Virus Pa Tho Genesis

8/3/2019 Virus Pa Tho Genesis

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Virus Pathogenesis

Virus pathogenesis is an abnormal situation of no value to the virus - the vastmajority of virus infections are sub-clinical, i.e. asymptomatic. For pathogenic viruses, there are a number of critical stages in replicationwhich determine the nature of the disease they produce:

1) Entry into the Host

The first stage in any virus infection, irrespective of whether the virus ispathogenic or not. In the case of pathogenic infections, the site of entry caninfluence the disease symptoms produced. Infection can occur via:

y Skin - dead cells, therefore cannot support virus replication. Mostviruses which infect via the skin require a breach in the physicalintegrity of this effective barrier, e.g. cuts or abrasions. Many virusesemploy vectors, e.g. ticks, mosquitos or vampire bats to breach thebarrier.

y Respiratory tract - In contrast to skin, the respiratory tract and allother mucosal surfaces possess sophisticated immune defencemechanisms, as well as non-specific inhibitory mechanisms (ciliatedepithelium, mucus secretion, lower temperature) which viruses must

overcome.y Gastrointestinal tract - a hostile environment; gastric acid, bile salts,

etcy Genitourinary tract - relatively less hostile than the above, but less

frequently exposed to extraneous viruses (?)

y Conjunctiva - an exposed site and relatively unprotected


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2) Primary Replication

Having gained entry to a potential host, the virus must initiate an infection byentering a susceptible cell. This frequently determines whether the infectionwill remain localized at the site of entry or spread to become a systemicinfection, e.g:

Localized Infections:

Virus: Primary Replication:

Rhinoviruses U.R.T.

Rotaviruses Intestinal epithelium

Papillomaviruses Epidermis

Systemic Infections:

Virus: Primary Replication: Secondary Replication:

Enteroviruses Intestinal epithelium Lymphoid tissues, C.N.S.

Herpesviruses Oropharynx or G.U.tract Lymphoid cells, C.N.S.

3) Spread Throughout the Host

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

y via the bloodstream


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y via the nervous systemVirus may get into the bloodstream by direct inoculation - e.g. Arthropodvectors, blood transfusion or I.V. drug abuse. The virus may travel free in theplasma (Togaviruses, Enteroviruses), or in association with red cells(Orbiviruses), platelets (HSV), lymphocytes (EBV, CMV) or monocytes(Lentiviruses). Primary viraemia usually proceeds and is necessary for spreadto the blood stream, followed by more generalized, higher titre secondaryviraemia as the virus reaches other target tissues or replicates directly inblood cells.

As above, spread to nervous system is preceded by primary viraemia. In somecases, spread occurs directly by contact with neurons at the primary site ofinfection, in other cases via the bloodstream. Once in peripheral nerves, the

virus can spread to the CNS by axonal transport along neurons (classic -HSV). Viruses can cross synaptic junctions since these frequently contain virus

receptors, allowing the virus to jump from one cell to another.

4) Cell/Tissue Tropism

Tropism - the ability of a virus to replicate in particular cells or tissues - iscontrolled partly by the route of infection but largely by the interaction of avirus attachment protein (V.A.P.) with a specific receptor molecule on the

surface of a cell, and has considerable effect on pathogenesis. Many V.A

.P.'sand virus receptors are now known.5) Host Immune Response

Discussed elsewhere - obviously has a major impact on the outcome of aninfection.6) Secondary Replication

Occurs in systemic infections when a virus reaches other tissues in which it iscapable of replication, e.g. Poliovirus (gut epithelium - neurons in brain &spinal cord) or Lentiviruses (macrophages - CNS + many other tissues). If avirus can be prevented from reaching tissues where secondary replication canoccur, generally no disease results.


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7) Cell/Tissue Damage

Viruses may replicate widely throughout the body without any diseasesymptoms if they do not cause significant cell damage or death. Retroviruses

do not generally cause cell death, being released from the cell by buddingrather than by cell lysis, and cause persistent infections, even being passedvertically to offspring if they infect the germ line. (All vertebrate genomesincluding humans are stuffed with retrovirus genomes which have been withus for millions of years). Conversely, Picornaviruses cause lysis and death ofthe cells in which they replicate, leading to fever and increased mucussecretion in the case ofRhinoviruses, paralysis or death (usually due torespiratory failure) for Poliovirus.8) Persistence vs. Clearance

The eventual outcome of any virus infection depends on a balance betweentwo processes:i) Persistence:

Long term persistence of virus results from two main mechanisms: a) Regulation of lytic potential

The strategy followed is the continued survival of a critical number of virusinfected cells - sufficient to continue the infection without killing the host.

y For viruses which do not usually kill the cells in which they replicate,this is not usually a problem, hence these viruses tend naturally tocause persistent infections, e.g.Retroviruses.

y For viruses which undergo lytic infection, e.g. Herpesviruses, it isnecessary to develop mechanisms which restrict virus gene expression,

and consequently, cell damage.

b) Evasion of immunesurveillance

Includes:

y antigenic variation


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y immune tolerance, causing a reduced response to an antigen, may bedue to genetic factors, pre-natal infection, molecular mimicry

y restricted gene expressiony down-regulation of MHC class I expression, resulting in lack of

recognition of infected cells e.g.A

denovirusesy down-regulation of accessory molecules involved in immune recognition

e.g. LFA-3 and ICAM-1 by EBV.y infection of immunocompromised sites within the body e.g. HSV in

sensory ganglia in the CNSy direct infection of the cells of the immune system itself e.g. Herpes

viruses, Retroviruses (HIV) - often resulting in immunosuppression.

ii) Clearance:

Example - Influenza virus:2 mechanisms allow influenza virus to alter its antigenic constitution:

y Antigenic Drift:The gradual accumulation of minor mutations (e.g.nucleotide substitutions) in the virus genome which result in subtlyaltered coding potential and therefore altered antigenicity, resulting in

decreased recognition by the immune system.

This process occurs in all viruses all the time, but at greatly differentrates, e.g. RNA viruses >>> DNA viruses. In response, the immune

system constantly adapts by recognition of and response to novelantigenic structures - but is always one step behind. In most caseshowever, the immune system is eventually able to overwhelm the virus,resulting in clearance.

y Antigenic Shift: Is a sudden and major change in the antigenicity of avirus due to recombination of the virus genome with another genome of


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a different antigenic type. This process result initially in the failure ofthe immune system to recognise a new antigenic type, giving the virus

the upper hand.

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