Infection and Infection and Immunity of virusImmunity of virus

What does a pathogen have to What does a pathogen have to do?do?

Infect (infest) a host Infect (infest) a host Reproduce (replicate) itself Reproduce (replicate) itself

Ensure that its progeny are transmitted to Ensure that its progeny are transmitted to

another hostanother host

Mechanisms of Mechanisms of TransmissionTransmission

AerosolsAerosols - inhalation of droplets, e.g. - inhalation of droplets, e.g. RhinovirusesRhinoviruses, the 'Common Cold Virus' or , the 'Common Cold Virus' or AdenovirusesAdenoviruses. .

Faecal-OralFaecal-Oral - e.g. - e.g. AstrovirusesAstroviruses, , CalicivirusesCaliciviruses; these viruses cause acute gastroenteritis. ; these viruses cause acute gastroenteritis.

Vector-borneVector-borne - e.g. in Arthropods such as m - e.g. in Arthropods such as mosquitos, ticks, fleas: osquitos, ticks, fleas: ArbovirusesArboviruses. .

Close personal contactClose personal contact - especially exchan - especially exchange of bodily fluids: Sex; Blood, e.g. ge of bodily fluids: Sex; Blood, e.g. HerpesvirusesHerpesviruses

Entry into the HostEntry into the Host SkinSkin - dead cells, therefore cannot support virus rep- dead cells, therefore cannot support virus rep

lication. Most viruses which infect via the skin requirlication. Most viruses which infect via the skin require a breach in the physical integrity of this effective be a breach in the physical integrity of this effective barrier, e.g. cuts or abrasions. Many viruses employ varrier, e.g. cuts or abrasions. Many viruses employ vectors, e.g. ticks, mosquitos or vampire bats to breaectors, e.g. ticks, mosquitos or vampire bats to breach the barrier. ch the barrier.

Respiratory tractRespiratory tract - In contrast to skin, the respirato - In contrast to skin, the respiratory tract and all other mucosal surfaces possess sophry tract and all other mucosal surfaces possess sophisticated immune defence mechanisms, as well as nisticated immune defence mechanisms, as well as non-specific inhibitory mechanisms (cilliated epithelion-specific inhibitory mechanisms (cilliated epithelium, mucus secretion, lower temperature) which virum, mucus secretion, lower temperature) which viruses must overcome. uses must overcome.

Entry into the HostEntry into the Host

Gastrointestinal tractGastrointestinal tract - a hostile - a hostile environment; gastric acid, bile salts, environment; gastric acid, bile salts, etc etc

Genitourinary tractGenitourinary tract - relatively less - relatively less hostile than the above, but less hostile than the above, but less frequently exposed to extraneous frequently exposed to extraneous viruses (?) viruses (?)

ConjunctivaConjunctiva - - an exposed site and an exposed site and relatively unprotectedrelatively unprotected

Sites of virus entrySites of virus entry

Transmission patternsTransmission patterns

Horizontal Transmission:Horizontal Transmission: Direct person-t Direct person-to-person spread. o-person spread.

Vertical TransmissionVertical Transmission:: Relies on Relies on PERSISTPERSISTENCEENCE of the agent to transfer infection fro of the agent to transfer infection from parents to offspring. Several forms of vem parents to offspring. Several forms of vertical transmission can be distinguished:rtical transmission can be distinguished:

1.Neonatal infection at birth, e.g. gonorrho1.Neonatal infection at birth, e.g. gonorrhorea, AIDS.rea, AIDS.

2.Infection in utero e.g. syphilis, CMV, Rub2.Infection in utero e.g. syphilis, CMV, Rubella (CRS), AIDS.ella (CRS), AIDS.

