infected cells are killed, a fraction survive, correlates with the amount of CD4 molecules
revert to a resting memory state expressed by the cell (macrophages express less
→ long-term latent reservoir than T lymphocytes)
• lysis of infected cells
• when exposed to antigen (foreign antigens): • syncytia formation
activation – release of virions • induction of apoptosis
• the proportion of infected cells and the level of • increased permeability of the plasma membrane
circulating virus increase as the infection – cytotoxic T-cell immune cytolysis
progresses
Pathogenesis 5
• immune response: restricts viral infection
but contributes to pathogenesis
– neutralizing antibodies: against gp120
– antibody-coated virus: still infectious – is
taken up by macrophages
– cytotoxic T lymphocytes (CTL) – can kill
infected cells
• BUT: they require activation by CD4+ cells, CTL
number decreases with CD4+ cell number –
disease progression
76
Untreated infected persons develop
HIV – escaping immune control
AIDS:
• rapid mutation – alteration of antigenicity • 5% within 3 years
– escape antibody clearance and the targeted • 20-25% by 6-7 years
killing of the CD4+ cell
• 5-10% each year
– several different viral genomes are present at
any time during an infection • <5% asymptomatic for more than 10 years
– regions of the envelope glycoproteins are the • 2% asymptomatic for more than 12 years
most variable
77
Primary infection Clinical latency
• 2-4 weeks after infection • years
• influenza- or mononucleosis-like disease – • continuous replication of the virus in
generalized lymphadenopathy – the lymphoid tissue
symptoms disappear spontaneously after 2-3 • increased turn-over of CD4+ cells –
weeks replacement of destroyed cells → balance
• immune response – seroconversion (3
months –serological window)
• number of CD4+ cells decreases
78
Treatment Transmission
• Antiviral drugs
– reverse transcriptase inhibitors • high titers of HIV: blood, semen
– protease inhibitors
– fusion inhibitors
• sexual contact
• HAART (1996) – highly active antiretroviral
• blood products
treatment
– combination therapy
• vertical transmission
– prolongs life – does not cure
79
Romania
children 2041
adults 2281
80
Cumulative HIV cases – adults and children Cumulative HIV cases (1992 – 2008) on children
(1992 – 2008) by counties (0-14 years at diagnosis date) by counties
yellow < 50 CASES yellow < 50 CASES
green 50-100 CASES green 50-100 CASES
blue 101-500 CASES blue 101-500 CASES
red > 500 CASES red > 500 CASES
Classification of parasites
Parasites
Helminths
Arthropods Trematoda (flukes)
Cestoda (tapeworms)
81
Protozoa Protozoa
• eukaryotes • amoebas • Sporozoa
– Entamoeba – Isospora
– nucleus, necleolus, cytoplasm, – Naegleria – Cryptococcus
– special organelles for movement – Acanthamoeba – Plasmodium
– sexual and asexual reproduction • Mastigophora – – Toxoplasma
flagellates • Ciliata
• Sizes: 2-3 – 60-80 µm – Chilomastix – Balantidium
• Forms – Giardia
– Dientamoeba
– Vegetative form – trophozoite – active form
– Trichomonas
– Cysts – Trypanosoma
– Leishmania
488
Morphology
Entamoeba histolytica
• Trophozoite (Entamoeba dysenteriae)
dysenteriae)
– single nucleus with an even lining of peripheral
chromatin and a prominent central nucleolus
– cytoplasm: hyalin outer margin and granular intern
region
– pseudopodes (finger-like)
– engulfed erythrocytes (diagnostic importance!)
