Transcript Antimicrobial responsesx

THE IMMUNE RESPONSES TO
EXTRACELLULAR PATHOGENS
PATHOGENS
Viruses, Bacteria, Fungi
Parasites
Unicellular protozoa
Multicellular worms
REQUIRES HIGH INITIAL DOSE FOR INFECTION
ESCAPE MECHANISMS TO AVOID DEFENSE MECHANISMS
HUMAN BODY
RESOURCE RICH ENVIRONMENT FOR PATHOGENS
DEFENSE MECHANISMS
Physical barriers/Innate immunity – STOP MOST INFECTIONS WITHOUT CALLING
Adaptive immunity
Diseases – Medical practice
DISEASE Innate immunity fails to terminate infection
Activation of adaptive immunity
Successful evasion and subversion of the immune
system by pathogens
Examples of extracellular bacteria
Physical barriers separate the body from its
external environment
Movie: Mucosal immune tolerance and immune response
Defence factors of the mouth
Secretory immunoglobulins become attached to
the mucus, where they stand ready to bind
commensal and pathogenic organisms
The systemic and mucosal immune systems use
different strategies for coping with infections
Neutrophil extracellular traps
Dentoalveolar abscess
Exotoxins vs. endotoxin
Exotoxins – secreted by living bacteria
- Cytotoxicity of various mechanisms
- Inhibition of various cellular functions
Endotoxin – released by dying cells
- Cell wall – Gram (-) LPS
- Induction of cytokines
septic shock
Sepsis/Septicemia
TNF-α→platelet activating factor by
endothelial cells→clotting, blockage
restricts plasma leakage & spread of
infection
Infection of blood – Sepsis
Sysemic edema, decreased blood
volume, collapse of vessels
Disseminated intravascular
coagulation, multiple organ failure
Adaptive immune responses to extracellular microbes
Cellular and Molecular Immunology, 7th ed., 2014 Elservier
Functions of Th17 cells
Cellular and Molecular Immunology, 8th ed., 2015 Elservier
MECHANISMS OF PROTECTION
INNATE IMMUNITY
Complement activation
Gram (+) peptidoglycan

Gram (-)
LPS
Mannose + MBL
alternative pathway

alternative pathway

lectin pathway
Phagocytosis
Antibody and complement mediated opsonization
Inflammation
LPS
Peptidoglycan


TLR macrophage activation
TLR macrophage activation
ACQUIRED IMMUNITY
Humoral immune response
Targets: cell wall antigens and toxins
T-independent
T-dependent
 cell wall polysaccharide
 bacterial protein
 isotype switching
 affinity maturation
 memory B cells
Cellular Immune response: Th17 cells
Evasion mechanisms of extracellular bacteria
Proteins to increase adhesion
Bordetella pertussis
Inhibition of phagocytosis
Str. pneumoniae M protein, S. aureus coagulase enzyme - fibrin capsule
Antigenic variants
Neisseria gonorrhoeae (pilin)
Inhibition of complement-dependent cell lysis
Str. pyogenes
Sialic acid rich capsule inhibits activation of the alternative complement pathway
Some Gram-neg bacteria have a lipidA component that inhibits the MAC complex
Scavenging of reactive oxigen intermediates
Catalase positive staphylococci
Degradation of IgA antibodies
Neisseria, H. influenzae
Bacterial superantigens activate CD4 T cells by cross-linking
MHC class II molecules with α:β T-cell receptors and
CD28 co-stimulatory molecules in the absence
of antigenic peptides
Subversion of the immune system by extracellular bacteria
Superantigens of staphylococci – staphylococcal enterotoxins (SE)
PROFESSIONAL APC
2
2
1
1


