CL3 (3).ppt

Immune response to Infectious
Diseases

 Defense against microbes is mediated by both innate
and adaptive immunity
 Immune system responds in specialized ways to
specific types of microbes
 Survival and pathogencity of microbes influenced by
their ability to evade or resist protective defenses
1.Introduction

Infection and immunity
 Pathogens
 Extracellular and intracellular bacteria
 Viruses
 Parasites
 Funguses and yeasts
 Host immune responses
 Innate immunity
 Adaptive immunity
 Pathogen/host interactions
 Mechanisms of survival and evasion
Introduction cont…

 Distinct effector responses obtained are dependent on
 Site of entry,
 Route of spread
 Tissue specificity, and
 Transmission
 Disease or tissue injury can be the consequence of the
 Pathogenicity of microbe as well as
 The host immune response itself
Introduction

2. Immune response to Viral Infections
 A number of specific immune effector mechanisms,
together with nonspecific defense mechanisms, are
called into play to eliminate an infecting virus
i. Innate immune response to viral infection
 The innate immune response to viral infection is
primarily through the induction of type I interferons
(IFN-alpha and IFN- beta) and the activation of NK
cells

Immune response to Viral Infections
i.i. Interferon
 A group of proteins produced in response to virus
infection which stimulates cells to make proteins that
block viral transcription, and thus protects them from
infection
 Double stranded RNA (dsRNA) produced during the viral
life cycle can induce the expression of INF-α and IFN-β
by the infected cell

 Monocytes , macrophages & fibroblasts also synthesize
interferon
 IFNs have no direct effect on extracellular virus
 INFs activity is not specific
Immune response to Viral Infections cont…

Immune response to Viral Infections ...
 Anti-viral activity of interferons (IFNs)
 IFN- α and IFN- β can induce an antiviral response or
resistance to viral replication by binding to the IFN α/β
receptor.
 Once bound, IFN- α and IFN- β activate the JAK-STAT
pathway, which in turn induces the transcription of
several genes
 One of these genes encodes an enzyme known as 2’-5’-
oligo-adenylate synthetase [2-5(A) synthetase], which
activates a ribonuclease (RNAse L) that degrades viral
RNA.

Immune response to Viral Infections ..
 IFN α/β binding induces a specific protein kinase called
dsRNA-dependent protein kinase (PKR), which inactivates
protein synthesis, thus blocking viral replication in
infected cells
 The binding of IFN- α and IFN- β to NK cells induces lytic
activity, making them very effective in killing virally
infected cells.

NK cells
 Destroy some virus-infected cells, and are not MHC
restricted
 Natural killer cell lyses virally infected cells

ii. Specific immune response
Humoral immunity
 Anti-viral antibodies :
 prevent spread during acute infection
 protect against re infection
 Block infection by preventing the binding of viral
particles to host cells.
 Secretory IgA in mucous secretions plays an
important role in host defense against viruses by
blocking viral attachment to mucosal epithelial
cells

 Virus neutralization:- In viraemic infections, antibodies
neutralize virus
 preventing its penetration by binding to epitopes that
are necessary to mediate fusion of the viral envelope
with the plasma membrane
e.g. Poliovirus, mumps, measles, rubella

 Antibodies or complement destroy free virus particles
directly by:
 Aggregation of virus and opsonization to facilitate
Fc- or C3b-receptor–mediated phagocytosis of the
viral particles

Cell mediated immunity(CMI)
 Once an infection is established, CMI mechanisms
are most important in host defense.
 In general, CD8+ TC cells and CD4+ TH1 cells are
the main components of cell-mediated antiviral
defense

 Activated TH1 cells produce a number of cytokines,
including IL-2, IFN-gamma and TNF
 IFN-gamma acts directly by inducing an antiviral
state in cells.
 IL-2 acts indirectly by assisting in the recruitment
of CTL precursors into an effector population.
 Both IL-2 and IFN-gamma activate NK cells

 CTLs kill virus infected cells directly after recognition
of viral antigens on cell surface in association with
MHC I
 TH-cells stimulated by viral antigens release cytokines.
Cytokines attract and activate macrophages to kill
virus infected cells

 Antibody-dependent cell mediated cytotoxicity (ADCC):
 Antibody binds to virus infected cells such cells are
lysed by NK cells and macrophages
Immune evasion by viruses
 Viruses can evade host defenses
 Overcome anti - viral effect of INFs by blocking the
action of protein kinase
Example: Hepatitis C virus

 Inhibition of antigen presentation by infected host cells.
 ICP47, HSV protein
 effectively inhibits the human transporter molecule
needed for antigen processing
 Inhibition of TAP blocks antigen delivery to class I
MHC thus preventing presentation of viral antigen to
CD8+ T cells

 Reduce surface expression of MHC-I, inhibiting antigen
presentation to CD8+ T cells.
Example : Adenoviruses & CMV
 Reduce MHC -II levels , thus blocking the function of
antigen-specific antiviral helper T cell.
Example: Measles ,CMV & HIV

 A large no. of viruses cause generalized immnodepression
Example : mumps , measles, EBV., CMV.,& HIV.
 Escape immune attack by constantly changing their
antigen (antigenic variation)
Example: influenza virus, rhinoviruses and HIV

Summery on Mechanisms of humoral and cell-mediated
immune responses to viruses
Source: Kuby Immunology 2007 5th
ed

a. Immunity to extracellular bacteria
1- The innate immunity:
a- Complement activation
b- Phagocytosis
c- The inflammatory response
2- The acquired immune responses:
a- The humoral mechanisms (antibodies) “main role”
b- Cell mediated immune response “less role”
3 Immune response to Bacterial Infections

 Antibody to a bacteria toxin may bind to the toxin and
neutralize it; the antibody-toxin complexes are then
cleared by phagocytic cells.
 In the case of some bacteria notably, the gram-negative
organisms complement activation on bacterial surfaces
can lead directly to lysis of the organism
Immune response to Bacterial Infections

 Antibody and the complement split product C3b bind to
bacteria, serving as opsonins to increase phagocytosis.
 The complement split products C3a, C4a, and C5a generated
by antibody initiated complement activation,
 induce local mast cell degranulation, releasing substances
that mediate vasodilation and extravasation of lymphocytes
and neutrophils thereby contributing to the buildup of
phagocytic cells at the site of infection.

