Review of Medical Microbiology and Immunology, 13th Edition

32. Pathogenesis

CHAPTER CONTENTS

Introduction

The Infected Cell

The Infected Patient

Transmission & Portal of Entry

Localized or Disseminated Infections

Pathogenesis & Immunopathogenesis

Virulence

Evasion of Host Defenses

Persistent Viral Infections

Chronic-Carrier Infections

Latent Infections

Slow Virus Infections

Pearls

Self-Assessment Questions

Practice Questions: USMLE & Course Examinations

INTRODUCTION

The ability of viruses to cause disease can be viewed on two distinct levels: (1) the changes that occur within individual cells and (2) the process that takes place in the infected patient.

THE INFECTED CELL

There are four main effects of virus infection on the cell: (1) death, (2) fusion of cells to form multinucleated cells, (3) malignant transformation, and (4) no apparent morphologic or functional change.

Death of the cell is probably due to inhibition of macromolecular synthesis. Inhibition of host cell protein synthesis frequently occurs first and is probably the most important effect. Inhibition of DNA and RNA synthesis may be a secondary effect. It is important to note that synthesis of cellular proteins is inhibited but viral protein synthesis still occurs. For example, 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.

Infected cells frequently contain inclusion bodies, which are discrete areas containing viral proteins or viral particles. They have a characteristic intranuclear or intracytoplasmic location and appearance depending on the virus. One of the best examples of inclusion bodies that can assist in clinical diagnosis is that of Negri bodies, which are eosinophilic cytoplasmic inclusions found in rabies virus–infected brain neurons. Another important example is the owls eye inclusion seen in the nucleus of cytomegalovirus-infected cells. Electron micrographs of inclusion bodies can also aid in the diagnosis when virus particles of typical morphology are visualized.

Fusion of virus-infected cells produces multinucleated giant cells, which characteristically form after infection with herpesviruses and paramyxoviruses. Fusion occurs as a result of cell membrane changes, which are probably caused by the insertion of viral proteins into the membrane. The clinical diagnosis of herpesvirus skin infections is aided by the finding of multinucleated giant cells with eosinophilic intranuclear inclusions in skin scrapings.

A hallmark of viral infection of the cell is the cytopathic effect (CPE). This change in the appearance of the infected cell usually begins with a rounding and darkening of the cell and culminates in either lysis (disintegration) or giant cell formation. Detection of virus in a clinical specimen frequently is based on the appearance of CPE in cell culture. In addition, CPE is the basis for the plaque assay, an important method for quantifying the amount of virus in a sample.

Infection with certain viruses causes malignant transformation, which is characterized by unrestrained growth, prolonged survival, and morphologic changes such as focal areas of rounded, piled-up cells. These changes are described in more detail in Chapter 43.

Infection of the cell accompanied by virus production can occur without morphologic or gross functional changes. This observation highlights the wide variations in the nature of the interaction between the virus and the cell, ranging from rapid destruction of the cell to a symbiotic relationship in which the cell survives and multiplies despite the replication of the virus.

THE INFECTED PATIENT

Pathogenesis in the infected patient involves (1) transmission of the virus and its entry into the host; (2) replication of the virus and damage to cells; (3) spread of the virus to other cells and organs; (4) the immune response, both as a host defense and as a contributing cause of certain diseases; and (5) persistence of the virus in some instances.

The stages of a typical viral infection are the same as those described for a bacterial infection in Chapter 7, namely, an incubation period during which the patient is asymptomatic, a prodromal period during which nonspecific symptoms occur, a specific-illness period during which the characteristic symptoms and signs occur, and a recovery period during which the illness wanes and the patient regains good health. In some patients, the infection persists and a chronic carrier state or a latent infection occurs (see later).

