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Viral Pathogenesis & Antiviral DefensesViral Pathogenesis & Antiviral Defenses
Youhua Xie(谢幼华)Youhua Xie(谢幼华)
MOH&MOE Key Lab of Medical Molecular VirologySh h i M di l C ll F d U i itShanghai Medical College, Fudan University
复旦大学上海医学院
分子病毒学教育部/卫生部重点实验室分子病毒学教育部/卫生部重点实验室
Only A Few Viruses Are Pathogenic to Humans
Most viruses do not infect humansMost viruses do not infect humans
Infections of many human viruses take place and proceed unnoticed, producing no diseases, p g
Non-pathogenic
Controlled by human antiviral defensesControlled by human antiviral defenses
Viral Epidemiology
Study the distribution of determinants of disease in human Study the distribution of determinants of disease in human populations
Endemic (infections present at fairly low but constant level)
Epidemic (infections occur greater than usually found in the population)
Pandemic (infections are spread worldwide)
Viral Pathogenesis
Th f d i di b i l i f tiThe process of producing diseases by viral infections
The factors that determine the development of viral diseases in the host involve complex and dynamic virus hostin the host involve complex and dynamic virus-host interactions
Disease severities are varied ranging from very mild to fatalDisease severities are varied, ranging from very mild to fatal, depending on the role of both viral and host factors in influencing viral infection and disease progression
Viral Pathogenesis
Viral transmission and entry into the host
Spread in the host (systemic or localized infections)Spread in the host (systemic or localized infections)
Tropism
Vi lVirulence
Patterns of viral infection and disease
Host factors & host defense
Viral Pathogenesis
St f P li i P th iStages of Poliovirus Pathogenesis
Common Routes of Viral Horizontal Transmission
ROUTE OF ENTRY
SOURCE/ MODE OF TRANSMISSION
EXAMPLES/VIRUSESENTRY TRANSMISSION
Respiratory Aerosol droplet inhalation Influenza virus, parainfluenza virus, respiratory syncytial virus, measles, mumps, rubella,
i ll t i h t ivaricella-zoster virus, hantavirusNose or mouth hand or object nose Common cold (rhinovirus, coronavirus,
adenovirus)Salivary Direct salivary transfer (eg kissing) Herpes simplex virus (oral labial herpes)Salivary Direct salivary transfer (eg, kissing) Herpes simplex virus (oral-labial herpes),
Epstein-Barr virus (infectious mononucleosis), cytomegalovirus
Gastrointestinal Stool hand mouth and/or stool Enteroviruses, hepatitis A virus, poliovirus, object mouth
, p , p ,rotavirus
Skin Skin discharge air respiratory tract Varicella-zoster virus, small pox virus
Skin to skin Human papilloma virus (warts)Skin to skin Human papilloma virus (warts)
Animal bite to skin Rabies virus
Blood Blood products, transfusion or Hepatitis B virus, hepatitis C virus, hepatitis D needle prick virus, human immunodeficiency virus (HIV),
human T lymphotropic virus, cytomegalovirus
Common Routes of Viral Horizontal Transmission
ROUTE OF SOURCE/ MODE OF EXAMPLES/VIRUSESENTRY TRANSMISSION
Blood Insect bite Arboviruses, dengue virus, yellow fever virus, West Nile virus, encephalitis causing arboviruses
Genital Genital secretions Hepatitis B virus, HIV, herpes simplex virus, cytomegalovirus
i i l i ( i )Urine Urine Polyomavirus (BK virus)
Eye Conjunctival Adenovirus, cytomegalovirus, herpes simplex virus 1
Zoonotic Animal bite Rabies
Arthropod bite Arboviruses
Mammals excreta Arenavirus hantavirus filovirusMammals excreta Arenavirus, hantavirus, filovirus
Chicken, wild birds–aerosol droplets
Avian influenza virus (bird flu, H5N1)
Vertical Transmission
SOURCE/ MODE OF TRANSMISSION
EXAMPLES/VIRUSESTRANSMISSIONPrepartum or transplacental Cytomegalovirus, parvovirus B19, rubella virus,
human immunodeficiency virus (HIV)I t t d i d li /bi th H titi B i h titi C i hIntrapartum or during delivery/birth Hepatitis B virus, hepatitis C virus, herpes
simplex virus, HIV, human papilloma virusPostpartum or via breast feeding Cytomegalovirus, hepatitis B virus, human T
l h t i i HIVlymphotropic virus, HIV
Major Patterns of Viral Infections
Ab ti i f ti ( i )Abortive infection (no progeny viruses)
Lytic infection
Persistent infection
Most persistent infections have an acute phase
Chronic infection (eg. HBV, HCV)
Latent infection (eg Herpesviruses)Latent infection (eg. Herpesviruses)
Slow virus infection (eg. HIV)
Vi l t f tiViral transformation
Factors Determine Viral Pathogenesis
Viral virulence (eg. cytopathic effect)
Cellular and tissue damages as a result of host antiviral defenses against viruses [eg. host defense mediated inflammation (localized or systemic]inflammation (localized or systemic]
Oncogenic factors
Viral oncogeneViral oncogene
Insertion of viral DNA in the host chromosome
Viral Virulence
The ability of a virus to cause disease in an infected hostThe ability of a virus to cause disease in an infected host (pathogenicity)
Molecular and genetic determinants of viral virulence are Molecular and genetic determinants of viral virulence are located throughout the viral genome
Different strains of the same virus may differ in the degree of virulence
Strains have mutated and lost their ability to cause cytopathic ff t (CPE) d di t d i l teffects (CPE) and disease are termed as avirulent or
attenuated strains
Multiple Layers of Antiviral Defence
Physical and chemical barriers: skin, mucous secretions, tears, low pH, etc.Physical and chemical barriers: skin, mucous secretions, tears, low pH, etc.
