Virus-Induced Changes in Cells

1.         Types of Virus-cell Interactions

2.            Cytopathic effects of Virus infections

a.            Cytocidal viruses kill the cells in which they replicate – the resulting cell damage is known as the cytopathic effect (CPE) of the virus, and the responsible virus is said to be cytopathogenic.

b.         This change in the appearance of the infected cell usually begins with a rounding and darkening of the cell and culminates in either lysis or giant cell formation.

c.         Clinical use:

i.          the nature and speed of development of the cytopathic effect are characteristic of the particular virus involved and therefore represent important criteria for the preliminary identification of clinical isolates.

ii.            detection of virus in a clinical specimen frequently is based on the appearance of CPE in cell culture.

iii.         in addition, CPE is the basis for the plaque assay, an important method for quantifying the amount of virus in a sample.

d.            Inclusion Bodies:

i.          these are discrete areas containing viral proteins or viral particles.

ii.          they have a characteristic intranuclear (herpesviruses, adenoviruses, and parvoviruses) or intracytoplasmic (poxviruses, paramyxoviruses, reoviruses and rabies virus) and appearance depending on the virus.

iii.         electron micrographs of inclusion bodies can aid in clinical diagnosis: Negri bodies – eosinophilic cytoplasmic inclusions found in rabies virus-infected brain neurons.

iv.         other inclusion bodies, such as those found in the nucleus of cells infected with herpesviruses, are the result of late degenerative changes and condensation and margination of chromatin.

e.         Polarity of Budding:

i.          in the course of their replication, viruses belonging to several families cause changes in the plasma membrane of the cell by insertion of viral glycoproteins.

ii.          viruses that mature at the apical surface of epithelial cells are shed into the environment, whereas those maturing at the basolateral surface move to other sites in the body, sometimes entering the bloodstream and establishing systemic infection.

iii.         for example, rabies virus is shed from the apical surface of salivary epithelium into the saliva of a rabid dog, whereas retroviruses bud through the basolateral surface and pass directly from cell to cell or become disseminated.

f.            Cytolysis by Immunologic Mechanisms:

i.          virus-encoded antigens in the plasma membrane constitute a target for specific immune mechanisms, both humoral and cellular.

ii.          this may result in lysis of the cell before significant numbers of new virions are produced, thus slowing the progress of infection and hastening recovery.

iii.         in some cases the immune response may precipitate immunopathologic disease.

g.         Cell fusion:

i.          fusion of virus-infected cells produces multinucleated giant cells, which characteristically form after infection with herpesviruses and paramyxoviruses.

ii.          fusion occurs as a result of cell membrane changes due to insertion of viral proteins into the membrane.

iii.         the clinical diagnosis of herpesvirus skin infections is aided by the finding of multinucleated giant cells with eosinophilic intranuclear inclusions in skin scrapings.

iv.         such multinucleated syncytia may represent an important mechanism of spread which avoids exposure of virions to neutralizing antibodies and also allows infection to be transmitted by subviral entities, e.g. nucleocapsids or viral nucleic acid.

h.            Hemadsorption:

i.          cells in monolayer culture infected with orthomyxoviruses, paramyxoviruses, or togaviruses, all of which bud from the plasma membrane, acquire the ability to adsorb erythrocytes.

ii.          this is due to the incorporation into the plasma membrane of viral glycoproteinss assembled into peplomers.

iii.         on the envelope of the virion, the same glycoprotein peplomers are responsible for hemagglutination – agglutination of erythrocytes by virions.

iv.         both techniques are used extensively in laboratory diagnosis.

I.          Other morphological changes:

i.          early changes in cell structure often involve proliferation of various cell membranes – herpesviruses cause increased synthesis of nuclear membrane, flaviviruses cause proliferation of endoplasmic reticulum.

ii.            infection by many viruses also leads to a disruption of cytoskeletal fiber systems by depolymerization of microfilaments and/or microtubules.

iii.         later in the course of infection, many lytic viruses cause nuclear, organelle, and cytoplasmic rarefaction and/or condensation, with terminal loss of host cell membrane integrity.

iv.            nonspecific changes – ‘cloudy swelling’ associated with increasing permeability of the plasma membrane.

v.         diffuse swelling of nucleus, distension of endoplasmic reticulum and mitochondria, and rarefaction of the cytoplasm.

vi.         cell destruction can be the consequence of further loss of osmotic integrity and leakage of lysosomal enzymes into the cytoplasm.

3.            Mechanisms of Cell Damage

a.         Cell damage due to viral infection can be caused by a series of biochemical insults to cellular metabolism.

b.            Shutdown of Cellular protein synthesis:

i.          most cytocidal viruses code for proteins that shut down the synthesis of cellular proteins.

ii.          may be due to competition for ribosome subunits by the large excess of viral mRNA.

iii.            inhibition of protein synthesis may provide selective advantage by allowing the viral message to bind to ribosomes and initiate transcription.

iv.         an adenovirus early protein inhibits the transport of processed cellular mRNAs from nucleus to cytoplasm, whereas certain herpesviruses bring about selective degradation of cellular mRNA.

v.            synthesis of cellular proteins is inhibited by viral protein synthesis still occurs.

vi.            poliovirus inactivates an initiation factor (IF) required for cellular mRNA to be translated into cellular proteins, but poliovirus mRNA has a special ribosome-initiating site that allows it to bypass the IF so that viral proteins can be synthesized.

c.            Shutdown of Cellular nucleic acid synthesis:

i.            inhibition of cellular DNA synthesis may be a secondary effect of inhibition of protein synthesis.

ii.          specific mechanisms include degradation of cellular DNA by a poxvirus DNase and displacement of cellular DNA from its normal site of replication, seen with herpesviruses.

d.            Cytopathic effects of viral proteins:

i.          large amounts of various viral components accumulate in the cell late in the replication cycle.

ii.          some of these, particularly certain capsid proteins, e.g. adenovirus penton, are toxic to cells.

iii.            insertion of viral proteins into the plasma membrane can change membrane permeability, leading directly to loss of osmotic integrity, cell swelling, and death.

4.            Noncytocidal Infections

a.            Noncytocidal viruses usually do not kill the cells in which they replicate.

b.         They may produce persistent infection, in which the infected cells produce and release virions but overall cellular metabolism is little affected, with the infected cells continuing to grow and divide.

c.            However, there may be slow, progressive changes that lead ultimately to cell death.

d.         In the body, cell replacement occurs so rapidly in most organs and tissues that the slow fall-out of cells due to persistent infection, may have no effect on overall function.

e.            Persistently infected differentiated cells may lose their capacity to carry out specialized functions, and neurons, once destroyed, are not replaced.

f.          Also, antigenic changes produced in the plasma membrane may provoke immune responses which can lead to destruction of the infected cells and often nearby uninfected cells.

g.         Effects on functions of specialized cells:

i.            lymphocytic choriomeningitis (LCM) virus replicating in beta cells of islets of Langerhans in the pancreas induce hyperglycemia.

ii.          beta-adrenergic receptors and opiate receptors are impaired in brain cells infected with measles virus.

iii.         virus that infect lymphocytes may induce a generalized immunosuppression.

iv.            rhinovirus infection of the nasal epithelium results in cilial stasis and later in the destruction of cilia, although the cells are often not killed.

5.            Interferons

a.         Viral interference occurs when a virus-infected cell population resists superinfection with the same or a different species of virus.

b.            Interferons are typical members of a large family of normal cellular regulatory proteins called cytokines which has antiviral properties.

c.            Properties of Human Interferons: