Mechanisms of Viral Pathogenesis

The mechanisms of viral pathogenesis are somewhat different than those observed in the interaction between bacteria and their hosts. First, viruses "live" only within the context of a cell. All viruses are parasites, according to our earlier definitions. However, we are seeing clear evidence that some viruses, endogenous retroviruses for example, have very long term relationships with their hosts— even across generations. Thus, viral pathogenesis is more a matter of degree than it is with bacteria. The virus must recognize its host, enter the cell, find a way to utilize or subvert the physiological processes of the cell for replication, keep the host from recognizing and destroying the infected cell during viral replication, and then move to new cells or hosts. In carrying out these functions, many viruses damage host cells and induce inflammatory responses, causing the signs and symptoms of disease.

Binding to Host Cells and Invasion

Viruses must recognize and bind to the cells in their hosts that will allow them to replicate and move to a new host. Many

478 Chapter 19 Host-Microbe Interactions viruses enter the body by binding to and infecting cells along the mucous membranes. Some viruses enter the body at sites that are damaged or penetrated—for instance by a needle or insect bite. In fact, a whole class of viruses is associated with insect transmission.

As discussed in chapter 14, all viruses have proteins on their surface that interact with specific receptors on the surface of certain host cells, enabling the virus to attach to the target cell. Once attached, many types of viruses are taken up because they stimulate the host cell to "collect receptors" from the surface and internalize them in the process of receptor-mediated endocyto-sis. Others will carry proteins that lead to the fusion of viral lipid coating with the cell membrane, releasing the viral capsid into the cell (see figure 14.8a). ■ receptor-mediated endocytosis, p. 72

The receptor used by a particular virus influences the host range and tissue tropism of that virus; only cells that bear the specific receptor can be infected. The human immunodeficiency virus uses CD4 as a receptor, and either CCR5 or CXCR4 as a co-receptor. Recall that CD4 is found on T-helper cells (as well as other cell types) and CCR5 and CXCR4 are chemokine receptors. Picorna viruses and reoviruses bind to receptors on M cells in the Peyer's patches of the intestinal tract. ■ CD4, p. 407 ■ chemokine receptors, p. 379

The viruses released from the infected cell may infect neighboring cells or they may disseminate in the bloodstream or lymphatic system to other tissues. Polioviruses for example, initially infect cells in the throat and intestinal tract. Upon release from these cells, the virus may spread via the bloodstream to infect motor nerve cells of the brain and spinal cord. ■ polio, p. 677

Avoiding Immune Responses

As intracellular obligate parasites, viruses must subvert or avoid the mechanisms that the body has developed to maintain a healthy internal environment. These include the production of interferon, induction of apoptosis, recognition of altered MHC class I expression, production and action of neutralizing antibodies, and production of effector T-cytotoxic cells capable of killing infected cells.

Avoiding the Antiviral Effects of Interferons

Early in the interaction between the body and a virus, interferon proteins play a large role in providing limits to the ability of viruses to spread among neighboring cells. Interferons alter the regulatory responses of cells and make them more sensitive to the physiological events involved in viral replication. On infection by virus, cells produce new proteins that regulate how those cells behave and limit viral replication. To avoid this, some viruses encode proteins produced early in infection that shut down translation of host mRNA. Others alter enzymatic activities in the cell that would otherwise help to protect the cell from viral infection. Influenza and HIV have mechanisms to do both. ■ interferon, p. 388

Regulation of Host Cell Death by Viruses

A hallmark of viral infection recognized in the early days of virology was damage and death of infected cells. Many of the viruses studied took control of cellular machinery and converted a large fraction of the total mass of the cell into viral components, leading to the loss of cell structure and integrity. As the study of viruses has expanded, we have learned that the types of interactions between viruses and their host cells can be much more complex. Some viruses kill the host cell after production of a large number of viral copies to allow them to spread to other cells. Others control certain aspects of immune surveillance to avoid premature death of their host cell.

Some types of viruses induce apoptosis, or programmed cell death, in their host cell to limit inflammatory response and stimulation of the immune response. Many viral products, particularly double-stranded RNA intermediates, initiate apoptosis. Certain viruses that replicate very rapidly induce the process of apoptosis to help them hide from the inflammatory and antigen-presenting functions of the immune system. A group of viruses that use this mechanism are vesicular stomatitis viruses (VSVs), which primarily infect domestic animals, causing symptoms similar to foot and mouth disease. Others inhibit the process of apoptosis by controlling a protein called p53 that regulates apoptosis activation in the cell. This gives the virus more time to replicate in the cell and produce new copies of itself. This inhibition of the p53 protein in the host cell is often associated with tumor development. Papillomaviruses, a group of viruses that cause various types of warts, interfere with the normal function of p53. ■ apoptosis, p. 387 ■ papillomavirus, p. 654

Some viruses block antigen presentation by MHC class I molecules, the mechanism that the immune system uses to recognize "corrupt cells." Normally, pieces of endogenous proteins are placed into the groove of MHC class I molecules and brought to the cell surface for "inspection" by the T-cytotoxic cells (CD8+) of the adaptive immune response. Some viruses such as herpesviruses block the processing and movement of MHC class I to the surface, making the immune system less aware of their presence in the body. The immune system has developed mechanisms to thwart this widespread "hijacking" of the normal mechanisms for identifying infected cells. Natural killer (NK) cells recognize cells that have "too few" MHC class I molecules and destroy them. Some viruses have also adapted methods to counteract this NK mechanism. Cytomegalovirus (CMV), a herpesvirus that causes severe problems in immunocompromised people, makes "counterfeit" MHC class I proteins and displays them on the surface of its host cells to trick the body into believing "all is well in this cell" (figure 19.15). These counterfeit molecules do not express viral peptides to identify the infection to the immune system and buy time for the virus to replicate. ■ antigen presentation by MHC class I, p. 408 ■ herpesviruses, p. 344 ■ natural killer cells, p. 411 ■ cytomegaloviruses, p. 757