Intrinsic defence and innate immunity
Detection of altered cell metabolismDetection of altered cell metabolism
Detection of macromolecules made only by invading virus
A t h t ti d ti d th thAutophagy, apoptotic and necrotic death pathway
Production of cytokines, interfere with early steps of viral replication
Ad i i iAdaptive immunity
Direct, amplified response by coordinated action of cytokines and lymphocytes
Virus clearance by antibodies, helper T cells, and cytotoxic T cells
Generation and maintenance of memory B and T cells
Multiple Layers of Antiviral Defence
Physical Intrinsic AdaptiveChemical Innate
Intrinsic Antiviral Defence
Directly restricts viral replication and assembly, thereby rendering a cell nonpermissive to a specific class or species of viruses (eg TRIM5a/HIV 1)of viruses (eg. TRIM5a/HIV-1)
Confered by mostly preexistent restriction factors
May be enhanced by viral infection
CRISPR system (clustered, regularly interspaced short li d i t ) (b t i d h )palindromic repeats) (bacteria and archaea)
RNA interference (Plants, invertibrates and perhaps vertibrates)vertibrates)
Cascade of Innate and Adaptive Antiviral Immunity
Pattern recognition Not recognized
receptorNot recognized
Sentinel cells (Antigen-presenting cells)Complement
Cytokines
No innate response Innate response
Complement
Sentinel cells (Antigen-presenting cells)NK cells, complement
Cytokines
Adaptive response
Cells in the immune systemimmune system
Immunobiology 6ed
Innate Antiviral Immunity
Function without the prior exposure to virus
Acti ated ithin min tes to ho rs after infectionActivated within minutes to hours after infection
Together with intrinsic antiviral defence, are the defences available for the first few days after infectionfirst few days after infection
Composed of cytokines, sentinel cells, complement, NK cells
li i i f “ lf” f i iRelies on recognition of “non-self” pattern of virus using pattern recognition receptors
Can inform and stimulate adaptive antiviral immunityCan inform and stimulate adaptive antiviral immunity
Generalized model of viral replication cycle
Curr Opin Immunol 2007, p17
Pattern Recognition Receptors
PRR LigandMBL (mannose-binding lectin) Mannose and fucose residues
ith t iwith correct spacingScavenger receptors Anionic polymersTLR-1/TLR-2 Peptidoglycan, lipoproteins,etc./ ep dog yc , pop o e s,e c.TLR-2/TLR-6 Peptidoglycan, lipoproteins,etc.TLR-3 dsRNATLR-4 LPS, lipoteichoic acidsTLR-5 FlagellinTLR 7 RNATLR-7 ssRNATLR-8 G-rich oligonucleotidesTLR-9 Unmethylated CpG DNATLR 9 Unmethylated CpG DNANOD1, NOD2 ProteoglycansRIG-1, MDA-5, LGP2 Cytosolic viral dsRNAAIM-2, DAI, IFI16, DDX41, RNA Pol III
Cytosolic viral dsDNA
Sensing of Viral Infection by Toll-like Receptors
J. Mol. Biol. (2014) 426, 1246-64
Cytosolic Viral dsRNA Sensor Signalling Pathway
Antiviral Research 100 (2013) 615-35
Human Interferons
Type Name Producer cellsType I IFN-α (13) Most nucleatedType I IFN α (13)
IFN-βIFN-ε
Most nucleated cells
IFN-ωIFN-κ
Type II IFN-γ T cells, NK cellsType III IFN-λ (3) ?