 Other complement split products are chemotactic for
neutrophils
ed

ii- Cell mediated immune mechanisms:
 Microbes are internalized by APCs and presented to TH
 TH cells are activated and release cytokines which;
 Activate phagocytosis their microbicidal functions
 Stimulate antibody production
 Induce local inflammation
Immune response to Bacterial infections cont…

b. Immunity to intracellular bacteria
 Innate immunity is not very effective against
intracellular bacterial pathogens.
 Intracellular bacteria can activate NK cells, which, in
turn, provide an early defense against these bacteria.
 Intracellular bacterial infections tend to induce a
CMI response, specifically, delayed type
hypersensitivity.
Immune response to Bacterial Infections cont…

 In this response, cytokines secreted by CD4+ T cells are
important—notably IFN, which activates macrophages to kill
ingested pathogens more effectively.
 Killing of phagocytosed bacteria as result of
 macrophage activation by T cell derived cytokines
 by direct lysis of infected cells
 by CD8+ cytotoxic T lymphocytes.

 A pathogenic outcome of chronic T cell and macrophage
stimulation to intracellular bacteria can be the formation
of granulomas.
ed

Mechanisms of escape of bacteria from immune response
 Existence of polysaccharide capsules
 Excretion of toxins (eg.streptolysins toxic for
neutrophils)
 Pathogen variability
 Persistence in cells
 Induction of cell apoptosis (shigella flexneri)

 Blockage of cell lysosome action (mycobacterium )
 Inactivation of complement components
 Enzymatic inhibition of active oxygen radicals (S.aureus)
 ‘’Hiding” from immune cells in other, such as epithelia
 Ability to interfere with the immune reactions

Host immune responses to bacterial infection
and bacterial evasion mechanisms
Source: Kuby. Immunology 2007 5th
ed).

4. Immune response to fungal infections
 Fungal infections are normally a superficial nuisance
(e.g. ringworm), but a few fungi can cause serious
systemic disease, usually entering via the lung in the
form of spores
 The outcome depends on the degree and type of
immune response, and may range from an unnoticed
respiratory episode to rapid fatal dissemination or a
violent hypersensitivity reaction

 Immune response to fungi consist mainly of :
1) Innate immunity is mediated by
 Neutrophils and macrophages
 Fungi are readily eliminated by phagocytes
 Activated neutrophils are critical in the defense against
disseminated candidiasis and aspergillosis
Immune response to fungal infections cont…

2) Acquired immunity (cell mediated immunity)
 CMI acts in a manner similar to its action against
intracellular bacteria
 Cell-mediated immunity predominates in protection
against cryptococcosis, histoplasmosis and mucosal
Candidia albicans infection

 In general, the survival mechanisms of successful fungi
are similar to those of bacteria: antiphagocytic capsules
(e.g. Cryptococcus), resistance to digestion within
macrophages (e.g. Histoplasma, etc.), and destruction of
polymorphs (e.g. Coccidioides).

5.Immune response to Protozoan Diseases
 Both humoral and CMI responses have been implicated
in immunity to protozoan infections.
 In general, humoral antibody is effective against blood-
borne stages of the protozoan life-cycle, but once
protozoans have infected host cells, cell-mediated
immunity is necessary.

 Similar process to that of bacteria
 Macrophages must be activated by T cells to enhance
killing mechanism
 Intercellular protozoa like malaria also need CMI
 Large protozoa utilize antibody mediated response
Immune response to Protozoan Diseases cont…

 Protozoans escape the immune response through several
mechanisms.
 Trypanosoma brucei—are covered by a glycoprotein
coat that is constantly changed by a genetic switch
mechanism.
 Others (including Plasmodium) slough off their
glycoprotein coat after antibody has bound to it.
Immune response to Protozoan Diseases cont…

Immune response to Diseases Caused by
Parasic Worms (Helminths)
 Helminths are large parasites that normally do not
multiply within cells.
 Although helminths generally are attacked by
antibody-mediated defenses, these may be
ineffective.

Cont…
 A cell-mediated response by CD4+ T cells plays a
critical role in the response to Schistosoma
 CMI in response to helminthic parasites is mediated
by TH2 cells that stimulate the production of IgE and
activation of eosinophils.

Helminth evasion of immune responses
 Antigenic disguise – parasites synthetise host-like
antigens to mask their own foreigness. Alternatively
they absorb host molecules to their surfaces
(Schistosomes)
 Concomitant immunity or premunition – worms live in
host for years with no evidence of immune response.
Cont…

Summary
 The immune response to viral infections involves both
humoral and cell-mediated components.
 Antibody to a viral receptor can block viral infections
of host cells.However, a number of viruses, including
influenza, are able to mutate their receptor
molecules and thus evade the humoral antibody
response
 Once a viral infection has been established, cell-
mediated immunity appears to be more important
than humoral.

Cont…
 The immune response to extracellular bacterial
infections is generally mediated by antibody.
 Both humoral and cell-mediated immune responses have
been implicated in immunity to protozoan infections.
 helminths generally are attacked by antibody-mediated
defenses, these may be ineffective.

CL3 (3).ppt

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