3. Germ line infection - via ovum or sperm. 3. Germ line infection - via ovum or sperm.

Primary ReplicationPrimary Replication

Having gained entry to a potential Having gained entry to a potential host, the virus must initiate an infection by host, the virus must initiate an infection by entering a susceptible cell. This frequently entering a susceptible cell. This frequently determines whether the infection will determines whether the infection will remain localized at the site of entry or remain localized at the site of entry or spread to become a systemic infectionspread to become a systemic infection

Localized InfectionsLocalized Infections

Viruses Viruses Primary ReplicatioPrimary Replicationn

Rhinoviruses U.R.T.Rhinoviruses U.R.T. Rotaviruses Intestinal epitheliuRotaviruses Intestinal epitheliu

mm Papillomaviruses EpidermisPapillomaviruses Epidermis

Systemic InfectionsSystemic Infections

Virus Virus Primary ReplicationPrimary Replication Secondary ReplicatioSecondary Replicationn

Enteroviruses Enteroviruses

Intestinal epitheliumIntestinal epithelium Lymphoid Lymphoid

tissues, C.N.tissues, C.N.S.S.

Herpesviruses Herpesviruses

Oropharynx or Lymphoid cells, Oropharynx or Lymphoid cells,

G.U.tract C.N.S.G.U.tract C.N.S.

Spread Throughout the HostSpread Throughout the Host

Apart from direct cell-cell contact, there Apart from direct cell-cell contact, there are 2 main mechanisms for spread are 2 main mechanisms for spread throughout the host: throughout the host:

via the bloodstream via the bloodstream via the nervous systemvia the nervous system

via the bloodstreamvia the bloodstream Virus may get into the bloodstream by direct iVirus may get into the bloodstream by direct i

noculation - e.g. Arthropod vectors, blood trannoculation - e.g. Arthropod vectors, blood transfusion or I.V. drug abuse. The virus may travesfusion or I.V. drug abuse. The virus may travel free in the plasma (Togaviruses, Enterovirusel free in the plasma (Togaviruses, Enteroviruses), or in association with red cells (Orbiviruses), or in association with red cells (Orbiviruses), platelets (HSV), lymphocytes (EBV, CMV) or s), platelets (HSV), lymphocytes (EBV, CMV) or monocytes (Lentiviruses). Primary viraemia usmonocytes (Lentiviruses). Primary viraemia usually proceeds and is necessary for spread to ually proceeds and is necessary for spread to the blood stream, followed by more generalizethe blood stream, followed by more generalized, higher titre secondary viraemia as the virus d, higher titre secondary viraemia as the virus reaches other target tissues or replicates direcreaches other target tissues or replicates directly in blood cellstly in blood cells

via the nervous systemvia the nervous system spread to nervous system is preceded by spread to nervous system is preceded by

primary viraemia. In some cases, spread primary viraemia. In some cases, spread occurs directly by contact with neurons occurs directly by contact with neurons at the primary site of infection, in other cat the primary site of infection, in other cases via the bloodstream. Once in peripases via the bloodstream. Once in peripheral nerves, the virus can spread to the heral nerves, the virus can spread to the CNS by axonal transport along neurons CNS by axonal transport along neurons (classic - HSV). Viruses can cross synapti(classic - HSV). Viruses can cross synaptic junctions since these frequently contaic junctions since these frequently contain virus receptors, allowing the virus to jun virus receptors, allowing the virus to jump from one cell to anothermp from one cell to another

Cell/Tissue TropismCell/Tissue Tropism

Tropism Tropism - the ability of a virus to - the ability of a virus to replicate in particular cells or tissues - is replicate in particular cells or tissues - is controlled partly by the route of controlled partly by the route of infection but largely by the interaction infection but largely by the interaction of a virus attachment protein (V.A.P.) of a virus attachment protein (V.A.P.) with a specific receptor molecule on the with a specific receptor molecule on the surface of a cell, and has considerable surface of a cell, and has considerable effect on pathogenesis. Many V.A.P.'s effect on pathogenesis. Many V.A.P.'s and virus receptors are now known. and virus receptors are now known.

Secondary Secondary ReplicationReplication Occurs in systemic infections wOccurs in systemic infections w

hen a virus reaches other tissuehen a virus reaches other tissues in which it is capable of replicas in which it is capable of replication, e.g. Poliovirus (gut epithelition, e.g. Poliovirus (gut epithelium - neurons in brain & spinal cum - neurons in brain & spinal cord) or Lentiviruses (macrophagord) or Lentiviruses (macrophages - CNS + many other tissues). Ies - CNS + many other tissues). If a virus can be prevented from rf a virus can be prevented from reaching tissues where secondareaching tissues where secondary replication can occur, generally replication can occur, generally no disease results. y no disease results.

:

Localized Infections:

Virus: Primary Replication:

Rhinoviruses U.R.T.

Rotaviruses Intestinal epithelium

Papillomaviruses

Epidermis

Systemic Infections:

Virus: Primary Replication:Secondary Replication:

Enteroviruses Intestinal epitheliumLymphoid tissues, C.N.S.

HerpesvirusesOropharynx or G.U.tract

Lymphoid cells, C.N.S.

Incubation periods of viral infectionsIncubation periods of viral infections

Influenza 1-2d Chickenpox 13-17d

Common cold 1-3d Mumps 16-20d

Bronchiolitis,croup 3-5d Rubella 17-20d

Acute respiratory disease

5-7d Mononucleosis 30-50d

Dengue 5-8d Hepatitis A 15-40d

Herpes simplex 5-8d Hepatitis B 50-150d

Enteroviruses 6-12d Rabies 30-100d

poliomyelitis 5-20d Papilloma 50-150d

Measles 9-12d HIV 1-10y

Types of InfectionTypes of Infection

Inapparent infection( Subclinical infInapparent infection( Subclinical infection)ection) . .

Apparent infectionApparent infection:: Acute infectionAcute infection Persistent InfectionPersistent Infection Chronic infectionsChronic infections

Latent Infection Latent Infection

Slow virus infectionsSlow virus infections

Chronic InfectionChronic Infection Virus can be continuously Virus can be continuously

detected ; mild or no clinical detected ; mild or no clinical symptoms may be evident.symptoms may be evident.

Latent infectionLatent infection The Virus persists in an occult, or cryptiThe Virus persists in an occult, or crypti

c, from most of the time. There will be intc, from most of the time. There will be intermittent flare-ups of clinical disease , Inermittent flare-ups of clinical disease , Infectious virus can be recovered during flfectious virus can be recovered during flare-ups . Latent virus infections typically are-ups . Latent virus infections typically persist for the entire life of the hostpersist for the entire life of the host

Slow virus infectionSlow virus infection

A prolonged incubation period, lasting A prolonged incubation period, lasting months or years, daring which virus months or years, daring which virus continues to multiply. Clinical symptoms are continues to multiply. Clinical symptoms are usually not evident during the long incubation usually not evident during the long incubation period .period .

Overall fate of the cellOverall fate of the cell

The cell dies in The cell dies in cytocidalcytocidal infections infectionsthis may be this may be acuteacute (when infection is brief and s (when infection is brief and self-limiting) or elf-limiting) or chronic chronic (drawn out, only a few c(drawn out, only a few cells infected while the rest proliferate)ells infected while the rest proliferate)--CytocidaCytocidal l effecteffect

The cell lives in The cell lives in persistentpersistent infections infectionsthis may be this may be productiveproductive or or nonproductivenonproductive (refe (refers to whether or not virions are produced) or it rs to whether or not virions are produced) or it may alternate between the two by way of may alternate between the two by way of latenlatencycy and and reactivationreactivation -- Steady state infectionSteady state infection

Special casesSpecial cases

TransformationTransformation--Integrated infection (VirIntegrated infection (Viruses and Tumor)uses and Tumor)

ApoptosisApoptosis

Types of Viral infections at the cellular Types of Viral infections at the cellular levellevel

Type Virus production Fate of cellType Virus production Fate of cell

Abortive - No effectAbortive - No effect

Cytolytic + DeathCytolytic + Death

Persistent Persistent

Productive + SenescenceProductive + Senescence

Latent - No effectLatent - No effect

TransformingTransforming

DNA viruses - ImmortalizationDNA viruses - Immortalization

RNA viruses + ImmortalizationRNA viruses + Immortalization

Inhibition of cellular protein synthesis

Polioviruses, HSV, poxviruses, togaviruses

Inhibition and degradation of cellular DNA

herpesviruses

Alteration of cell membrane structureGlycoprotein insertionSyncytia formationDisruption of cytoskeletonpermeability