• Cyst:
– four nuclei
– thick wall
– chromatoidal bodies with round ends
492
82
Entamoeba histolytica E. histolytica
(Entamoeba dysenteriae)
dysenteriae) ingestion of the cyst
excystation
replication (8 metacysts
metacysts)
coecum (ulcers)
ulcers)
colon (encystatio
(encystation
n)
494
495 496
497
83
Liver abscess Intestinal ulcerative lesions
504
84
Morphology Giardia lamblia
• trophozoite
– pear-shaped
– 2 nuclei
– 2 axostyles (rod-like supporting organelles)
– 4 pairs of flagella
– suction disk
– dancing motion (falling leaf motility)
• cyst
– 4 nuclei
– several internal fibers
506
507 508
S.J. Upton
G. lamblia
- ingestion of cysts
- excystation - pH < 3
- attachment to intestinal
epithelium
-multiplication (binary
fission)
- encystation in the colon
509 510
85
M.Lisci MD and G.Cera MD:
511 512
kleintiermedizin.ch
513
515
86
Pathogenesis, epidemiology Cryptosporidium parvum
• fecal-oral transmission of oocysts
• pathogenesis of diarrhea: unknown
• outbreaks of cryptosporidia: inadequate
purification of drinking water
518
519
Trichomonas vaginalis
• flagellate
• disease: trichomoniasis
• morphology: S.J. Upton
– pear-shaped organism
– one nucleus
– 4 anterior flagella
– the fifth flagellum delimits an undulating membrane
– axostyl
– no cyst form
521 522
87
Trichomonas vaginalis T. vaginalis
524
Trichomonas vaginalis
• worldwide occurrence
525 526
528
88
T. gondii Life cycle
• intermediate host: animals, humans
– asexual reproduction
– ingested oocysts release sporozoites – circulate in
the body – invade different cells (especially
macrophages) → trophozoites, multiply, break out,
spread in the organism
• rapidly multiplying cells (tachyzoites) - responsible of acute
stage disease
– slowly multiplying toxoplasma cells (bradyzoites) –
form tissue cysts (pseudocysts) – responsible for
chronic stage disease
• pseudocysts are infective
– ingested by a cat – sexual reproduction
– ingested by other animal or humans – asexual reproduction
530
Morphology
• Trophozoites
– boat shaped thin-walled cells
– stain with Giemsa’s stain
• Cysts: cells filled with trophozoites
531
Trophozoites Pseudocyst
533 534
89
Trophozoites of T. gondii Pathogenesis
• Tachizoite: destructs the infected cell
• usually asymptomatic – mononucleosis-like
symptoms may develop
• immune response
• congenital infections in case of the infection of
the mother during pregnancy:
– stillbirth, eye lesions, intracerebral calcifications,
psychomotor disturbances, hydrocephaly,
microcephaly
– prenatal toxoplasmosis is a major cause of blindness
535
90
General properties
Cestoda
• Morphology – segmented parasites
– head – scolex
• suckers
Taenia group (giant and minute tapeworms) • anterior rings of hooks
Hymenolepis group – neck
Diphyllobotrium group (fish tapeworm) – body – strobila
• ribbon-like chain of segments (proglottids)
• each segment contains male and female reproductive organs
(hermaphroditic)
• no digestive system (nutrients are absorbed directly from the
gut lumen)
scolex
91
Life cycle T. solium life cycle
• humans ingest pork containing small bladder-
like larvae (cysticerci) → release of larval
worms, attach to gut wall → adult
multisegmented worms (3 months) – egg-filled
terminal segments are eliminated with feces →
eggs are eaten by pigs → muscular larvae
(cysticerci)
• particularity: eggs can also infect humans, affect
various organs (brain, eyes) → cysticercosis
• similar to T. solium
92
T. saginata Taenia egg
• yellow-brown
• round to oval
• 30-40 µm
Proglottid
Scolex
• thick radially striated
shell
• oncosphere with
visible hooks
554
Taenia solium
Taenia saginata Echinococcus granulosus
• “dog tapeworm”, hydatid worm
• minute, three-segmented tapeworm
• Final host: dog, other carnivores
• Intermediate hosts: herbivores, humans
• Life cycle:
– herbivores ingest eggs – in the gut oncospheres are released –
spread to organs (especially liver) – the larvae form huge, fluid-
filled cysts (hydatid cyst) in which thousands of scoleces form
– dogs are infected when they ingest internal organs of herbivores
containing hydatid cyst
– humans are infected from dog feces – hydatic cysts can form in
different organs - hydatidosis
555 556
93
Hymenolepis nana
Hymenolepis nana egg
• 40-60 - 30-50 µm
• 2 membranes,
Scolex: armed rostellum, 4 suckers filaments between
them
rosette-shaped uterus
at the center of each proglottid
• operculated eggs,
• 58-75 by 40-50 µm
• a small knob is
visible at the
opposite site of the
operculum
