Download Immune responses in viral infections

L.7 / 2016-2017
Microbiology/Immunology
Asst.Prof.Dr. Ifad Kerim Al-Shibly
Microbial immunity
The immune system has developed to protect the host from pathogens and other
foreign substances, self/non-self discrimination is one of the hallmarks of the immune
system. Most pathogens can elicit both an antibody (humoral) and a cell-mediated
response, both of which may contribute to ridding the host of the pathogen. However,
for any particular pathogen one type of immune response whether antibody or a cellmediated immune response may be more important than the other type for the host to
defend against the pathogen.
Defense against infections is mediated by the early reactions of innate immunity and
the later responses of adaptive immunity. The immune system is specialized to
generate different effector mechanisms for different types of microbes. The survival
and pathogenicity of pathogens in a host and so the outcome of infections is
determined by the balance between host defenses and the ability of microbes to evade
or resist immunity. Immune responses to microbes are themselves capable of causing
tissue injury (Immunopathology). Antigenic mimicry is where a protein sequence of a
foreign antigen is similar to a self-protein which results in unintentional cross
reactivity of antibodies or T cell epitopes. This pathology can occur long after
infectious agent has been eliminated (e.g. rheumatic fever after strept. infection).
Immune responses in viral infections
Viruses are obligatory intercellular pathogens that replicate within cells. They use the
nucleic acid and protein synthetic machineries of the host cell. It can infect a variety
of cell populations by utilizing normal cell surface molecules as receptors to enter
cell. Infected cells use their major histocompatibility complex molecules to put pieces
of the invading microbes on their surfaces, flagging down cytotoxic T lymphocytes to
destroy the infected cells. ☺The primary defense against viruses is cell-mediated
responses CMI, the cytotoxic T lymphocyte. Antibodies also can assist in the
immune response by opsonizing and blocking viruses before they have a chance to
enter cells.
Innate immunity:
1. The principal mechanisms of innate immunity against viruses are inhibition of
infection by interferons (INF). Interferons are antiviral proteins, or glycoproteins
produced by several types of cells in response to viral infection: INFα by leucocytes,
INFβ by fibroblast, and INFγ by natural killers (NK) cells. IFNs function to inhibit
viral replication in both infected and uninfected cells.
2. NK cell –mediated killing of infected cells. NK cells are the host adaptation for
killing class I MHC-negative virus infected cells.
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L.7 / 2016-2017
Microbiology/Immunology
Asst.Prof.Dr. Ifad Kerim Al-Shibly
Adaptive immunity:
1. Because antibodies do not get into host cells, they are ineffective against
intracellular pathogens. Antibodies opsonize and neutralize viruses and prevent
infection. Block infectious virus early in course of infection (before entering cells) or
after release from infected cells (prevents cell-to-cell spread).
2. CTLs recognize antigens from the virus that are displayed on the surface of the
infected cell in association with MHC-I and kill the cell thereby preventing the spread
of the infection to neighboring cells. In some latent viral infections (EBV, CMV),
CTLs control but do not eradicate the infection; defective T cell immunity leads to
reactivation of the virus (in HIV, immunosuppression caused by leukemia, treatment
for graft rejection).
Mechanisms of Immune Evasion by Viruses :
1. Antigenic variation (Influenza, HIV, rhinovirus). Viruses can alter their antigens,
influenza viruses show changes in antigenicity(antigenic shifts and drifts). Because of
antigenic variation, a virus may become resistant to immunity generated in the
population by previous infection.
2. Inhibition of the class I MHC antigen processing pathway (e.g. CMV).
3. Different viruses use different mechanisms.
4. Production of immune modulators. Some viruses produce molecules that inhibit
innate and adaptive immunity. EBV produces a protein that is homologous to IL-10
and may function to inhibit CMI. Soluble cytokine receptors may act as “decoys” and
block actions of cytokines (poxviruses).
5. Infection of immune cells (HIV infect CD4 T cells).
Immune responses in bacterial infections
 Intracellular Bacteria:
Intercellular bacteria have the ability to survive and even replicate within phagocytes
where they are inaccessible to circulating antibodies, for example, Mycobacterium
tuberculosis, the causative agent of tuberculosis. Elimination of intracellular bacteria
requires immune responses that are very different from the responses against
extracellular bacteria. By living inside a host cell they avoid many effective host
immune strategies (antibodies, phagocytosis, and complement). However these
bacteria need to have strategies to escape lysosomes. Some intracellular bacteria
choose to escape from the endosome and replicate in cytoplasm like viruses. Others
stay in protected endosome and alter it in order to prevent fusion with lysosome.