Antibodies and Viruses

Antibodies generally control the spread of virus from cell to cell by neutralizing extracellular viral particles (see figure 16.6). To subvert the role of antibodies, some viruses have developed methods to directly transfer virus from one cell to its immediate neighbors. For example, Mereck's disease virus, a herpesvirus of chickens, transfers from cell to cell within the infected bird by "pushing" viral proteins and DNA into neighboring cells. It only produces whole virus particles in the pinfeathers of infected birds, enabling

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Virus Attack


Eukaryotic cell

Virus-infected cell presents viral antigen fragments in groove of MHC Class I molecules.

19.9 Mechanisms of Viral Pathogenesis 479 Immune System Counter Attack Result

Virus Attack

Virus-infected cell presents viral antigen fragments in groove of MHC Class I molecules.

T-cell x receptor

T-cytotoxic cell

Effector T-cytotoxic cell recognizes an antigen fragment and kills the virus-infected cell.

Virus-infected cell suppresses MHC expression so no antigen can be presented.

Natural killer (NK) cells can recognize abnormal cells that lack MHC Class I molecules and kill them.

Natural killer cell

Natural killer (NK) cells can recognize abnormal cells that lack MHC Class I molecules and kill them.

Cell death

Virus in infected cell directs the cell to make fake MHC proteins that cannot display antigen.

Neither T-cytotoxic cells nor NK cells can recognize virus-infected cell with fake MHC; virus-infected cell survives.

Cell survives

Virus in infected cell directs the cell to make fake MHC proteins that cannot display antigen.

Neither T-cytotoxic cells nor NK cells can recognize virus-infected cell with fake MHC; virus-infected cell survives.

Cell survives

Figure 19.15 Cytomegalovirus-Immune Cell Interactions (a) Normal killing of virus-infected cell by T-cytotoxic cell. (b) Some viruses can evade destruction of their host cell by suppressing MHC expression, but NK cells of host can kill cells lacking MHC molecules. (c) Virus causes cell to produce fake MHC that neitherT-cytotoxic cells nor NK cells can recognize, and so the virus-infected cell survives.

Cell death its transfer to a new host. Other viruses remain intracellular by forcing all the cellular neighbors to join a "commune," fusing to form what is called a syncytium. Viruses like HIV avoid the neutralizing activity of antibodies by inducing syncytia formation.

Some viruses, like the coronavirus that causes feline infectious peritonitis (FIP), actually use antibody to enhance their ability to infect cells. These viruses use the "free ride" given by Fc-mediated uptake of viral-antibody complexes into macrophages to enhance infection and damage the host. This is referred to as antibody-mediated enhancement of infection. HIV also uses antibody-mediated enhancement of infection, causing problems in the secondary lymphoid tissue of infected patients.

Another way viruses deal with the development of antibody is to outpace the body's capacity to produce them by shifting surface antigens. RNA viruses contain, on average, one mutation per new viral particle. Their polymerases copy RNA without any proofreading, so the mutation frequency is about 1 base in 100,000. There are more than 100,000 bases in the average RNA virus, so about 1 error per new virus. The accumulation of mutations by these viruses generates pools of genetically altered viruses called pseudo-species. The development of these families of new genetic lines provide a large number of "escape" mutants that come into dominance as the "parent" viruses are rapidly neutralized by antibody. Thus, the body keeps selecting for new viral "strains" over the course of infection. Many of these viruses are eventually cleared as a result of an immune response against epitopes of essential proteins that cannot tolerate extensive mutations. Other viruses, like HIV, exploit this pseudo-species method to infect the host for a very long time.

480 Chapter 19 Host-Microbe Interactions

Viruses and Damage to the Host

Viruses can damage host cells in many ways. Some viruses just take over the host cell, use up the internal components, and then burst it to release new copies of themselves. The combination of tissue damage and presence of viral antigens evokes the innate and adaptive immune responses. Damage is caused by a combination of events including the inflammatory response and the destruction of host cells by both the virus and T-cytotoxic cells.

Other viruses cause host cell death by activation of apopto-sis, either by design or accident. Apoptotic death generally minimizes local inflammatory responses and retards development of an immune response. Some infections cause such little damage to most tissues they cause no symptoms. In critical tissues such as nerves, however, even slight damage can be symptomatic. At times the number of infected cells in a critical tissue is large enough that the immune destruction of infected cells causes the symptoms of disease. If enough cells are lost even in non-critical tissues, functional changes occur in the host, signaling danger and eliciting a response from the host defenses.

In other instances, like the common cold, the body responds vigorously to the infection and causes many cycles of damage and response—far out of proportion with the damage done directly by the virus. Here the damage done to cells the virus is exploiting leads to more inflammatory response, more damage and more response through many rounds of activation. Thus, we suffer a long time from the common cold even after the virus has moved on.

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  • elisa
    What do you mean by viral pathogenesis..?
    2 years ago

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