Transmission & Portal of Entry

Viruses are transmitted to the individual by many different routes, and their portals of entry are varied (Table 32–1). For example, person-to-person spread occurs by transfer of respiratory secretions, saliva, blood, or semen and by fecal contamination of water or food. The transfer of blood, either by transfusion or by sharing needles during intravenous drug use, can transmit various viruses (and bacteria). The screening of donated blood for human immunodeficiency virus, human T-cell lymphotropic virus, hepatitis B virus, hepatitis C virus, and West Nile virus (as well as Treponema pallidum) has greatly reduced the risk of infection by these pathogens.

TABLE 32–1 Main Portal of Entry of Important Viral Pathogens

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Transmission can occur also between mother and offspring in utero across the placenta, at the time of delivery, or during breast feeding (Table 32–2). (Transmission between mother and offspring is called vertical transmission. Person-to-person transmission that is not from mother to offspring is called horizontal transmission.)

TABLE 32–2 Viruses That Commonly Cause Perinatal Infections

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Animal-to-human transmission can take place either directly from the bite of a reservoir host as in rabies or indirectly through the bite of an insect vector, such as a mosquito, which transfers the virus from an animal reservoir to the person. The zoonotic diseases caused by viruses are described in Table 32–3. In addition, activation of a latent, nonreplicating virus to form an active, replicating virus can occur within the individual, with no transmission from an external source.

TABLE 32–3 Medically Important Viruses That Have an Animal Reservoir

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Localized or Disseminated Infections

Most viral infections are either localized to the portal of entry or spread systemically through the body. The best example of the localized infection is the common cold caused by rhinoviruses, which involves only the upper respiratory tract. Influenza is localized primarily to the upper and lower respiratory tracts. Respiratory viruses have a short incubation period because they replicate directly in the mucosa, but systemic infections such as poliomyelitis and measles have a long incubation period because viremia and secondary sites of replication are required.

One of the best-understood systemic viral infections is paralytic poliomyelitis (Figure 32–1). After poliovirus is ingested, it infects and multiplies within the cells of the small intestine and then spreads to the mesenteric lymph nodes, where it multiplies again. It then enters the bloodstream and is transmitted to certain internal organs, where it multiplies again. The virus reenters the bloodstream and is transmitted to the central nervous system, where damage to the anterior horn cells occurs, resulting in the characteristic muscle paralysis. It is during this obligatory viremia that circulating IgG antibodies induced by the polio vaccine can prevent the virus from infecting the central nervous system. Viral replication in the gastrointestinal tract results in the presence of poliovirus in the feces, thus perpetuating its transmission to others.

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FIGURE 32–1 Systemic viral infection by poliovirus, resulting in paralytic poliomyelitis. CNS, central nervous system. (Modified and reproduced with permission from Brooks GF et al. Medical Microbiology. 20th ed. Originally published by Appleton & Lange. Copyright 1995 by McGraw-Hill.)

Some viral infections spread systemically, not via the bloodstream, but rather by retrograde axonal flow within neurons. Four important human pathogens do this: rabies virus, herpes simplex type 1, herpes simplex type 2, and varicella-zoster virus. As an example, rabies virus is introduced into the body at the site of an animal bite. The virus infects a local sensory neuron and ascends into the central nervous system by retrograde axonal flow, where it causes encephalitis.

Some of the molecular determinants of pathogenesis have been determined by using reovirus infection in mice as a model system. This virus has three different outer capsid proteins, each of which has a distinct function in determining the course of the infection. One of the proteins binds to specific receptors on the cell surface and thereby determines tissue tropism. A second protein conveys resistance to proteolytic enzymes in the gastrointestinal tract and acts as the antigen that stimulates the cellular immune response. The third protein inhibits cellular RNA and protein synthesis, leading to death of the cell. Alternatively, this third protein can play a role in the initiation of persistent viral infection.

Pathogenesis & Immunopathogenesis

The signs and symptoms of most viral diseases undoubtedly are the result of cell killing by virus-induced inhibition of macromolecular synthesis. Death of the virus-infected cells results in a loss of function and in the symptoms of disease. For example, when poliovirus kills motor neurons, paralysis of the muscles innervated by those neurons results. Also, the hemorrhages caused by Ebola virus are due to the damage to the vascular endothelial cells caused by the envelope glycoprotein of the virus.

