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Antiviral immunity Paul Zhou Institut Pasteur of Shanghai

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					Antiviral immunity
Paul Zhou Institut Pasteur of Shanghai

Viruses that initiate infection via the skin, eye, or genital tract
Site of infection Skin Method of infection Minor breaks/cuts Virus family Hepadnaviridae Herpesviridae Papovaviridae Poxviridae Herpesviridae Rhabdoviridae Bunyaviridae Flaviviridae Reoviridae Togaviridae Flaviviridae Hepadnaviridae Herpesviridae Retroviridae Adenoviridae Picornaviridae Flaviviridae Hepadnaviridae Herpesviridae Papovaviridae Retroviridae Examples Hepatitis B Herpes simplex 1 Papillomavirus Vaccinia Herpes monkey B Rabies Rift Valley fever Yellow fever, Dengue Colorado tick fever Eastern encephalitis Hepatitis C Hepatitis B Cytomegalovirus HIV, HTLV-1 Adenovirus Enterovirus 70 Hepatitis C Hepatitis B Herpes simplex 2 Papillomavirus HIV

Animal bite
Vector bite

Injection

Conjunctiva Genital tract

Contact Contact

Viruses that initiate infection via the respiratory tract
Localization of disease Virus family
Upper respiratory tract Adenoviridae Picornaviridae

Example
Adenovirus Rhinoviruses, some enteroviruses Sin Nombre Coronavirus Influenza Parainfluenza, RSV

Lower respiratory tract

Bunyaviridae Coronaviridae Orthomyxoviridae Paramyxoviridae

Generalized systemic disease without initial respiratory symptoms Arenaviridae Lassa fever Bunyaviridae Hantaan virus Herpesviridae Varicella, cytomegalovirus Papovaviridae BK and JC viruses Paramyxoviridae Mumps, measles Poxviridae Smallpox (extinct) Togaviridae Rubella

Viruses that initiate infection via the alimentary tract
Site of infection Virus family Examples

Mouth/oropharynx

Herpesviridae

Herpes simplex, Epstein-Barr virus, cytomegalovirus
Adenovirus 40, 41 Astrovirus Norwalk agent Rotavirus Poliovirus Hepatitis A

Intestinal tract Producing enteritis

Adenoviridae Astroviridae Caliciviridae Reoviridae Picornaviridae

Producing generalized disease usually without enteric illness Usually symptomless

Adenoviridae Picornaviridae Reoviridae

Some adenoviruses Enterovirus Reovirus

Relationship between initial site of viral infection and disease production
Site of infection Oropharynx Local Systemic Cytomegalovirus Epstein-Barr virus Herpes simplex 1 Influenza virus RSV Rhinovirus Measles Mumps Rubella Varicella Lassa Norwalk Hepatitis A Polio Hepatitis B Hepatitis C HIV

Respiratory tract

Intestinal tract

Rotavirus

Genital tract

Papilloma virus

Viruses that infect circulating blood cells
Cell type Monocytes Virus CMV Dengue Ebola HIV Lassa Measles Rubella Yellow fever EBV HIV Human T-cell leukemia virus I/II Human herpes 6,7 Colorado tick fever

B cells T cells

Erythroblasts

Viral transmission
Mode of transmission Aerosol/saliva respiratory or salivary spread Example Influenza virus EBV Measles Mumps Polio Hepatitis A Rotavirus HSV HPV HIV Comment Transmission is difficult to control

Fecal-hand-mouth spread

Controllable by public health measures

Venereal spread

Controllable by appropriate precautions

Zoonoses Insect to human Animal to human Animal to Insect to human Dengue, Rabies Human infection can be Lassa, Hanta, controlled by controlling Yellow fever vectors (insects) and/or by controlling animal infection

Innate immunity against viruses
• Cells – immune cells and non-immune cells

• Receptors – TRL 3, 7, and 8 and C-type lectin receptors: MMR, DEC205, Langerin, BDCA-2, and DC-SIGN
• Cytokines and their mechanisms – Direct and indirect • Regulations – Positive and negative

Cytokines with potential to promote innate immunity during viral infections
Functions

Cytokine
IFN-a/b

Nonadaptive cell sources
Monocytes/macrophages Virus-infected immune and nonimmune cells Monocytes/macrophages NK Cells Other nonimmune cells NK Cells Monocytes, macrophages PMN’s, dendritic cells Monocytes/macrophages Other nonimmune cells Monocytes/macrophages Other nonimmune cells Monocytes/macrophages Other nonimmune cells Monocytes/macrophages Other nonimmune cells Monocytes/macrophages Other nonimmune cells Monocytes/macrophages Other nonimmune cells

Antiviral
XXX

Immunoregulatory
XXX

TNF

XXX

XXX

IFN-g IL-12 IL-1a, IL-1b IL-6 IGIF IL-15

XXX XX ? ? ? ?