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L.7 / 2016-2017
Microbiology/Immunology
Asst.Prof.Dr. Ifad Kerim Al-Shibly
Innate immunity:
The major defensive and protective immunological response against intracellular
bacteria is CMI. During the innate immune response to intracellular bacteria
phagocytes ingest and attempt to destroy it. Phagocytosis occurs initially by
‫٭‬neutrophils and later by ‫٭‬macrophages, intracellular bacteria are resistant to
degradation within phagocytes. ‫٭‬NK cells function by two means direct killing of
infected cells and by activating of macrophages through the production of IFN-γ.
Adaptive immunity:
1. Cell-mediated immune response (CMI): is the major specific immune response
against intracellular bacteria. Helper and cytotoxic T cells cooperate in cell-mediated
immunity against intracellular microbes. There are two types of cell-mediated
reactions: killing of phagocytosed intracellular bacteria as a result of macrophage
activation by ‫٭‬Th1 cell – derived cytokines, and lysis of infected cells by ‫٭‬CTLs.
Th1 cells, is the primary defense against intracellular bacteria that live within vesicles
(phagosomes). Th1 cells recognize antigen from the bacteria that are expressed on the
surface of infected antigen presenting cells in association with MHC-II and release
cytokines that activate these cell. Th1 cytokines IFN-γ, TNF-α activate macrophages.
Once activated, they can then kill the pathogen. Activated macrophages kill
phagocytosed microbes by producing microbicidal reactive oxygen intermediates,
nitric oxide and lysosomal enzymes. The same activated helper T cells, if present in
the vicinity of cytotoxic T cells, provide cytokine signals (IL-2) that stimulate
cytotoxic T cells to proliferate. Activation of cytotoxic T cells leads to their
proliferation and differentiation into effector cytotoxic T cells capable of cytolytic
functions. The most specific feature of cytotoxic cell differentiation is the
development of membrane bound cytoplasmic granules that contain proteins,
including perforins and granzymes. CTLs also express a membrane protein called Fas
ligand (FasL), which binds to its target protein Fas that is expressed in many cell
types. The production of perforines and granzymes, and the interaction of Fas-FasL
results in apoptosis and death of the target cell.
2. Antibodies (AMI) /Th2 cytokines help with protection from reinfection but may be
less effective for elimination.
Mechanisms of Immune Evasion by Intracellular Bacteria:
Intracellular bacteria’s ability to resist elimination by phagocytes is an important
mechanism for survival and evasion of the immune response. Some intracellular
bacteria do this by inhibiting phagolysosome fusion, while others produce hemolysin
that blocks bacterial killing in macrophages.
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L.7 / 2016-2017
Microbiology/Immunology
Asst.Prof.Dr. Ifad Kerim Al-Shibly
 Extracellular Bacteria :
Extracellular bacteria are capable of replicating outside of the host cells. They are fast
replicating to avoid elimination. They cause disease by two principle mechanisms:
1.They induce inflammation. 2. Many of these bacteria produce toxins (endotoxins
and exotoxins). The immune responses against extracellular bacteria are aimed at
eliminating the bacteria and at neutralizing the effects of their toxins.
Innate immunity:
1. Phagocytosis by macrophages and neutrophils.
2. Complement activation and inflammation. Complement activation leads to
phagocytosis and lysis. Gram positive bacteria contain peptidoglycan that activate
alternative complement cascade, complement components induce inflammation.
Adaptive immunity:
1. Humoral immunity (AMI) is the principle specific immune response against
extracellular bacteria. Strong IgM responses are caused by polysaccharides.
Antibodies IgM and IgG against bacteria surface antigens and toxins stimulate three
types of effector mechanisms: opsonization, toxin neutralization, and complement
fixation.
2. Cellular immunity: Th2 cytokines important for B cell activation. Th1 CKs have
some role for activating macrophages.
