IMMUNITY OF

BACTERIAL
INFECTIONS
PLAN
• INTRODUCTION
I. GENERALITIES
II. INNATE IMMUNITY TO BACTERIAL INFECTIONS
III. ADAPTATIVE IMMUNITY TO BACTERIAL INFECTIONS
IV. BACTERIAL VIRULENCE FACTORS AND HOW THEY THWART THE
HOST IMMUNITY
V. CASE STUDY
INTRODUCTION

L’immunité bactérienne met en jeu un ensemble de mécanismes

cellulaires et moléculaires qui sont devenus de plus en plus complexes
au fur et à mesure de l’évolution des espèces de l’adaptions réciproque
des écosystèmes bactériens et de leurs hôtes. Parmi ces mécanismes,
les plus importants pour la survie de l’hôte appartiennent à l’immunité
non spécifique : complément, cellules phagocytaires, cytokines.
• Leur action coordonnée aboutit à la mise en jeu d’une réponse
immédiate visant à la capture et à la destruction du pathogène, tandis
qu’une réaction inflammatoire permet d’éviter la diffusion des
microbes.
• L’immunité spécifique adaptative utilise tous les mécanismes
effecteurs de l’immunité naturelle et confère à l’organisme une
capacité de résistance vis-à-vis d’une nouvelle infection par le même
microorganisme (immunité de réinfection).
I. GENERALITIES
1) Les facteurs qui influencent le développement de la maladie

L’invasion microbienne peut être facilitée par les causes suivantes :

• Les facteurs de virulence : la capsule, les enzymes, les toxins
• L’adhérence microbienne: le biofilm
• La résistance aux antimicrobiens
• Les anomalies des mécanismes de défense de l’hôte
2) Preferential infection of some bacterial species

Brain/meninges : Neisseria meningitidis, Haemophilus influenza

Skin, dermis : Staphylococcus aureus, Mycobacterium leprae

Urinary bladder : Escherichia coli, Staphylococcus aureus

Nasopharynx : Streptococcus pyogenes, Haemophilus influenza

Lungs/airways :Streptococcus pneumonia, Mycobacterium tuberculosis

Intestines: Escherichia coli, Salmonella enterica

3) Les voies de transmission des infections bacteriennes

Par voie aérienne : via de fines gouttelettes émises dans

l’environnement proche de sujets infectés exemples; les bactéries
responsables de la tuberculose
Par voie digestive : via l’eau ou les aliments contaminés
Par voie transcutanée : c’est-à-dire au travers de la peau via une
piqûre, une morsure, une plaie ( la bactérie responsable du tétanos)
Par voie sexuelle : le Neisseria gonorrhea
Par voie sanguine : le meningocoque
4) Les étapes de l’infection bactérienne :
• La contamination : contact entre le microorganisme et l’organisme
• La période d’incubation : pas de signes cliniques, la bactérie
commence à se multiplier ou à sécréter des toxines
• La période d’invasion : les signes cliniques apparaissent, ils sont
d’ordre général (fièvre, nausées, fatigue, maux de tête…)
• La période d’état : les signes physiques cliniques spécifiques
apparaissent et permettent de poser un diagnostic
• La période de déclin : diminution des signes de la maladie
• La période de convalescence : l’organisme se rétablit
5) Les bacteries de la flore normal de
l’homme
 II. INNATE IMMUNITY TO
BACTERIAL INFECTIONS
 First line of host defense during infection

It is represented by physical, chemical, and biological barriers;

specialized cells and soluble molecules; present in all individuals,
irrespective of previous contact with offending agents or
immunogens, and does not change qualitatively or quantitatively after
contact.
Main effector cells of innate immunity are : macrophages,
neutrophils, Dendritic Cells, and natural killer cells, we also have mast
cells.
Relies on recognition of evolutionarily conserved structures on
pathogens, termed pathogen-associated molecular patterns (PAMPs),
through a limited number of germ line-encoded pattern recognition
receptors (PRR) found on immune cells.

