Transcript 30_Intracellular bact

THE IMMUNE RESPONSE AGAINST
INTRACELLULAR BACTERIA
Examples of intracellular bacteria
Intracellular replication of Listeria monocytogenes
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
Cooperation of CD4+ and CD8+ T cells in defense against
intracellular microbes
Cellular and Molecular Immunology, 7th ed., 2014 Elservier
Mutual activation of macrophages and effector
lymphocytes in the immune response to intracellular
bacterial infections
Infection by Mycobacterium tuberculosis
Effector functions of macrophages
Cellular and Molecular Immunology, 7th ed., 2014 Elservier
Infected macrophages send signals that recruit
nearby lymphocytes
Uninfected macrophages and lymphocytes
surround the infected cells
They encase the infected cells in a “cage” of
“extracellular matrix” proteins
where they can stay for years!
We are actually quite good at keeping TB at bay
only one-third of exposed patients
will become infected and only 3-5%
develop TB in the first year
Clin Microbiol Rev. 2003 July; 16(3): 463–496.
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
„Lepromatous” skin blebs
Tuberculoid form
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 pneumophila
Scavenging of reactive oxigen intermediates
Mycobacterium leprae (phenolic glycolipid)
Disruption of phagosome membrane,
escape into cytoplasm
Listeria monocytogenes
(listeriolysin protein)
THE IMMUNE RESPONSE TO PARASITES
Unicellular protozoa
Plasmodium (malaria)
Toxoplasma
The principal innate immune response to protozoa is phagocytosis,
but many of these parasites are resistant to phagocytic killing and
may even replicate within macrophages.
Inoue SI et al. (2013) Front Immunol 4:258.
The life cycle of Plasmodium
Immune response
Malaria
TH1 cells – secretion of
cytokines
Role of antibody?
Effector mechanism
IFN-g, TNF activate
macrophages, neutrophils
to kill parasites
Life cycle of Toxoplasma
Immune response
Toxoplasma
Strong TH1 response
Effector mechanism
IFN-g, TNF activate
macrophages, neutrophils
to kill parasites
Toxoplasma gondii, the „brain-hacker” parasite
The genome of T. gondii encodes two aromatic
hydroxylases that allow the parasite to synthesize
dopamine. This may influence the behavior of
seropositive indviduals (e.g. increased risk-taking).
Recently, T. gondii infections have been
correlated with many neuropsychiatric diseases:
- schizophrenia (38 large cohort studies, strong
positive correlation);
- obsessive-compulsive disorder (7 large cohort
studies, positive correlation)
credit: DJP Feruson/University of Oxford
Multicellular parasites (helminths)
Trichina worm - Trichinella spiralis
Broad fish tapeworm - Diphyllobothrium latum
They are too large to be ingested by phagocytes.
Immune response
Effector mechanism
TH2 cells --> IL-4, IL-5 Eosinophils kill IgE-coated
--> IgE, eosinophils
parasites (form of ADCC)
Functions of Th2 cells
Cellular and Molecular Immunology, 8th ed., 2015 Elservier
Responses to intestinal helminths
The role of T cell-mediated responses in defense
against helminths
Eosinophils are better at killing helminths than are other
leukocytes; the TH2 response and IgE provide a mechanism
for bringing eosinophils to helminths and activating the cells.
Activated eosinophils attack parasites
Eosinophil granulocytes
Mast cells
Features that characterize a protective immune
response to a helminth infection
Escape mechanisms of parasites
• Poor antigenicity
• Variations in surface structure – gene conversion
• Alternating expression (Trypanosoma)
• Privileged sites isolated from the immune system (cyst)
• Intracellular (Leishmania, Toxoplasma)
• Inhibition of phagosome and lysosome fusion (Toxoplasma)
• Antigen masking by bound self proteins
• Complement (DAF) like structures