All enveloped virusesHSV, VZ virus, HIVHSV, naked virusesTogaviruses, herpesviruses

Inclusion bodies Rabies

Toxicity of Virion components Adenovirus fibers

Mechanisms of viral cytopathogenesis

3. Viral Immunopathology3. Viral Immunopathology

Viral ImmunopathogenesisViral Immunopathogenesis

Influenza-like symptoms( IFN, lymphokins): Influenza-like symptoms( IFN, lymphokins):

DTH and inflammation(Tcell, PMNs): DTH and inflammation(Tcell, PMNs): Immune-complex disease(AB, complement): Immune-complex disease(AB, complement): Hemorrhagic disease( T cell,AB, ComplemenHemorrhagic disease( T cell,AB, Complemen

t): t): Postinfection cytolysis( T cells): enveloped viPostinfection cytolysis( T cells): enveloped vi

rusesruses Immunosuppression: HIV; CMV; Immunosuppression: HIV; CMV; measlesvirus and influmeaslesvirus and influ

enzaenza

PersistencePersistenceLong term persistence of virus results froLong term persistence of virus results fro

m two main mechanisms: m two main mechanisms: a) Regulation of lytic potentiala) Regulation of lytic potential b) Evasion of immune surveillanceb) Evasion of immune surveillance

Persistence vs. ClearancePersistence vs. Clearance

Antiviral ImmunityAntiviral Immunity

Overview of the Immune Overview of the Immune SystemSystem

H um ora l C ellular

N onspecific

H um ora l C ellular

Specific

macrophages, neutrophils

NK cell

complement, interferon, TNF etc.

T cells; other effectors cells

antibodies

Components of the Immune System

Components of the Immune System

Innate or Nonspecific Innate or Nonspecific ImmunityImmunity

Innate or Nonspecific Innate or Nonspecific ImmunityImmunity

Anatomic andAnatomic and Physiologic BarriersPhysiologic Barriers::

Intact skin / Mucus membrane Intact skin / Mucus membrane

Temperature /Acidity of gastric juices Temperature /Acidity of gastric juices

Protein factorsProtein factors Phagocytic BarriersPhagocytic Barriers : : 3 major types of phag3 major types of phag

ocytic cellsocytic cells Inflammatory Barriers and feverInflammatory Barriers and fever Mucociliary clearanceMucociliary clearance

IFNIFN

Interferons are proteins produced by cInterferons are proteins produced by cells infected with viruses, or exposed tells infected with viruses, or exposed to certain other agents, which protect oto certain other agents, which protect other cells against virus infection or decrher cells against virus infection or decrease drastically the virus yield from suease drastically the virus yield from such cells. Interferon itself is not directly ch cells. Interferon itself is not directly the the anti-viralanti-viral agent, but it is the inducer agent, but it is the inducer of one or many anti-viral mechanismsof one or many anti-viral mechanisms

Anti-tumor and regulation of immunityAnti-tumor and regulation of immunity

Interferon inducing agentsInterferon inducing agents

(1) Viruses. (1) Viruses. (2) dsRNA is a potent inducer, both vir(2) dsRNA is a potent inducer, both vir

al intermediates, and synthetic polyI-C. al intermediates, and synthetic polyI-C.   

(4) Certain Bacterial infections, and the (4) Certain Bacterial infections, and the production of endotoxin.  production of endotoxin.  