Among the PAMPs that present the pathogens are

lipopolysaccharide (LPS) specific to Gram negative bacteria and
peptidoglycan (PGN) specific to Gram positive bacteria.
During inflammation what happens?
• Mast cells release histamine, heparine and cytokines. DCs also release
cytokines.
• Macrophages, neutrophils act as phagocytes.
• Natural killer cells kill infected cells and produced IFN-gamma that
activates macrophages to kill phagocytosed microbes
• Macrophages and dendritic cell move out of infected area to lymph
nodes and act as APCs. This marks the end of innate immune
response.
MAST CELL DENDRITIC CELL
 III. ADAPTATIVE IMMUNE RESPONSE
TO BACTERIAL INFECTIONS
Adaptative immunity to extracellular bacteria
Humoral immunity is the major protective immune
response against extracellular bacteria, and it functions to block infection, to
eliminate the microbes, and to neutralize their toxins.
The effector mechanisms used by antibodies to combat these infections
include:
• neutralization
• Lysis mediated by the complement (classical pathway)
• opsonization and phagocytosis,
• Antibody-dependent cell-mediated cytotoxicity
Neutralization is mediated by high-affinity IgG, IgM;
Opsonization by some subclasses of IgG;
And complement activation by IgM and subclasses of IgG.
1) Neutralisation of microbes and toxins
2) Opsonization and phagocytosis of
microbes
3) Antibody-dependent cellular cytotoxicity
 4) Complement activation
i) Lysis of microbes
ii) Phagocytosis of microbes opsonised with
complement fragments ( example C3b)
 Adaptative immunity to intracellular bacteria
The major protective immune response against intracellular bacteria
is T cell-mediated immunity.
Individuals with deficient cell-mediated immunity, such as patients
with acquired immunodeficiency syndrome (AIDS), are extremely
susceptible to infections with intracellular bacteria.
CD4+ T cells recruit macrophages and activate them through the
actions of CD4O ligand and IFN-y to produce microbiocidal substances
like; nitric oxides, lysosomal enzymes and reactive oxygen species
resulting in killing of phagocy-tosed microbes, and CD8+ cytotoxic T
lymphocytes (CTLs) kill infected cells.
Action of CD8 T cells
Action of CD4 or T helper cells
Activation of B cells
Naïve B cell Matured B cell
 Th2 which
produce IL-4
IV. LES FACTEURS DE VIRULENCES BACTÉRIENNES ET
LEUR ÉCHAPPEMENT AUX MÉCANISMES DE L’HÔTE .

• Un facteur de virulence est une molécule produite par un agent

infectieux (bactéries, virus, mycètes, protozoaires) qui contribue
au caractère pathogène, de ces organismes en leur permettant :
• d'occuper une niche chez l'hôte,(colonisation) ce qui
passe par l'attachement à ses cellules ;
• d'échapper au système immunitaire de l'hôte
(immunévasion) ;
• d'inhiber le système immunitaire de l'hôte
(immunosuppression) ;
• d'absorber les nutriments de l'hôte.
 Typologie

 Les facteurs de virulence acquis agissent de deux manières différentes

pour assurer la survie et la croissance de ces germes :

• ils favorisent la colonisation de l'hôte, comme les adhésines, les

invasines et les facteurs antiphagocytaires ;

• ils affaiblissent ou détruisent l'hôte, comme les toxines, les

hémolysines, les lipases et les peptidases.
Il existe 4facteurs de virulences des bacteries: l’adhésines, facteurs
d’invasion, facteurs antiphagocytaire, intoxination(endotoxines et
exotoxines)
 • Les adhésines sont des protéines
Les adhésines membranaires ou des pili qui
permettent aux bactéries
d'adhérer aux cellules cibles,
. Elles réagissent avec des
récepteurs homologues des cellules
hôtes.
Facteurs d’invasion

