Virus Pathogenesis

Virus pathogenesis is an abnormal situation of no value to the virus - the vast majority of virus infections are sub-clinical, i.e. asymptomatic.

For pathogenic viruses, there are a number of critical stages in replication which 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 is pathogenic or not. In the case of pathogenic infections, the site of entry can influence the disease symptoms produced. Infection can occur via:

Skin - dead cells, therefore cannot support virus replication. Most viruses which infect via the skin require a breach in the physical integrity of this effective barrier, e.g. cuts or abrasions. Many viruses employ vectors, e.g. ticks, mosquitos or vampire bats to breach the barrier.
Respiratory tract - In contrast to skin, the respiratory tract and all other mucosal surfaces possess sophisticated immune defence mechanisms, as well as non-specific inhibitory mechanisms (ciliated epithelium, mucus secretion, lower temperature) which viruses must overcome.
Gastrointestinal tract - a hostile environment; gastric acid, bile salts, etc
Genitourinary tract - relatively less hostile than the above, but less frequently exposed to extraneous viruses (?)
Conjunctiva - an exposed site and relatively unprotected

2) Primary Replication

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

via the bloodstream
via the nervous system

Virus may get into the bloodstream by direct inoculation - e.g. Arthropod vectors, blood transfusion or I.V. drug abuse. The virus may travel free in the plasma (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 spread to the blood stream, followed by more generalized, higher titre secondary viraemia as the virus reaches other target tissues or replicates directly in blood cells.

As above, spread to nervous system is preceded by primary viraemia. In some cases, spread occurs directly by contact with neurons at the primary site of infection, 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 - is controlled partly by the route of infection but largely by the interaction of a virus 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.'s and virus receptors are now known.

5) Host Immune Response

Discussed elsewhere - obviously has a major impact on the outcome of an infection.

6) Secondary Replication

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

7) Cell/Tissue Damage

Viruses may replicate widely throughout the body without any disease symptoms if they do not cause significant cell damage or death. Retroviruses do not generally cause cell death, being released from the cell by budding rather than by cell lysis, and cause persistent infections, even being passed vertically to offspring if they infect the germ line. (All vertebrate genomes including humans are stuffed with retrovirus genomes which have been with us for millions of years). Conversely, Picornaviruses cause lysis and death of the cells in which they replicate, leading to fever and increased mucus secretion in the case of Rhinoviruses, paralysis or death (usually due to respiratory failure) for Poliovirus.

8) Persistence vs. Clearance

The eventual outcome of any virus infection depends on a balance between two 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 virus infected cells - sufficient to continue the infection without killing the host.

For viruses which do not usually kill the cells in which they replicate, this is not usually a problem, hence these viruses tend naturally to cause persistent infections, e.g. Retroviruses.
For viruses which undergo lytic infection, e.g. Herpesviruses, it is necessary to develop mechanisms which restrict virus gene expression, and consequently, cell damage.

b) Evasion of immune surveillance

Includes:

antigenic variation
immune tolerance, causing a reduced response to an antigen, may be due to genetic factors, pre-natal infection, molecular mimicry
restricted gene expression
down-regulation of MHC class I expression, resulting in lack of recognition of infected cells e.g. Adenoviruses
down-regulation of accessory molecules involved in immune recognition e.g. LFA-3 and ICAM-1 by EBV.
infection of immunocompromised sites within the body e.g. HSV in sensory ganglia in the CNS
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:

Antigenic Drift: The gradual accumulation of minor mutations (e.g. nucleotide substitutions) in the virus genome which result in subtly altered 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 different rates, e.g. RNA viruses >>> DNA viruses. In response, the immune system constantly adapts by recognition of and response to novel antigenic structures - but is always one step behind. In most cases however, the immune system is eventually able to overwhelm the virus, resulting in clearance.
Antigenic Shift: Is a sudden and major change in the antigenicity of a virus due to recombination of the virus genome with another genome of a different antigenic type. This process result initially in the failure of the immune system to recognise a new antigenic type, giving the virus the upper hand.