563
94
Diphyllobotrium latum life cycle
Nemathelminthes
(Nematodes)
565
95
Ascaris lumbricoides Life cycle
• the largest intestinal nematode (20-35 cm)
• life cycle:
– fertilized eliminated eggs become infectious
after 2 weeks spent on soil (larva formation) -
geohelminth
– the ingested egg releases the larva →
penetrates the duodenal wall → blood stream
→ liver → heart → lung → alveoli of the lung
→ coughed up, swallowed → small intestine:
maturation to adult form
576
96
A. lumbricoides egg containing Ascaris lumbricoides unfertilized
larva egg
577 578
97
Trichuris trichiura egg Life cycle
• dark bile staining
• lemon shape
• polar plugs in the
eggshell
583 584
• perianal pruritus
• scratching predisposes to secondary
bacterial infection
• Diagnosis:
– eggs are not found in the stool
– scotch tape technique
98
Enterobius vermicularis eggs Life cycle
• elongated and
flattened on one side
• thick colorless shell,
• 50-60 / 20-30 mm
589 590
99
Life cycle
• ingestion of meat containing encysted
larvae → in the small intestine the larvae
develop into adults → females produce
larvae (vivipar) → blood stream → larvae
coil in striated muscles
• most commonly invaded muscles:
– muscles of eye, tongue, deltoid, pectoral and
intercostal muscles, diaphragm,
gastrocnemius muscle
100
Plasmodium species Plasmodium – life cycle
• asexual cycle:
• P. vivax, P. malariae, P. ovale, P. – schizogony in humans
falciparum • sexual cycle:
• disease: malaria – gametogony (production of gametes) in
• infect red blood cells and tissue (liver, humans – but to complete the sexual cycle
kidney, brain) the gametocytes must be taken up by
mosquitos
– sporogony (production of sporozoites) in
mosquito
601
Anopheles
Merozoite
• erythrocytes
Sporozoite
• salivary glands
• hepatocytes
Ookinete
• epithelial cells –
Anopheles gut
101
cold stage
Clinical findings • feeling of intense cold
• vigorous shivering, rigor
• lasts 15-60 min
• incubation period
– exoerythrocytic phase + at least one
erythrocytic cycle
• 10-15 days – P. vivax, P. falciparum
• 28 days – P. malariae
• symptoms:
– severe chills, high fever, sweating + other
symptoms
102
Laboratory diagnosis Thin film
• microscopic examination
– thick film (a method of concentration)
– thin film of blood – species identification
• serology
– for epidemiological survey
– screening blood donors
Thick film
Plasmodium
falciparum
Plasmodium falciparum
103
Plasmodium
vivax Plasmodium
vivax
• enlarged erythrocyte
• Schüffner’s dots
• ‘ameboid’ trophozoite
• many merozoites in mature segmenter
104
Plasmodium Plasmodium
malariae malariae
Epidemiology Treatment
• Transmission:
– through mosquito bite • supportive measures
– rarely: congenital acquisition, blood transfusion
– often seasonal (rainy season) • chemotherapy
• endemic in Africa, Asia, Oceania, South America
• P. vivax
– chloroquine, primaquine
– most prevalent
– tropics, subtropics, temperate regions
• P. ovale
– tropical Africa (often more prevalent than P. vivax), Asia, South America
• P. malariae • chemoprophylaxis
– less prevalent
• P. falciparum
– tropical, subtropical regions
Hemoflagellates Trypanosoma
• Trypanosoma
• African: Trypanosoma brucei rhodesiense,
Trypanosoma brucei gambiense
• Leishmania
– sleeping disease (vector: tsetse fly)
• American: Trypanosoma cruzi
– Chagas’ disease (vector: triatoma)
105
Morphology Trypanosoma in blood smear
• in the blood: trypomastigotes
– elongated body
– longitudinal lateral undulating membrane
– flagellum that borders the free edge of the membrane
– at the anterior pole of the cell: free whip-like
extension
• other developmental forms
– leishmanial intracellular stage - amastigote
– flagellated extracellular stage without undulating
membrane – promastigote
– elongated extracellular stage with short undulating
membrane - epimastigote
106
Diagnosis Leishmania
• blood, CSF, lymph node aspirates, bone marrow
• L. tropica - cutaneous leishmaniasis (oriental
• microscopy sore)
– thick, thin films • L. brasiliensis - mucocutaneous leishmaniasis
• culture (espundia)
• animal inoculation • L. donovani - visceral leishmaniasis (kala-azar)
• serology
• morphology: identical
• xenodiagnosis (Chagas’ disease) – laboratory – in mammals: intracellular nonflagellated amastigotes
triatoma bugs are fed on the patient – their feces (macrophages)
are examined in 7-10 days • vector: sandfly
Sandfly Pathogenesis
• L. tropica
– dermal lesion at the site of entry
– oriental sore, Delhi sore, etc.