(5) Metabolic activators/inhibitors. Mito(5) Metabolic activators/inhibitors. Mitogens for gamma induction, also a variegens for gamma induction, also a variety of tumor promoters induce IFNs. , in ty of tumor promoters induce IFNs. , in particular PTA-phorbol tetradecanoate particular PTA-phorbol tetradecanoate acetate, butyrate, dexamethasoneacetate, butyrate, dexamethasone

Properties of human interferonsProperties of human interferons

Property IFN-alpha IFN-beta IFN-gamma

Principal cell source

Epithelium leukocytes

Fibroblasts Lymphocytes

genes >20 1 1

Introns in genes no no yes

induction Viruses dsRNA Viruses dsRNA Immune activation

Glycosylation no yes yes

Stability at pH2 stability stability labile

Function Antiviral infection activation of NK cell

anti-tumor regulation of enhancement of CMI immunity

Activities of interferonActivities of interferonAntiviral actions

Interferons initiate an antiviral state in cells

Interferons block viral protein synthesis

Inferons inhibit cell growth

Immunomodulatory actions

Interferons-alpha and IFN-beta activate NK cells

Interferons-alpha activates macrophages

Interferons-gamma activate macrophages

Interferons increase MHC antigen expression

Interferons regulate the activities of T cells

Other actions

Interferons regulate inflammatory processes

Interferons regulate tumor growth

Mechanism of actionMechanism of action

Release from an initial infected cell occursRelease from an initial infected cell occurs IFN binds to a specific cell surface receptoIFN binds to a specific cell surface recepto

r on an other cellr on an other cell IFN induces the “antiviral state” : synthesiIFN induces the “antiviral state” : synthesi

s of protein kinase, 2’5’ oligoadenylate syns of protein kinase, 2’5’ oligoadenylate synthetase, and ribonuclease L thetase, and ribonuclease L

Viral infection of the cell activates these eViral infection of the cell activates these enzymesnzymes

Inhibition of viral and cellular protein syntInhibition of viral and cellular protein synthesis occurshesis occurs

Diseases currently treated withDiseases currently treated with IFN-alphaIFN-alpha and and IFN-betaIFN-beta

hepatitis C hepatitis C hepatitis Bhepatitis B papilloma warts and early trials with cervical cpapilloma warts and early trials with cervical c

arcinomaarcinoma Kaposi sarcoma of AIDS, Kaposi sarcoma of AIDS, colon tumorscolon tumors kidney tumors ( usually in combination with othkidney tumors ( usually in combination with oth

er drugs). er drugs). Basal cell carcinomaBasal cell carcinoma Breast cancer combined with tamoxifan.Breast cancer combined with tamoxifan.

Nature killer/ NK cellNature killer/ NK cellNK cells are Activated by IFN-alpha/betaNK cells are Activated by IFN-alpha/beta

NK cells are Activated by IFN-alpha and IL-NK cells are Activated by IFN-alpha and IL-2 and 2 and

Activate macrophageActivate macrophageNK cells target and kill virus infected cellsNK cells target and kill virus infected cells

NK cellNK cell

MacrophagesMacrophages

Macrophages filter ciral particles from Macrophages filter ciral particles from bloodblood

Macrophages inactivate opsonized viruMacrophages inactivate opsonized virus particless particles

Macrophages present viral antigen to Macrophages present viral antigen to CD4 T cellsCD4 T cells

ComplementComplement

Enhancing neutralization of AntiboEnhancing neutralization of Antibodydy

Enhancing phagocytosis of virus pEnhancing phagocytosis of virus particlesarticles

Lysis Lysis

Specific immunitySpecific immunity

Active/passiveActive/passive

Overview of Specific immunityOverview of Specific immunity

specific recognition and selective eliminspecific recognition and selective elimination of foreign molecules.ation of foreign molecules.

Involves specificity, diversity, memory, aInvolves specificity, diversity, memory, and self/nonself recognition.nd self/nonself recognition.

The Role of MHCThe Role of MHC

The molecular basis of antigen recognition The molecular basis of antigen recognition by T cells is well understood. The TcR recby T cells is well understood. The TcR recognizes short antigen-derived peptide seqognizes short antigen-derived peptide sequences presented in association with self uences presented in association with self MHC class I or MHC class II molecules at MHC class I or MHC class II molecules at the surface of anthe surface of an antigen presenting cell antigen presenting cell (APC). (APC).

The Role of MHCThe Role of MHC

T cell recognition, therefore, involves direcT cell recognition, therefore, involves direct cell-cell contact between the antigen-spet cell-cell contact between the antigen-specific TcR on the T lymphocyte and an MHcific TcR on the T lymphocyte and an MHC compatible cell which presents the procC compatible cell which presents the processed antigen in association with surface essed antigen in association with surface MHC molecules.MHC molecules.