Mechanisms of Immune Evasion by Extracellular Bacteria:
1. IgA specific proteases (e.g. niesseria).
2. Antigenic variation: genetic variation of the surface antigen to evade specific
immunity (e.g. pilli variation in salmonella).
3. Polysaccharide capsule gives resistance to phagocytosis.
4. Molecular mimicry: Pertussis toxin mimic selectins and can block selectin activity
and leukocyte recruitment to site of infection.
5. The capsule contain one or more sialic acid residues that inhibit complement
activation by the alternative pathway.
Immune responses in fungal infections
Fungi are eukaryotes that tend to cause serious infections primarily in individuals
with impaired immunity.
Innate Immunity:
The principal mediator of innate immunity against fungi is the ‫٭‬neutrophils and
‫٭‬macrophages. They liberate fungicidal substances, by the production of toxic
molecules through oxygen-dependent mechanisms - nitric oxide, reactive oxygen
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L.7 / 2016-2017
Microbiology/Immunology
Asst.Prof.Dr. Ifad Kerim Al-Shibly
intermediates (ROIs), and reactive nitrogen intermediates (RNIs) forming the
respiratory burst. Fungi have developed evasion mechanisms to inhibit the respiratory
burst through the production of specific scavengers of oxidative killing by
phagocytes- catalase, mannitol and melanin. The oxygen-independent mechanisms
consist of degranulation and release of neutrophil cationic peptides, lysozyme,
antimicrobial peptides- defensins, arachidonic acid and iron sequestration. The
phagocytes also secrete cytokines and chemokines which are involved in the
protective immune response in order to phagocytose fungi for intracellular killing.
Adaptive immunity:
Cell-mediated specific immunity is the major defense against fungal infections. Fungi
that are present intercellularly in macrophages are eliminated by the same cellular
mechanisms that are effective against intracellular bacteria (see above). CMI
activated by Th1 cells are the major mechanisms of adaptive immunity against fungal
infection. Generally Th1 response is protective to the host during fungal infection,
while Th2 response is detrimental.
Immune responses in parasitic infections
In infectious disease terminology, “parasitic infection” refers to infection with animal
parasites, such as protozoa, helminthes, and ectoparasites. Humans are only part of
the complex life cycle of parasites.
Innate Immunity:
Protozoa and helminthic parasites that enter the blood stream or tissue are often able
to survive and replicate because they are resistant to host innate immune responses.
Parasites in humane host are usually resistant to complement. Macrophages can
phagocytose protozoa, but the tegument of helminthic parasites makes them resistant
to the cytocidal effects of both neutrophils and macrophages.
Adaptive immunity:
Different parasites elicit quite distinct specific immune responses. CMI is the
principal defense against protozoa that survive within macrophages. Protozoa that
replicate inside cells and lyse host cells stimulate specific ‫٭‬CTL responses, similar to
cytopathic viruses. ‫٭‬Th2 cells also play a vital role in immunity to helminthic
infections since they induce inflammatory reactions that are dominated by
eosinophils and mast cells. Th2 cells, secrete IL-4 and IL-5. IL-4 stimulates the
production of helminthic-specific IgE antibodies, which opsonize the helminthes. IL5 activates eosinophils, which bind to IgE coated on helminthes (type of ADCC).
Eosinophil granules contain major basic protein and eosinophil cationic protein; these
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L.7 / 2016-2017
Microbiology/Immunology
Asst.Prof.Dr. Ifad Kerim Al-Shibly
proteins are toxic to several parasites. Degranulation of these contents by ADCC
leads to death of the helminth.
Mechanisms of Immune Evasion by Parasites:
1. Some parasites survive and replicate inside cells.
2. Antigen masking is an effective form of immune response evasion by parasites.
Some parasites develop cysts shedding their antigenic coats e.g. Entameoba
histolytica that are resistant to immune responses.
3. Parasites can develop a tegument that is resistant to damage by antibodies and
complement or CTLs. Parasites become resistant to immune system during their
residence in the host, schistosoma larva travel to the lungs of infected host and
develop a thick tegument to resist the action of CTLs and complement system.
4. Antigenic variation: parasites change their surface Ag during their life cycle in the
infected host: e.g. Plasmodium.
5. Inhibition of host immune response by induction of T cells anergy (in ability to
response), e.g. filarial infection.
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