Il s'agit d'éléments favorisant la propagation des agents

infectieux à travers les tissus,
par exemple :
- les flagelles, qui assurent la motilité de certains germes
pathogènes, et participent à leur propagation.
Facteurs Les facteurs antiphagocytaires protègent les
antiphagocytaires bactéries de la phagocytose. Ces facteurs sont
de plusieurs ordres :
• une capsule : protéger de :
-Complément, anticorps,
phagocytose;
• la coagulase, sécrétée par
divers microorganismes, dont certains
(staphylocoques dorés), réagit avec
la prothrombine pour former de
la staphylothrombine et
• convertir le fibrinogène en fibrine dans
le plasma sanguin, ce qui a pour effet
d'entourer la bactérie d'une couche protectrice
qui la protège de la phagocytose et du système
immunitaire de l'hôte ;
 Les endotoxines
Les endotoxines sont des toxines thermostables de la membrane
externe de certaines bactéries à Gram négatif.
• Il s'agit du lipide A, constituant du lipopolysaccharide, qui est libéré
lors de la lyse de ces bactéries, et est susceptible d'entraîner un
syndrome de réponse inflammatoire systémique. Ces endotoxine
induisent une série d'effets :
• libération d'interleukine 1 par les macrophages,
• libération de facteurs de nécrose tumorale(TNF)
• liaison du lipide A aux récepteurs des cellules B,
• activation alternative du système du complément ;
Endotoxines
Exotoxine
Les exotoxines sont des toxines sécrétées par des bactéries
vivantes, contrairement aux endotoxines qui sont libérées lors de
la destruction de ces bactéries. Elles sont souvent produites par
des bactéries elles-mêmes infectées par des bactériophages. Elles
agissent de différentes manières :
• les lipases contribuent à la destruction de la membrane
plasmique des cellules cibles ; c'est par exemple le cas de la
lécithinase C, également appelée toxine α de Clostridium
perfringens;
• a toxine cholérique de Vibrio cholerae provoque la diarrhée
aqueuse du choléra ;
Exotoxines
 CASE STUDY
MYCOBACTERIUM TUBERCULOSIS
INTRODUCTION
• Mycobacterium tuberculosis
• rod shaped bacteria and the
causative agent of the disease
tuberculosis.
• It is an air borne disease and
transmitted from person to
person by infected aerosols.
• It is intracellular and mainly
attacks macrophages and
inhibits their apoptosis.
• Riley et al. exposed hundreds of Mtb-susceptible guinea pigs to air
from a ward of Mtb-infected patients continuously for months to
demonstrate airborne transmission of Mtb , indicating that
aerosolization and transmission of Mtb is a rare event. This
observation is corroborated by epidemiologic and modeling data
indicating that the likelihood of transmission of Mtb is proportional to
the duration of exposure to an infectious person and inversely
proportional to the volume of space within which exposures occur.
• Despite the availability of a vaccine for nearly 100 years, the global
infection rate of Mycobacterium tuberculosis (MTB) is still
approximately one in three people .
• However, the pathogen is eliminated in only 10% of people, while it
can escape during the process of infection and remain dormant in old
lesions, so the infection is hard to control. A decline in immunity may
lead to the resuscitation of MTB in response to perturbations of the
immune response and active tuberculosis ensues
host immune response to Mtb
• When inhaled, Mtb encounters a first line of defense consisting of
airway epithelial cells (AECs) and “professional” phagocytes
(neutrophils, monocytes and dendritic cells) . If this first line succeeds
in eliminating the Mtb rapidly, the infection aborts . Otherwise,
phagocytes are infected and the Mtb reproduces inside the cells,
initially causing few, if any, clinical manifestations . The establishment
of the infection, the development of active TB (ATB) rather than latent
TB infection (LTBI) and the eventual evolution of LTBI to ATB depends
on the complex relation between bacterial and host factors.
 Macrophages and CD4+ T lymphocytes, together with granuloma
formation, are traditionally considered the pillars of immune
defense against Mtb and their role stands out clearly
• Mtb infects the alveoli eptihelial cells which then trigger the immune
reaction. Infected cells will trigger a local inflammatory response that
will attract immune cells into the site of infection. These cellular
aggregates, that contain many cell types, form the granulomas, the
pathological hallmarks of TB
• The successful establishment of Mtb infection largely depends on its
early interactions with host innate immune cells, such as
macrophages, dendritic cells (DCs), neutrophils and natural killer (NK)
cells.These immune cells express a variety of pattern recognition
receptors (PRRs) that reognise PAMPS on the surface of the Mtb.
Innate Immunity
Airway Epithelial Cells
AECs are the first cells to come in contact with Mtb. Beyond their major
role as physical barriers, they display several immunological functions
and are traditionally considered as “non-professional” immune cells.
Through pattern recognition receptors (PRRs), AECs can perceive the
presence of Mtb and consequently modulate the composition of the
airways surface liquid improving its antimicrobial capacity .
Moreover, PRRs activation leads to the production of inflammatory
cytokines and to the activation of mucosal-associated invariant T cells
stimulating IFN-γ and tumor necrosis factor (TNF)-α production .
Innate Immune cell Role
Macrophages primary cellular niche for Mtb during both early and
chronic infection. Macrophages can eliminate Mtb via
multiple mechanisms, including the production of
oxygen and nitrogen components and cytokines,
phagosome acidifification and the autophagy of
intracellular Mtb, among other processes.

