Viruses can replicate only inside living cells. Consequently, the first pathogenic manifestations of viral infection are seen at the cellular level. The course of events following initial exposure to some viruses may include rapid onset of observable symptoms, which is referred to as an acute infection. Alternatively, the initial infection by other viruses may be mild or asymptomatic. Following the initial infection, the most common outcome is that the virus is cleared completely from the body by the immune system. For some viruses, the initial infection is followed by either a persistent infection or a latent infection.

 A. Viral pathogenesis at the cellular level

Cells show a variety of different responses to viral infection, depending on the cell type and virus. Many viral infections cause no apparent morphologic or functional changes in the cell. When changes do occur, several (potentially overlapping) responses can be recognized (Figure 1).

Fig1. Types of viral pathogenesis at the cellular level.

1. Cell death: A cell can be directly killed by the virus. In most cases, this is due to the inhibition of synthesis of cellular DNA, RNA, and protein. Some viruses have specific genes responsible for this inhibition. Dead or dying cells release a brood of progeny viruses that repeat the replication process. Examples of viruses that kill their host cells are adenovirus and poliovirus .

2. Transformation: Some viruses transform normal cells into malignant cells. In many ways, this is the opposite of cell death, because malignant cells have less fastidious growth requirements than do normal cells, and they have an indefinitely extended life time. Transformation is an irreversible genetic process caused by the integration of viral DNA into the host’s DNA .

 3. Cell fusion: Infection of cells with certain viruses causes the cells to fuse, producing giant, multinucleate cells. Viruses with this property include herpesviruses and paramyxoviruses . The ability of infected cells to fuse is apparently due to virus-induced changes in the structure of the cell membrane.

4. Cytopathic effect: Cytopathic effect (CPE) is a catch-all term that refers to any visible change in appearance of an infected cell, for example, cell rounding, patches of stainable viral proteins inside the cell, and cell disintegration. Some viruses can be roughly identified by the time of onset and pattern of CPE in cell culture as well as by the types of cells in which these viruses cause CPE.

B. Initial infections

 Following initial multiplication at the primary site of entry, the viral infection may remain localized or become disseminated. The infection may be asymptomatic (unapparent). Alternatively, typical symptoms of disease may occur, often in two temporally distinct forms: 1) early symptoms at the primary site of infection and 2) delayed symptoms due to dissemination from the primary site, causing infection of secondary sites. Virus transmission can occur before symptoms of the generalized illness are apparent, making it difficult to control the spread of viral diseases.

 1. Routes of entry and dissemination to secondary sites: Common routes by which viruses enter the body are essentially the same as for bacterial infections (that is, through the skin or respiratory, GI, or urogenital tracts). In each case, some viruses remain localized and cause disease that is largely restricted to the primary site of infection. Other viruses undergo multiplication in cells at the primary site, which may be accompanied by symptoms, followed by invasion of the lymphatic system and the blood. [Note: The presence of virus in the blood is termed viremia.] Virus is disseminated throughout the body via the bloodstream and can infect cells at secondary sites characteristic for each specific virus type, thus causing the disease typically associated with that species (Figure 2).

Fig2. Examples of dissemination of virus to secondary sites in the body.

2. Typical secondary sites of localization: Secondary sites of infection determine the nature of the delayed symptoms and, usually, the major characteristics associated with the resulting disease. Viruses frequently exhibit tropism for specific cell types and tis sues. This specificity is usually caused by the presence of specific host cell surface receptors recognized by particular viruses. Although any tissue or organ system is a potential target for virus infection, the fetus represents an especially important site for secondary localization of virus infections. Virus from the maternal circulation infects cells of the placenta, thereby gaining access to the fetal circulation and, ultimately, to all tissues of the developing fetus (Figure 3). Fetal death or developmental abnormalities are often the result. Neonatal infection can also occur during birth when the fetus comes into contact with infected genital secretions of the mother or after birth when the infant ingests infected breast milk.

Fig3. Mother-to-infant (vertical) transmission of viral infections.

3. Virus shedding and mode of transmission: The mode of trans mission of a viral disease is largely determined by the tissues that produce progeny virus and/or the fluids into which they are released. These are not necessarily the secondary sites of infection but, in fact, are often the site of primary infection at a time before symptoms are apparent. The skin, respiratory and GI tracts, and bodily fluids are commonly sites of viral shedding.

 4. Factors involved in termination of acute infection: In a typical, uncomplicated, acute infection, virus is totally eliminated from the host in 2 to 3 weeks. This outcome is primarily a function of the host’s immune system, with involvement of both cell-mediated and humoral responses. The relative importance of these two responses depends on the virus and the nature of the disease.

 a. Cell-mediated responses: The earliest immune system response to virus infection is a generalized inflammatory response, accompanied by nonspecific killing of infected cells by natural killer cells. This latter activity, enhanced by interferon and other cytokines, begins well before the virus-specific immune response. Later, cytolysis by virus-specific cytotoxic T lymphocytes that recognize virus peptides displayed on the cell surface also eliminates infected cells. These cellular responses are especially significant in that they help limit the spread of the infection by killing infected cells before they have released progeny virus. Cell surface immunodeterminants recognized by T cells are often derived from nonstructural or internal proteins of the virus. Thus, this response complements the inactivation of free virus by humoral antibody, which is directed against capsid or envelope proteins.

 b. Humoral response: Although circulating antibodies may be directed against any virus protein, those that are of greatest significance in controlling an infection react specifically with epitopes on the surface of the virion and result in inactivation of the virus’s infectivity. The process is called neutralization. This response is of primary importance in suppressing dis eases that involve a viremic stage, but secretory antibodies (for example, immunoglobulin A) also play an important protective role in primary infections of the respiratory and GI tracts. Humoral antibodies also take part in killing infected cells by two mechanisms. The first is antibody-dependent, cell-mediated cytotoxicity, in which natural killer cells and other leukocytes bearing Fc receptors bind to the Fc portions of antibodies that are complexed to virus antigens on the surface of the infected cell and kill it. The second mechanism is complement-mediated lysis of infected cells to which virus-specific antibody has bound.

مواضيع ذات صلة

VIRUSES

Human Cytomegalovirus

Influenza Virus Infections in Humans

Varicella-Zoster Virus

Adenovirus Coinfection with SARS-CoV-2

Genetic Polymorphisms susceptibility to SARS-CoV-2

Acute viral hepatitis

Human receptor of coronavirus and Adenovirus

Antiviral Chemotherapy

Humoral Immune Responses to SARS-CoV-2 Infection

Cellular Immune Responses to SARS-CoV-2

Pathogenesis of SARS-CoV-2