Antiviral Functions of Interferons
Induce resistance to viral replication in cellsInduce resistance to viral replication in cells
Increase MHC class I expression and antigen presentation in cells
A ti t d d iti ll d hActivate dendritic cells and macrophages
Activate NK cells to kill virus-infected cells
Interferon Signalling Pathway
Nat Rev Immunol. 2008, 8:559
OAS(2’-5’-oligoadenylate synthetase)-RNaseL
Nat Rev Immunol. 2008, 8:559
Crosstalk between Innate and Adaptive Antiviral Immunity
CD8 T cells
Lysis of infected cellscells cells
Innnate imm
Mature DCCytokines
TH1 Activate macrophage
munity Complement
NK cells
CD4 T Activate B TH2
macrophage
cells cellsTH2
TH17 Inflammation
Dendritic Cells (DCs)
Immature DCs circulate in periphery, around body cavities, under mucosal surfacesunder mucosal surfaces
Virus-interacting DCs maturize in lymph nodes, present internalized viral protein epitopes on MHC class II tointernalized viral protein epitopes on MHC class II to lymphocytes
Link innate and adaptive immune responses
DCs can directly inhibit viral replication by producing cytokines
Activation of Naïve T Cells by DC
Cytokines
A diverse group of soluble proteins, peptides, or glycoproteins which act as immunomodulating regulators
Proinflammatory cytokines: necessary to initiate an i fl t ( it l t dinflammatory response (recruit granulocytes, and lymphocytes etc.), such as TNF-a, IL-1, IL-6, IL-12, etc.)
Anti inflammatory cytokines: serve to reduce inflammationAnti-inflammatory cytokines: serve to reduce inflammation and promote healing once the injury/infection/foreign body has been destroyed, such as IL-10, IL-4, TGF-b, etc.)
Complement System
The complement system helps or “complements” the abilityThe complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism
Circulating complement molecules are usually inactive precursors (pro-proteins). During activation, proteases in the system cleave pro proteins to initiate an amplifying cascadesystem cleave pro-proteins to initiate an amplifying cascade of further cleavages.
It can be recruited and brought into action by the adaptiveIt can be recruited and brought into action by the adaptive immune system
Natural killer cells (NK cells)
NK cells are a type of large granular, cytotoxic lymphocyteyp g g y y p y
Differentiate and mature in the bone marrow, lymph node, spleen, tonsils and thymus, and enter into the circulation
Recognize stressed cells in the absence of antibodies and MHC
Provide rapid responses to virally infected cells and respond toProvide rapid responses to virally infected cells and respond to tumor formation
Inflammatory Response
Readness heat swelling painReadness, heat, swelling, pain
Reflect the communication of innate and adaptive immunity
No inflammatory response, ineffective adaptive immune response
C t thi i ll i d t i fl tCytopathic viruses generally induce strong inflammatory response
Some viruses barely induce inflammatory responseSome viruses barely induce inflammatory response
Inflammatory response may progress out of control and cause serious clinical outcomescause serious clinical outcomes
Neutralizing Antibodies
Neutralize virus particles in blood preventing infection ofNeutralize virus particles in blood, preventing infection of cells
Mucosal neutralizing antibodies prevent virus fromMucosal neutralizing antibodies prevent virus from penetrating the mucous surface
Production of neutralizing antibodies are essential for the gsuccess of many if not all existing vaccines against virus infection
Cytotoxic T Cell
Essential for clearing most viral infections
Lysis of target cells
Transfer of cytoplasmic granules containg perforin and grazymes
Apoptosis
Non-cytolytic pathway: production of antiviral cytokines such IFN-g
T Helper Cells
Th1 cells secrete cytokines that cause naïve CD8 T cells toTh1 cells secrete cytokines that cause naïve CD8 T cells to differentiate into CTL
Th2 cells secrete cytokines that activate B cells to make antibody y y
The balance of Th1 vesus Th2 is determined by cytokine mixture
Negative regulation of immune response
Immunoregulatory cytokines: IL-10 TGF-βImmunoregulatory cytokines: IL-10, TGF-β
Inhibitory receptors: PD-1, CTLA-4, LAG-3, etc
R l t T llRegulatory T cells
Altered antigen-presenting cell: DC loss or dysfunction; Non professional APCsdysfunction; Non-professional APCs
Antiviral Immune Response
Nature Review Microbiology 2004