• L. brasiliensis (Amazonian South America)
– nasopharyngeal leishmaniasis
– slow-growing extensive lesions
– erosion, destruction of nasal septum and surrounding regions
• L. donovani: inoculation → RES (liver, bone marrow,
spleen, lymph nodes), marked spleen, liver hyperplasia
– growing weakness
Phlebotomus - vector of visceral Leishmaniosis – irregular fever
– untreated is fatal
107
Kala-azar Diagnosis
• lymph node aspirates, scrapings, biopsies
• microscopic examination
• culture
• serology
108
Necator americanus Transmission and epidemiology
109
Strongyloides stercoralis Pathogenesis and clinical findings
• asymptomatic cases
• inflammation of the intestinal mucosa →
Tail of filariform larva watery diarrhea
larva in lung Filariform larva
– massive autoinfection: sepsis due to mucosal
injury
• pneumonitis (during migration of larvae)
• “ground itch”
• Epidemiology
Wuchereria bancrofti
– primarily in the tropics, especially Southeast
• filariasis
Asia
• tissue nematode
• Laboratory diagnosis
• vector: mosquito
– detecting the larvae in the stool
• Life cycle: bite of female mosquito → larvae in
– eosinophilia wound → migrate to the lymphatic system (in the
• Prevention arms, legs, groin) → adults: mate after 3 to 12
– proper disposal of sewage months microfilariae (larvae) → blood →
ingested by mosquitoes → after several stages
– wearing shoes
of development infective larvae are formed
110
Elephantiasis Transmission, epidemiology
• transmitted by female mosquitoes:
Anopheles, Culex (depending on
geographic area)
– tropical regions of Africa, Asia, Latin America
– 200-300 million people are affected
Onchocerca volvulus
• Diagnosis • tissue nematodes
– thick blood smears • onchocerciasis (river blindness)
• Prevention • vector: blackfly
– mosquito control • Life cycle: bite of female blackfly in
– protective clothing, mosquito netting, subcutaneous tissue → adult worms (skin
repellents nodules) → females produce microfilariae
→ interstitial fluid → ingested by blackflies
→ infective larvae
Microfilariae Pathogenesis
• microfilariae migrate in subcutaneous
tissue, concentrate in eye: blindness
• adult worms: inflammatory nodules in skin
• scaly dermatitis “lizard skin” (thick, dry,
scaling skin)
• loss of subcutaneous elastic fibers:
“hanging groin” (inguinal region)
111
Onchocerca volvulus Epidemiology
• Africa, Central America
• major cause of blindness
• river blindness: blackflies develop in rivers
• infection rate: >80% in edemic area
keratic precipitates and microfilaria
onchocerca nodule on inside surface of cornea
(adult curled up within)
112
Dracunculus medinensis Loa loa
• Loiasis
• Tissue nematode
• Life cycle: bite of deer fly (mango fly) →
infective larvae crawl in the skin → adults
→ migrate subcutaneously; females
produce microfilariae → blood; ingested by
deer flies → infective larvae;
113
Schistosoma spp.
