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VIRAL PATHOGENESIS

 

The consequences of a viral infection depend on a number of viral and host factors that affect pathogenesis. Viral infection was long thought to produce only acute clinical disease but other host responses are being increasingly recognized. These include asymptomatic infections, induction of various cancers, chronic progressive neurological disorders and possible endocrine diseases.

Cellular and Viral Factors in Pathogenesis

Viral virulence, like bacterial virulence, is under polygenic control. It is frequently associated with several characteristics that promote viral multiplication and cell change. The susceptibility of a particular cell to viral infection depends mainly on the presence of cellular receptors. Hence cells resistant to a virus may be susceptible to its extracted nucleic acid. Cultivation may markedly alter the viral susceptibility of cells from that in the original organ. For instance, polioviruses, which multiply in the nervous tissue but not in the kidney of a living monkey, multiply well in culture cells derived from the kidneys, since receptors develop in the cultivated kidneys cells. Marked changes in susceptibility accompany the maturation of animals. Many viruses are much more virulent in newborn animals than in adults e.g. coxsackieviruses, HSV or vice-verse e.g. polioviruses, hepatitis A. Genetic factors are also thought too play an important role in determining the susceptibility of an animal to a virus.

Cellular Response to Viral Infection

Cells can respond to virus infection in 3 different ways;-

  1. no apparent change
  2. CPE and death
  3. loss of growth control (transformation)

Patterns of disease

In a host, viruses cause 3 basic patterns of infection: localized, disseminated, and inapparent.

Localized - viral replication remains localized near the site of entry e.g. skin, respiratory or the GI tract)

Systemic (disseminated) - systemic infections usually take place through several steps;

  1. Entry of virus
  2. Spread to regional lymph nodes
  3. Primary viraemia spread to other susceptible organs such as the liver and spleen
  4. More intense secondary viraemia dissemination to other organs, such as the skin.  

Immunological and Other Systemic Factors

1. Circulating antibodies

Abs in the serum and extracellular fluid provide the main protection against primary viral infections i.e. at the site of entry into the host. For infections where viraemia is an essential feature of the disease e.g. measles, polio, mumps and smallpox, the degree of protection is directly related to the level of neutralizing antibodies in the blood when the virus enters it. In experimental HSV infections, the B-cell response limits the spread of the virus to the CNS and reduces the establishment of latency in the peripheral ganglia. Protection of the respiratory and the GI tract is associated with IgA antibodies that are secreted into the extracellular fluid. Hence, by inducing the secretion of IgA antibodies, natural infections produce specific local as well as systemic immunity. The protective role of Abs is also evident in the prophylactic effectiveness of passive immunization. Administration of immune serum before or early in the incubation period can prevent or modify the disease.

Although humoral antibodies generally develop during recovery from a viral disease, they appear to play a less prominent role in this process than in protection. Most patients with agammaglobulinaemia make a normal recovery from most viral diseases, although some affected children may develop persistent or fatal echovirus infections. Furthermore, even patients with selective IgA deficiency do not develop more prolonged or more severe respiratory or enteric disease. The limited effect of humoral Abs on recovery is not surprising, since they are ineffective against intracellular viruses. Furthermore, many viruses can spread directly to contiguous, uninfected cells and thus remaining inaccessible to Abs. However, Abs do play a role in restricting the dissemination of some viruses eg. polioviruses and togaviruses, the pathogenesis of which depends on the viraemic stage.

Long-lasting immunity, with persistence of circulating Abs, follows infection with a number of viruses, especially those causing viraemia. Second attacks are extremely rare in measles, smallpox, yellow fever or poliomyelitis. In contrast, second infections are common with most acute localized infections without viraemia, particularly respiratory diseases. It is thought that adequate levels of neutralizing antibodies do not persist in respiratory secretions, even though sufficient circulating antibodies are present. Adenoviruses are notable exceptions, perhaps because they frequently terminate in a latent infection of the lymphoid tissue in the respiratory and the GI tract.  

2. Cell-Mediated Immunity

Patients who lack immunoglobulins but develop CMI ordinarily recover from viral diseases without difficulty. Whereas patients with defective CMI but normal humoral immunity recover poorly from certain viral infections, such as vaccination with vaccinia. CMI also appears to play a critical role in maintaining latent virus infections. Such infections are frequently reactivated in patients undergoing organ transplants whose CMI is suppressed by therapy. These latent infections include CMV, VZV, HSV, EBV, adenoviruses, measles, human papillomaviruses, JC and BK viruses. Herpesvirus infections are also often activated in patients with extensive burns (HSV and CMV) and in the aged (VZV) owing to diminished CMI. Activation of these viruses is also a common event in AIDS.    

3. Diseases Based on Virus-Induced Immunological Response

The immune response itself often contribute to the production of disease e.g.

  1. Dengue haemorrhagic fever - this is associated of infection in an individual who had prior infection with a different serotype
  2. RSV - children immunized with inactivated RSV develop unusually severe disease if subsequently infected with the same virus.

These examples of enhanced viral injury could be due to one or a mixture of the following mechanisms;-

  1. Increased secondary response to Tc cells
  2. Specific ADCC or complement mediated cell lysis
  3. Binding of un-neutralized virus-Ab complexes to cell surface Fc receptors, and thus increasing the number of cells infected
  4. Immune complex deposition in organs such as the brain or kidney.