Dendritic cells DCs play a central role in Mtb antigen presentation and
are thus critical in bridging innate and adaptive
immunity.
neutrophils Release factors during respiratory bursts, such as
elastase, collagenase and myeloperoxidase,
indiscriminately damage bacterial and host cells. Thus,
neutrophils constitute apotent population of effector
cells that can mediate both antimycobacterial activity
and immunopathology during Mtb infection.

Natural killer cells NK cells are granular innate lymphocytes that possess
potent cytolytic capacity. NK cells act early during
infection and are not MHC-restricted
Adaptative immune system

• The immune response of T lymphocytes begins at the moment that

Mtb spreads inside the lymph nodes but its arousal lays in the early
activation of the innate immune system. Inside the lymph nodes, T
lymphocytes undergo a process of activation and expansion of the
specific populations for the Mtb antigens.
• Lymphocytes T CD4+
• Lymphocytes T CD8+
Humoral Adaptive Immunity

• The role of humoral adaptive immunity in TB is extremely uncertain .

Complement-mediated opsonization does not alter Mtb survival. High
levels of antibody titers correlate with more serious conditions of
infection and disease, and passive immunization with antibodies does
not confer protection . Patients with a defective antibody-production
mechanism and/or B lymphocyte defect are not particularly at risk of
TB infection.
Pathogen
recognition by
innate immune
cells triggers a
cascade of cellular
events, such as
• phagocytosis
• Autophagy; Autophagy is a homeostatic and inducible intracellular
processby which cells eliminate damaged organelles, protein
aggregates and intracellular pathogens.
• Apoptosis ; apoptosis is a highly regulated and controlled process of
cell death. The twobest-understood activation mechanisms of
apoptosis are the extrinsic pathway and the intrinsic pathway (also
called the mitochondrial pathway).
• inflammasome activation.
• During microbial infection, certain members of the NLR (Nod-like receptors)
family and the cytosolic DNA sensor assemble into a multimeric inflammasome
complex to mediate the activation of inflammatory caspase-1. This, in turn,
leads to maturation of the pro-inflammatory cytokines IL-1β and IL-18 and
induction of pyroptosis, which is a form of necrotic and inflammatory
programmed cell death that is induced by inflammatory caspases.
Inflammasomes are cytosolic multiprotein oligomers of the innate immune
system responsible for the activation of inflammatory responses inorder to
control or eliminate invading pathogens and to augment antigen presentation,
thereby contributing to the induction of adaptive immunity
PATHOGENESIS OF TUBERCULOSIS
The Immune Escape Mechanisms of
Mycobacterium tuberculosis
• There are various aspects of macrophage-mycobacterium
interactions, such as the binding of MTB to macrophages via surface
receptors , phagosome-lysosome fusion , mycobacterial growth,
inhibition/damage through free-radical mechanisms (reactive oxygen
and nitrogen intermediates) , cytokine-mediated mechanisms to
recruit accessory immune cells for a local inflammatory response and
the presentation of antigens to T cells for the development of
acquired immunity.
Escape route example of Mechanism by M. tuberculosis

Inhibits phgagosome lysosome fusion Secrete sulfatides that have an anti-fussion

M. tuberculosis Inhibits the Maturation of
Phagolysosomes
effect
Rab5 protein of mtb causes maturation
arrest of phagosome. Recruitment and
retention of coronin-1 on phagosomal wall
causes escape of bactericidal effect of
macrophage by Mtb

M. tuberculosis Inhibits the Acidifification of Blockage of protein pumps(H-ATPase)

Phagolysosomes resulting in lack of acidification.
Production of ammonia to neutralise intra-
lysosomal content

M. tuberculosis Inhibits Oxidative Stress and Secretion of oxidative stress proteins such
the Function of Reactive Oxygen and as Ahpc (an alkalyl hydroxyperoxidase
Reactive Nitrogen Intermediates reductase ) that detoxifies organic hydrogen
peroxidesSecreation of nitric oxide
reductase NarG which quenches reactive
nitrogen species
• Apoptosis; Production of anti-apoptotic Mtb antigens include PtpA,
NuoG, PknE, SecA2, SodA, SigH, MPT64 and Rv3354
• TRIM27 restricts the survival of mycobacteria in macrophages by
promoting cell apoptosis, whereas Mtb PtpA antagonizes those
TRIM27-promoted innate immune responses by competitively binding
to the RING domain of TRIM27, indicating a dynamic antagonism
between Mtb and its host during infection.
TREATMENT

• Isoniazid, rifampicin, pyrazinamid and ethambutol for two months

then isoniazid and rifampicin alone for four months.
CONCLUSION