The Role of MHCThe Role of MHC

The finding that self MHC molecules are involveThe finding that self MHC molecules are involved in the recognition of antigen by T lymphocytes d in the recognition of antigen by T lymphocytes led to the concept of "MHC restriction" of T cell rled to the concept of "MHC restriction" of T cell responses, and pointed to the important role that esponses, and pointed to the important role that products of the major histocompatibility complex products of the major histocompatibility complex play in the cell mediated immune response. The play in the cell mediated immune response. The major histocompatibility complex consists of a clmajor histocompatibility complex consists of a cluster of genes, most of which encode products uster of genes, most of which encode products with immunologically related functions.with immunologically related functions.

The Role of MHCThe Role of MHC In humans, the MHC is located on the short arm of chroIn humans, the MHC is located on the short arm of chro

mosome 6 and spans approximately 4 megabases of Dmosome 6 and spans approximately 4 megabases of DNA. It can be divided into three regions termedNA. It can be divided into three regions termed class I, class I, class II and class III:class II and class III:

The The class IIIclass III region contains genes which encode a nu region contains genes which encode a number of complement components and the tumour necrmber of complement components and the tumour necrosis factor cytokines, amongst other molecules. osis factor cytokines, amongst other molecules.

MHC class I moleculesMHC class I molecules consist of a polymorphic, MHC- consist of a polymorphic, MHC-encoded, membrane-spanning heavy chain, and a monencoded, membrane-spanning heavy chain, and a monomorphic light chain, beta2-microglobulin. omorphic light chain, beta2-microglobulin.

MHC class II moleculesMHC class II molecules consist of a heterodimer of two consist of a heterodimer of two MHC-encoded, membrane-spanning proteins, the alphMHC-encoded, membrane-spanning proteins, the alpha and beta polypeptide chains of the MHC class II molea and beta polypeptide chains of the MHC class II molecule.cule.

The Role of MHCThe Role of MHC

MHC class I molecules MHC class I molecules present antigen to CD8+ T present antigen to CD8+ T

cellscells

MHC class II molecules MHC class II molecules present antigen to CD4+ T present antigen to CD4+ T

cellscells

T cellsT cellsT cells are essential for controlling enveloped and noncytolytic viral infections

T cells recognizes viral peptides presented by MHC molecules on cell surfaces

Antigenic viral peptides can come from any viral protein

TH1 CD4 responses are more important than TH2 responses

CD8 cytotoxic T cells respond to viral peptide-class I MHC protein complexes on the cell surface

TH2 CD4 responses are important for the maturation of antibody response

TH2 CD4 responses may be detrimental if they prematurely limit the TH1 inflammatory and cytolytic responses

Antibody Antibody

Antibody neutralizes extracellular virue:

it blocks viral attachment proteins

it destablilizes viral structure

Antibody opsonizes virus for phagocytosis

Antibody promotes killing of target cell by the complement cascade and antibody-dependent cellular cytotoxicity

Antibody resolves lytic viral infections

Antibody blocks viremic spread to target tissue

IgM is an indicator of recent or current infection

IgG is more effective than LgM

Secretory IgA is important for protecting mucosal surfaces

Humoral ImmunityHumoral Immunity

Antibody dependent cellular Antibody dependent cellular cytotoxicity or ADCCcytotoxicity or ADCC

AntibodyAntibodyIgG IgM IgA

Function MemoryBlood and tissue

Primary responseClear viruses in blood

Mucus immunit

y

C: classic pathway

+++ - -

C : C3 pathway

- - +

placenta +++ - -

ADCC ++ - -

AntibodyAntibody

Neutralization antibodyNeutralization antibody Other antibodyOther antibody

Passive ImmunityPassive Immunity

A high titer of antibody against a A high titer of antibody against a specific virusspecific virus

A pooled sample from plasma donors A pooled sample from plasma donors that contains a heterogeneous that contains a heterogeneous mixture of antibodies with lower titermixture of antibodies with lower titer