• schistosomiasis
• trematode (blood fluke)
• adults exist as 2 sexes but are attached to each other
• intravascular parasites approx. 1 cm
• life cycle: humans are infected by cercariae penetrating
skin → larvae → blood vessels → liver → adults →
portal vein: mesenteric venules (S. mansoni, S.
japonicum) or bladder venules (S. haematobium) →
eggs penetrate the gut or bladder wall → excreted →
hatch in fresh water → ciliated larvae
114
• Fungi (yeasts and molds): eukaryotic
organisms
– nucleus, nucleolus
– cytoplasm: mitochondria and endoplasmic
Mycology reticulum are present
– cell membrane: contains ergosterol in contrast to
human cell membrane which contains
cholesterol
– cell wall – chitin = long chains of N-acetyl-
glucose-amin (NAG)
– may have capsule
686
115
Risk factors for fungal disease Mycoses
• Systemic mycoses
– coccidioidomycosis
– Histoplasma
• underlying diseases – tumours, diabetes – Blastomycosis
mellitus, immunosuppression • Opportunistic mycoses
– Candida
• trauma – burns – Cryptococcus
– Aspergillus
• medical interventions – catheters, corticosteroid – Mucor, Rhizopus
– Fusarium
therapy, antibiotics, cytostatic therapy – Pneumocystis
• alcoholics, drug addicts • Cutaneous, subcutaneous mycoses
– dermatophytoses
• medical personnel working in laboratories, – Malassezia furfur
– others
dermatology
691 692
Arthrospores
In the lung: spherule
Mold phase - macroconidia Yeast form in the
containing endospores
lungs
• Habitat
– widely distributed
– present in the normal flora
• Morphology
– oval/round yeast cells – blastospores (3-5 µm)
Candida genus – pseudohyphae – elongated yeast cells that
visually resemble hyphae but are not true hypae
– Gram-positive
C. albicans – Candida albicans
Non-albicans species: • Chlamydospores – on special culture media
695 696
116
Candida albicans Disease
• candidiasis/candidosis
• in the presence of risk factors
• in persons with normal immunity – local factors that allow
infection (disturbances of the balance of normal flora) –
benign infections
– oropharynx (soor, glossitis, gingivitis, stomatitis,
angulus infectiosus oris, atrophic candidiasis, others)
– genitalia (vulvo-vaginitis – favored by high pH, diabetes,
use of antibiotics, balanitis)
yeast cells and chlamydospore – skin, nails – when repeatedly immersed in water
Gram stain
pseudohyphae (wet mount) – organs (urinary, respiratory tract, CNS, disseminated)
698
Disease Diagnosis
• underlying diseases, immunosuppression – more severe
candidiasis, dissemination
• cultivation and identification to species
– disseminated oralis candidiasis level is important to guide therapy
– oesophagitis • non-albicans species are emerging and
– pneumonia involved more and more often in infections
– nephritis
– endocarditis
– sepsis
• Intravenous drug users, indwelling catheters, hyperalimentation also
predispose to disseminated candidiasis
699
701
117
Aspergillus infections Aspergillus spp.
• Molds – widely distributed in the environment
• A. flavus, A. fumigatus
• Disease
– skin – burns, traumatic wounds, external ear
– pulmonary aspergillosis – neutropenic patients –
aspergilloma (fungus ball) – severe disease, high
mortality
– allergic bronchopulmonary aspergillosis – asthmatic
symptoms
703
Dermatophytes
Penicillium
• infections of skin structures
• only superficial keratinized structures are infected
• spread by direct contact,
• chronic infections – warm, humid areas of body
(athlete’s foot, jock itch); ringworm lesions; broken hair,
thickened broken nails;
– tinea capitis, corporis, pedis, barbae, cruris, unguium, manum
• scrapings of skin or nail placed in 10% KOH on a glass
slide show hyphae under microscope
• dermatophytid – hypersensitivity reactions
706
Microsporum
• Epidermophyton floccosum
• Microsporum spp.
• Trichophyton spp.
707
118
Athlete’s foot Tinea capitis
Dermatophytoses (Tinea)
ringworm lesions
119