The central role of the immune response in the development of some viral diseases is demonstrated in mice infected with LCM virus. In adult mice, severe and often fatal disease follows about a week after intracerebral inoculation, but if the immune response is suppressed (by neonatal thymectomy, chemicals, irradiation, or anti-lymphocytic serum), disease fails to develop although viral multiplication and spread are unrestrained. Moreover, after infection in utero or at birth, specific CMI is not detectable and the mice appear normal for 9 to 12 months in spite of widespread viral multiplication that produces persistent viraemia and viruria, with viral Ags demonstrable in most organs.

In adult mice, viral multiplication and spread are usually restricted in both neural and extraneural tissues, but the CMI response is quick to develop and a critical number of virally infected cells are killed, resulting in lethal disease. In the foetus, neonate, or immunosuppressed adult mouse, infection proceeds unimpeded to eventual involvement of all tissues. Antibodies produced from immune complexes with the virus, and are deposited in the kidney resulting in glomerulonephritis. In addition, necrotic lesions appear in the liver, brain, spleen and other organs, apparently resulting from the reaction between virus-sensitized killer T-lymphocytes and viral Ags present on the surface of many cells. Therefore, in the absence of effective CMI, LCM virus multiplies harmlessly for a long time in mice, producing an inapparent infection.

Non-Specific Systemic Factors

Nonspecific factors that influence resistance to viral infection include various hormones, temperature, NK cells and phagocytes. Hormones have a potential effect on viral infections e.g. pregnancy increases the severity of several viral diseases. cortisone enhances the susceptibility of many animals to viral infection and commonly potentiate the severity of the disease. In humans, it aggravates the clinical course of herpetic corneal ulcers and increases the likelihood of VZV pneumonia.  

Latent Virus Infections

In latent infections, overt disease is not produced, but the virus is not eradicated. This equilibrium between host and parasite is achieved in various ways by different parasites and hosts. The virus may exist in a truly latent noninfectious occult form, possibly as an integrated genome or an episomal agent, or as an infectious and continuously replicating agent, termed a persistent viral infection.

Infectious agents causing chronic persistent infections have found a way of escaping a cell-mediated immune response. The mechanisms include

  1. generation of cells that escape a cell-mediated immune response.
  2. down regulation of MHC production in infected cells so that they are not recognized and destroyed by T cells.
  3. infection of cells in immunoprivileged sites such as the brain.

Examples of latent infection include

  1. Chronic Congenital Rubella, CMV, EBV, hepatitis B, HIV
  2. Latent HSV, VZV, adenovirus and some retroviral infections
  3. SSPE, PML, Kuru, CJD, progressive rubella panencephalitis

1. Chronic Persistent Infections

Enveloped viruses such as paramyxoviruses, some herpesviruses eg. EBV, retroviruses and arenaviruses appear particularly suited to initiate persistent infections. Infection appear to persist because the virus does not disrupt the essential housekeeping functions of the cells. (DNA, RNA and protein synthesis). Some persistently infected cells, such as in measles (SSPE) may be assisted by the capacity of humoral Abs to cap viral Ags on the cell surface. This promotes the shredding of viral Ags from the cell surface, leaving the cell surface free of viral glycoproteins and thus the infected cell is protected from CTLs and K cells.  

2. Latent Occult Viral Infections

Some DNA and RNA viruses, may become undetectable following a primary infection only to reappear and produce acute disease. This latency can be accomplished in different ways.

a. HSV - primary infection usually occurs between 6 to 18 months of age following which the virus persists and cannot be found except during recurrent acute episodes. The form in which the latent occult virus persists is uncertain. Virus cannot be isolated from tissue homogenates, but by cocultivating cells of sensory ganglia with susceptible cells. Virus has been detected in the trigeminal, thoracic, lumbar and sacral dorsal root ganglia. Hybridization studies have detected the viral genome in normal brains as well as peripheral ganglia. These data suggests that the DNA exist in a linear, unintegrated form, perhaps as episomes.

It may be that, as in virus-carrier cultures, infection is confined to only a small proportion (0.01-0.1%) of the ganglion cells because of Abs, CMI, viral interference or metabolic factors. Because there is humoral Abs present, most of the extracellular virus is neutralized and goes undetected. Acute episodes, in which there is a burst of viral replication, probably depends on a transient change in the local level of immunity or changes in the susceptibility of the uninfected cells induced by a variety of physical and physiological factors such as fever, intense sunlight, fatigue or menstruation. The other herpesviruses that infect humans also commonly produce latent infections: VZV in the sensory ganglia, CMV in lymphocytes and macrophages, and EBV in B-lymphocytes.

b. Adenovirus - adenovirus infections in humans are usually self-limiting but the virus frequently establishes a latent, persistent infection of the tonsils and the adenoids. Though these tissues fail to yield infectious virus when homogenized and tested in sensitive cell cultures, cultured fragments of about 85% of these "normal" tonsils and adenoids, after a variable time, show characteristic adenovirus-induced CPE and yield infectious virus. Failure to recover infectious virus initially may be due to the paucity of virions, to their association with either Ab or receptor material, or to the absence of mature virions. The latent infection is probably not the result of lysogeny, since DNA in peripheral lymphocytes appears to be in a linear episomal form.

c. SSPE - latency occurs as a result of incomplete viral production. Immature viral measles virus nucleocapsids are produced.

Latent viral infections affect the incidence and pathogenesis of acute viral disease in several ways. A reactivated virus may spread and initiate an epidemic among susceptible contacts eg. VZV. Viral latency can also be seen in the development of several chronic diseases dependent on the immunological response eg. SSPE and PML. Some latent states induce tumourigenesis.

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