immunity to viruses - mbchb iii_2011(1)
TRANSCRIPT
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Outline Viral tropism and general biology
Innate immunity to viral infections
Specific Immunity (humoral and cell mediated)
Evasion of host immune responses
Discussion points/take home message
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Background Viruses are intracellular microbes, use host
biosynthetic machinery for survival=obligatory
Viral replication within cells lead to cytopathic
effects (lytic) e.g. T cell apoptosis in HIV infection
Some viruses dont cause cytopathic effects (nonlytic)= virus resides in cells but produceproteins to which specific immunity is raised=latent infections
Host IR to cytopathic and non cytopathic viralinfections are different
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Viral tropism Utilize natural/normal cellular receptors to gain entry
and infect host cells
Infect a wide variety of cells using normal cell surfacereceptors
HIVCD4, CCR
EBVCR2 (complement receptor on B cells, CD21
RhinovirusICAM-1(on most cells), CD54
Viral antigens are dominantly proteins or glycoproteins
Internal antigens are usually not relevant to protectiveimmunity
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Innate Immunity
PhagocytosisNeutrophils,
Macrophages
Viral infection directly stimulates
production of IFN by infected cells
IFN ()released from virus
infected cells induce antiviral state
in neighboring uninfected cells
coupled with high MHC 1 expression
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IFN cont.
Cells produce enzymes e.g. 2-5
oligoadenylate synthatase that inhibit
viral rep.
Increase lytic potential of NK cells
Up regulation of MHC I (efficient CTL),
but inhibit MHC II ???
Clinical use of cytokine e.g. antiviral
agent in viral hepatitis, HPV
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Innate Immunity
NK cells lyse a wide variety of virally
infected cells (peforins, granzymes,
proteoglycans)
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NK Cell
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Specific humoral IRs
Humoral IRs target viruses before entry into
host cells, and are less effective inintracellularly replicating viruses
NB: IRs to virions are mostly humoral whilst
CTLs target virally infected cells
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Specific humoral IRs
Specific Ab in early course of infection neutralising Absprevent viral attachment by
targeting specific viral antigens e.g.
haemaglutinin of influenza virus more
neutralising than Ab to other sites
Prevent viral attachment and entry
Complement assists neutralization by coatingvirus or lysing those with lipid membranes
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Neutralisation
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Complement Activation
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Specific humoral IRs
Opsonising Abenhance phagocytic clearanceof viral particles
NB opsonisation may also enhance invasionof Fc-receptor bearing cells by virus e.g HIV
infection of mononuclear cells
Ab may also result in modulation/stripping ofviral antigens from cell surface allowinginfected cells to avoid destruction by
cytotoxic cells.NB Ab bind to virus then their Fc
receptors are recognized by phagocytes
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Opsonisation
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Antibody dependent cell mediated
cytotoxicity (ADCC)NKs are major effector
cells
NK cell mediated lysis of Ab coated virusinfected cell
Specific humoral IRs
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ADCC
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Points to note in humoral
Ab important before viral entry
into cell: intracellular viruses areuntouchable
Purified Ab based vaccines have
shown less protection
In vitroprotection (experiments)
not correlated to in vivo
protection
IS AB BASED IRs ENOUGH TOPROTECT FROM VIRAL
INFECTIONS?
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Specific CTL IRs CTLs physiological function of
immunesurveillance of viral infection
Principal mechanism against established viral
infections especially non-cytopathic viruses
CD8 T cells recognize viral antigen in association
with MHC class I.
CTLs require CD4 Th cytokinesIL-2, IFN-g or
costimulators expressed on APC
CTLs lead to specific cell lysis, enzymatic lysisof viral particles, cytokine secretion (interferon
activity)
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CTL
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Specific CTL IRs
Despite the strong CTL IRs, progression of
viral disease suggesting the importance of
both Innate and specific (humoral and CTL) incontrolling viral infections
e.g. influenza specific CTLs target matrix
protein and nucleoprotein (internal proteins)
whilst Ab target envelope glycoproteins(hemagglutinin and neuraminidase)
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Specific CTL IRs Involvement of macrophages Immune responses may produce disease esp non
cytopathic viruses
Killing of cells that are infected but notinjured by virus
Persistent viral infection e.g. HBV resulting information of circulating immune complexes ofviral particles and specific Ag, - systemicvasculitis
Autoimmunitymolecular mimicry (viral a.aseq similar to self Ag)
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Escaping IRs by viruses Antigenic variation (serologically
distinct strains of viruses) e.g.influenza epidemics of 1918, 1957,1968; HIV mutation!
Antigenic drift (minor genetic change),antigenic shift (major genetic change)
Inhibition of MHC I presentation of Ag
Suppression of transcription of MHC
I genes (Adenovirus type 12) Inhibition of antigen processing
(HSV, CMV)
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Discussion points
Immune response to some antigens may be much moreeffective than to others
Response could be beneficial or detrimental e.g.autoimmunity, hypersensitivity e.g. mice models showCTLs for lymphocytic choriomeningitis virus (LCMV)leading to spinal cord meninges
Transformation of host cells e.g. oncogenic viruses(leukemias-HTLV-1)
Remember to READ READ READREAD!!!!
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