– toxic shock syndrom toxin-1 (TSST-1)
Mimic specific antigen
Induce massive but ineffective T-cell activation and
proliferation in the absence of specific peptide
2 – 20% of CD4+ T-cells, which are not specific for the
bacteria but share V get activated and develop to effector
T-lymphocytes
Over production of cytokines – IL-1, IL-2, TNF-α
Systemic toxicity – shock
T cell
Suppression of adaptive immunity by
apoptosis
THE IMMUNE RESPONSE AGAINST
INTRACELLULAR BACTERIA
Examples of intracellular bacteria
Cooperation of CD4+ and CD8+ T cells in defense against
intracellular microbes
Cellular and Molecular Immunology, 7th ed., 2014 Elservier
Immune responses to Listeria monocytogenes
MHC I
MHC II
IL-12
NK cell
CD4+ Th1 cell
CD8+ cytotoxic T cell
IFNγ
Macrophage activation
Escape of bacteria to
the cytoplasm
listeriolysin
Lysis of macrophage
Killing of bacteria in the macrophage
Innate and adaptive immunity to intracellular bacteria
Cellular and Molecular Immunology, 7th ed., 2014 Elservier
Infection by Mycobacterium tuberculosis
Mutual activation of macrophages and effector
lymphocytes in the immune response to intracellular
bacterial infections
Granulomatous disease can become
quite extensive. Here are numerous
confluent granulomas in a case of
pulmonary tuberculosis
Pulmonary granulomas. Granulomatous inflammation
typically consists of epithelioid macrophages, giant
cells, lymphocytes and fibroblasts. There may be
some neutrophils.
Role of T cells and cytokines in determining
the outcome of infections
Cellular and Molecular Immunology, 7th ed., 2014 Elservier
Infection by mycobacterium leprae
„Lepromatous” skin blebs
Infectious bacteria
Suppressed Th1 response
No efficient protection
Small lesion
Minimal response
Tuberculoid
Vigorous T-cell response
Local inflammation
Balanced protection Granulomas
Peripheral nerve damage
SPECTRAL DISEASE DEPENDING ON THE IMMUNE RESPONSE
Genetically/environmentally determined Th1/Th2
The immune response to intracellular bacteria
INNATE IMMUNITY
Phagocytosis –
neutrophil granulocyte
macrophage
NK cells –
direct activation of macrophages by IFNγ
macrophage – mediated activation by IL - 12
ACQUIRED IMMUNITY
Cell mediated –
macrophage activation by CD4+ Th1 cells
activation of CD8+ cytotoxic T cells
Granuloma -
isolation of bacteria, which resist elimination
localized inflammatory response
Movie
Allthree
Evasion of immune mechanisms by intracellular bacteria
Inhibition of phagolysosome formation
Mycobacterium tuberculosis
Legionella pneumophilia
Scavenging of reactive oxigen intermediates
Mycobacterium leprae (phenolic glycolipid)
Disruption of phagosome membrane,
escape into cytoplasm
Listeria monocytogenes
(listeriolysin protein)
THE IMMUNE RESPONSES TO
VIRUSES
Mechanisms of induction of type I interferons by viruses
Cellular and Molecular Immunology, 7th ed., 2012 Elsevier
Major functions of the type I interferons
Activation of NK cells by receptors of innate and
adaptive immunity
Antibody Dependent Cellular Cytotoxicity (ADCC)
Induction of T cell responses to virus-infected cells
Cellular and Molecular Immunology, 7th ed., 2012 Elsevier
Kinetics of various anti-viral mechanisms
Cellular and Molecular Immunology, 7th ed., 2012 Elsevier
Innate and adaptive immune responses against viruses
Cellular and Molecular Immunology, 7th ed., 2012 Elsevier
Evolution of new influenza variants by antigenic drift
Generation of new influenza virus strains
by genetic recombination (antigenic shift)
Cellular and Molecular Immunology, 7th ed., 2012 Elsevier
Mechanisms by which viruses inhibit antigen processing
and presentation
Cellular and Molecular Immunology, 7th ed., 2012 Elsevier
The immunopathogenesis of HIV
infection
The life cycle of HIV
After infection with HIV there is a gradual
extinction of CD4 T cells
The natural course of an HIV infection and the immune
response against it
Some opportunistic infections that kill patients with AIDS
Candida infection in oral cavity and esophagy
Three main transmission routes for HIV have been
identified
Sexual
The risk of female-to-male transmission is 0.04% per act
and
male-to-female transmission is 0.08% per act.
Blood products
Blood transfusion, intravenous drug users, piercings, tattoos
Mother-to-child
The risk of transmission is 20-33 %.
Perinatal > intrauterin > breast feeding
Broadly neutralizing antibodies recognize four epitopes
of the HIV envelope glycoprotein that trimerizes
to form the viral spike