XXX XXX XX XX XX XX

IL-10
TGF-b

?
X

XX
X

Adaptive immunity against viruses
Effector system Recognition molecule
Antibody Surface glycoproteins or outer capsid proteins

Mechanism of viral control
Neutralization of virus Opsonization of virus particles

Viral glycoproteins expressed on membrane of infected cells
CD4 T cells Viral peptides (15 mers) presented by MHC II

ACDC and ADC of virus infected cells Downregulation of intracellular viral gene expression
Viral peptide derived from any exogenous proteins (surface, internal, or nonstructural) Release of antiviral cytokines (IFN-g, TNF) Activation/recruitment of macrophages. Help for antiviral antibody production Help for CD8 CTL responses Kill viral infected cells Viral peptide which usually are derived from endogenous viral proteins Cross priming for exogenous peptide Killing of virus-infected cells Release of antiviral cytokines (IFN-g, TNF) Activation/recruitment of macrophages

CD8 T cells

Viral peptides (8 mers) presented by MHC I

Humoral response to acute viral infection in humans
Example Serum antibody (yr) . Systemic infections Dengue Yellow fever Measles Mumps Polio Hepatitis A Smallpox Vaccinia Rubella Mucosal antibody (mo)

32 75 65 12 40 25 40 15 14

Mucosal infections Coronavirus Influenza virus Respiratory syncytial virus Rotavirus

12 30 3 12

Models of long-term antibody production
Mechanism Re-exposure to virus - Persistent viral infection - Immune complexes on follicular dendritic cells - Cross-reactivity to self or environmental antigens - Idiotypic networks Long lived plasma cells Comments Conventional models for maintaining humoral immunity in which short-lived plasma cells are continuously replenished by memory B cells proliferating and differentiating into plasma cells Long-lived plasma cells provide an additional mechanism for maintaining persistent antibody production

Effector mechanisms of cell mediated immunity

Predictive value of MHC class I allele specific motifs and binding affinity in identifying CD8 T-cell epitopes during viral infection
_________________________________________________________________ Class I # of Class I Total # of motif-fitting peptides (IC50) in LCMV glycoprotein allele binders and nucleoprotein _________________________________________________________________ High Intermediate Low # of CTL epitopes during LCMV infection (% of total motif-fitting peptides)

Db 26 2 (2) 3 (2) 3 (0) 4 (15) Kb 28 2 (0) 4 (2) 6 (0) 2 (7) Dd 18 0 0 3 (0) 0 (0) Kd 16 1 (0) 4 (2) 2 (0) 2 (12) _______________________________________________________________ Total 88 5 (2) 11 (6) 14 (0) 8 (9)

Viruses that persist in humans
Virus group
DNA viruses Adenovirus CMV

Site of persistence

Consequences

Adenoids, tonsils, lymphocytes None known Kidneys, salivary glands, Pneumonia, retinitis lymphocytes?, macrophages, stromal cells EBV Pharyngeal epithelial cells, B cells Infectious mononucleosis, Burkitt’s lymphoma, nonpharyngeal carcinoma, non-Hodgkin’s lymphoma, oral hairy leukoplakia HSV 1 and 2 Sensory ganglia neurons Cold sores, genital herpes, encephalitis, keratosis HSV 6 Lymphocytes Exantem subiturn HSV 8 PBMC, Endothelial spindle cells Kaposi sarcoma VZV Sensory ganglia neurons and/or Varicella zoster satellite cells Hepatitis B virus Hepatocytes Hepatitis, hepatocellular carcinoma Hepatitis D virus Hepatocytes Exacerbation of chronic HBV infection

Virus group

Site of persistence

Consequences

Papillomavirus Parvovirus B19

Epithelial skin cells Erythroid progenitor cells in BM

Polyomavirus BK Kidney Polyomavirus JC Kidney, oligodendrocytes in CNS RNA viruses Hepatitis C virus Hepatocytes Measles virusa Neurons and others in CNS

