Viral pathogenesis

Viral pathogenesis is the study of the process and mechanisms by which viruses cause diseases in their target hosts, often at the cellular or molecular level. It is a specialized field of study in virology.

Pathogenesis is a qualitative description of the process by which an initial infection causes disease. Viral disease is the sum of the effects of viral replication on the host and the host's subsequent immune response against the virus. Viruses are able to initiate infection, disperse throughout the body, and replicate due to specific virulence factors.

Mechanisms of infection

Viruses need to establish infections in host cells in order to multiply. For infections to occur, the virus has to hijack host factors and evade the host immune response for efficient replication. Viral replication frequently requires complex interactions between the virus and host factors that may result in deleterious effects in the host, which confers the virus its pathogenicity.

Important steps of a virus life cycle that shape pathogenesis

thumb|300px|right|Typical sites of virus entry into the body: The first steps of viral infection is determined by the site at which the virus implants into the body. This would subsequently dictate the mechanisms of viral pathogenesis.

Transmission from a host with an infection to a second host
Entry of the virus into the body
Local replication in susceptible cells
Dissemination and spread to secondary tissues and target organs
Secondary replication in susceptible cells
Shedding of the virus into the environment
Onward transmission to third host

thumb|400px|alt=A photograph of the upper body of a man labelled with the names of viruses that infect the different parts|Overview of the main manifestations of viral infection

Primary transmission

Three requirements must be satisfied to ensure successful infection of a host. Firstly, there must be sufficient quantity of virus available to initiate infection. Cells at the site of infection must be accessible, in that their cell membranes display host-encoded receptors that the virus can exploit for entry into the cell, and the host anti-viral defense systems must be ineffective or absent. Otherwise, the virus can be released into extracellular fluids.

Examples of localised infections include: common cold (rhinovirus), flu (parainfluenza), gastrointestinal infections (rotavirus) or skin infections (papillomavirus). Interestingly, HIV-1 can undergo a tropism switch, where the virus glycoprotein gp120 initially uses CCR5 (mainly on macrophages) as the primary co-receptor for entering the host cell. Subsequently, HIV-1 switches to bind to CXCR4 (mainly on T cells) as the infection progresses, in doing so transitions the viral pathogenicity to a different stage.

The accessibility of host tissues and organs to the virus also regulates tropism. Accessibility is affected by physical barriers,

Virus factors are largely influenced by viral genetics, which is the virulence determinant of structural or non-structural proteins and non-coding sequences. For a virus to successfully infect and cause disease in the host, it has to encode specific virus factors in its genome to overcome the preventive effects of physical barriers, and modulate host inhibition of virus replication.

Virus factors encoded in the genome often control the tropism, routes of virus entry, shedding and transmission. In polioviruses, the attenuating point mutations are thought to induce a replication and translation defect to reduce the virus' ability of cross-linking to host cells and replicate within the nervous system. As such, viruses capable of manipulating the host cell response to infection as an immune evasion strategy exhibit greater pathogenicity.

Host factors

Viral pathogenesis is also largely dependent on host factors. Several viral infections have displayed a variety of effects, ranging from asymptomatic to symptomatic or even critical infection, solely based on differing host factors alone. In particular, genetic factors, age and immunocompetence play an important role is dictating whether the viral infection can be modulated by the host. Mice that possess functional Mx genes encode an Mx1 protein which can selectively inhibit influenza replication. Therefore, mice carrying a non-functional Mx allele fail to synthesise the Mx protein and are more susceptible to influenza infection. Alternatively, immunocompromised individuals due to existing illnesses may have a defective immune system which makes them more vulnerable to damage by the virus. Furthermore, a number of viruses display variable pathogenicity depending on the age of the host. Mumps, polio, and Epstein-Barr virus cause more severe disease in adults, while others like rotavirus cause more severe infection in infants. It is therefore hypothesized that the host immune system and defense mechanisms might differ with age.

Disease mechanisms: How do viral infections cause disease?

A viral infection does not always cause disease. A viral infection simply involves viral replication in the host, but disease is the damage caused by viral multiplication.

thumb|center|upright=2.0|alt=Diagram representing the various ways viral infections can induce damage and disease to host cells|Mechanisms by which viruses cause damage and disease to host cells

Damage caused by the virus

Once inside host cells, viruses can destroy cells through a variety of mechanisms. Viruses often induce direct cytopathic effects to disrupt cellular functions. This could be through releasing enzymes to degrade host metabolic precursors, or releasing proteins that inhibit the synthesis of important host factors, proteins, DNA and/or RNA. Namely, viral proteins of herpes simplex virus can degrade host DNA and inhibit host cell DNA replication and mRNA transcription.

Lytic viruses are capable of destroying host cells by incurring and/or interfering with the specialised functions of host cells. An example would be the triggering of necrosis in host cells infected with the virus. However, many viruses encode proteins that can modulate apoptosis depending on whether the infection is acute or persistent. Induction of apoptosis, such as through interaction with caspases, will promote viral shedding for lytic viruses to facilitate transmission, while viral inhibition of apoptosis could prolong the production of virus in cells, or allow the virus to remain hidden from the immune system in chronic, persistent infections.

Persistent viruses can sometimes transform host cells into cancer cells.

Specifically, immunopathology is caused by the excessive release of antibodies, interferons and pro-inflammatory cytokines, activation of the complement system, or hyperactivity of cytotoxic T cells. Secretion of interferons and other cytokines can trigger cell damage, fever and flu-like symptoms.

In some instances, viral infection can initiate an autoimmune response, which occurs via different proposed mechanisms: molecular mimicry and bystander mechanism. Molecular mimicry refers to an overlap in structural similarity between a viral antigen and a self-antigen.

Incubation period

Viruses display variable incubation periods upon virus entry into the host. The incubation period refers to the time taken for the onset of disease after first contact with the virus.

Surprisingly, generalised infections by togaviruses have a short incubation period due to the direct entry of the virus into target cells through insect bites.

An example of the evolution of virulence in emerging virus is the case of myxomatosis in rabbits. The release of wild European rabbits in 1859 into Victoria, Australia for sport resulted in a rabbit plague. In order to curb with rabbit overpopulation, myxoma virus, a lethal species-specific poxvirus responsible for myxomatosis in rabbits, was deliberately released in South Australia in 1950. This led to a 90% decrease in rabbit populations, and the disease became endemic in a span of five years. Significantly, severely attenuated strains of the myxoma virus were detected in merely 2 years of its release, and genetic resistance in rabbits emerged within seven years.