Papilloma, carcinomas Aplastic crisis in hemolytic anemia, chronic BM deficiency Hemorrhagic cystitis Progressive multifocal leukoencephalopathy
Hepatitis, hepatocellular carcinomas Subacute sclerosing panencephalitis, measles -inclusion body encephalitis Progressive rubella panencephalitis, IDDM? juvenile arthritis? AIDS T-cell leukemia, tropical spastic paraparesis, polymyositis None known

Rubella virusa

CNS

HIV HTLV-I

CD4 T cells, monocytes/ macrophages, microglia T cells

HTLV-II

T cells

Mechanisms
Restricted gene expression; virus remains latent in the cell with minimal to no expression
Infection of sites not readily accessible to immune system

Example
EBV in B cells, HIV in resting T cells HSV and VZV in latently infected neurons,
HSV, VZV, measles, and rubella in CNS CMV, polyomaviruses BK and JC in the kidney EBV and CMV in the salivary gland Papillomaviruses in the epidermis CMV protein UL18 is a MHC class I homologue that inhibits NK activity. Antibody escape variants in SIV/HIV CTL escape variants in HIV, EBV, and HBVT-cell receptor antagonism by HIV and HBV variants Suppression of MHC class I molecules by adenoviruses, CMV, HSV, and HIV Decreased expression of cell adhesion molecules LFA-3 and ICAM-1 by EBV Suppression of MHC class II molecules by CMV, HIV, and measles

Inhibition of NK function

Antigenic variation; virus rapidly evolves and mutates antigenic sites that are critical for recognition by antibody and T cells

Suppression of cell surface molecules required for T-cell recognition

Interference with antigen processing and presentation

HSV ICP47 protein and CMV U6 protein interfere with TAP to inhibit MHC class I antigen presentation. EBV protein EBNA-1 contains gly-ala repeats that confer resistance to proteasome mediated degradation and subsequent MHC class I presentation. CMV protein pp65 phosphorylates the CMV immediate–early protein and inhibits its processing and/or presentation Adenovirus proteins E3 and E1B protect infected cells from lysis by TNF Adenovirus VA RNA, EBV EBER RNA, and HIV TAR RNA inhibit function of interferon. EBV protein BCRF1 (a homologue of IL10) blocks synthesis of cytokines such as IL-2 and interferon gamma. Clonal deletion–anergy of virus-specific CTLs in HBV carriers, HIV(?) SSPE caused by measles

Viral defense molecules that interfere with the function of antiviral cytokines and chemokines

Immunologic tolerance Cell-to-cell spread by snycytia

Immunopathology of viral infection
• Virus-induced immune complex disease
Virus-antibody complex formation in fluid can be cleared through opsonization of Fc and/or complement receptors on macrophages or activated lymphocytes Or deposited onto renal glomeruli, arteries, and choroid plexus leading to glomerulonephritis, arteritis, and choroiditis Diagnosis of virus-induced immune complex disease is based on identification of presence of immune complex) viral antigen, host Ig, and complement in the pathological sites

• Virus-induced autoimmune disease
Evidences:
1. Human autoimmune responses are made de novo in or are enhanced during, infection by a wide variety of DNA and RNA viruses 2. In experimental animal models, both acute and persistent virus infections can induce, accelerate or enhance autoimmune disease in high-responder mice 3. Investigation of molecular mimicry indicates that a number of etiologic agents may cause autoimmune disease Mechanisms: 1. through a mitogenic effect on lymphocyte subsets 2. through infect lymphocytes and macrophages to cause cytokine and chemokine release, which in turn modulates immune responses Molecular mimicry and epitope spread

Two models
Acutely cytopathic viruses
- Excessive damage of infected tissues
- Require a rapid control for host to survive - e.g. neurotropic poliovirus, rabies virus, smallpox virus in human and VSV in mouse

Poorly or non-cytopathic viruses - Do not directly induce cellular damage
- Immunopathology - HBV, HCV, possibly HIV in human and LCMV in mouse

Factors influencing antigenicity and immunogenicity of the native viral surface
• Accessibility to antibodies (numbers of antigenic sites, density of molecules, oligomerization, glycosylation

• Structural arrangement of accessible site
• Frequency of germline-encoded immunoglubulin VH and VL combinations with specificity for epitopes in the accessible sites

Summary
• Understanding anti-viral immunity is a key for efficient vaccine development • Virus and host immune system are co-evolved (or co-adapted) in both population and individual levels (immune control and viral evasion is a constant battle) • Immune responses to viral infection is also a double edge sword (immune control versus immunopathology) • The interaction between host immune system and individual viruses varies greatly. So far no single mechanism or a set of mechanisms can count for all viruses. Therefore, the devil is in detail!


				
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