However, there are some diseases that are not caused by the virus damaging or killing the infected cell. For example, rotavirus-induced diarrhea is caused primarily by stimulation of the enteric nervous system. It is thought that the rotavirus-infected enterocytes produce cytokines that stimulate the enteric neurons, resulting in excess fluid and electrolyte secretion into the bowel lumen.

There are other diseases in which cell killing by immunologic attack plays an important role in pathogenesis. Both cytotoxic T cells and antibodies play a role in immunopathogenesis.

(1) The best-studied system is lymphocytic choriomeningitis (LCM) in mice; LCM occurs in humans also but is quite rare. When LCM virus is inoculated into the brain of an adult mouse, virus replication occurs and death follows. However, when LCM virus is inoculated into the brain of an immunosuppressed adult mouse or a newborn mouse, the animal remains well despite extensive virus replication. When immune lymphocytes are inoculated into these infected, but otherwise healthy mice, death ensues. It appears that death of the cells is caused by immune attack by cytotoxic T cells on the new viral antigens in the cell membrane rather than by virus-induced inhibition of cell functions.

(2) Cytotoxic T cells are involved in the pathogenesis of hepatitis caused by hepatitis A, B, and C viruses. These viruses do not cause a CPE, and the damage to the hepatocytes is the result of the recognition of viral antigens on the hepatocyte surface by cytotoxic T cells. The rash of measles is similarly caused by these cells attacking the infected vascular endothelium in the skin.

(3) Immune-mediated pathogenesis also occurs when virus–antibody-complement complexes form and are deposited in various tissues. This occurs in hepatitis B virus infection, in which immune complexes play a role in producing the arthritis characteristic of the early stage of hepatitis B. Immune complexes also cause the arthritis seen in parvovirus B19 and rubella virus infections. The pathogenesis of pneumonia caused by respiratory syncytial virus in infants is attributed to immune complexes formed by maternal IgG and viral antigens.

Virulence

Strains of viruses differ greatly in their ability to cause disease. For example, there are strains of poliovirus that have mutated sufficiently such that they have lost the ability to cause polio in immunocompetent individuals (i.e., they are attenuated). These strains are used in vaccines. The viral genes that control the virulence of the virus are poorly characterized, and the process of virulence is poorly understood.

Evasion of Host Defenses

Viruses have several ways by which they evade our host defenses (Table 32–4). These processes are often called immune evasion. Some viruses encode the receptors for various mediators of immunity such as interleukin-1 (IL-1) and tumor necrosis factor (TNF). For example, vaccinia virus encodes a protein that binds to IL-1, and fibroma virus encodes a protein that binds to TNF. When released from virus-infected cells, these proteins bind to the immune mediators and block their ability to interact with receptors on their intended targets, our immune cells that mediate host defenses against the viral infection. By reducing our host defenses, the virulence of the virus is enhanced. These virus-encoded proteins that block host immune mediators are often called cytokine decoys.

TABLE 32–4 Important Mechanisms by Which Viruses Evade Host Defenses

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In addition, some viruses (e.g., human immunodeficiency virus [HIV] and herpesviruses, such as herpes simplex virus and cytomegalovirus [CMV]) can reduce the expression of class I MHC (major histocompatibility complex) proteins, thereby reducing the ability of cytotoxic T cells to kill the virus-infected cells, and others (e.g., herpes simplex virus) inhibit complement. Several viruses (HIV, Epstein–Barr virus, and adenovirus) synthesize RNAs that block the phosphorylation of an initiation factor (eIF-2), which reduces the ability of interferon to block viral replication (see Chapter 33). CMV encodes a microRNA that binds to the mRNA of a cell surface ligand for natural killer cells. Binding of the microRNA prevents synthesis of the ligand, which prevents killing of the CMV-infected cells by the natural killer cells. Measles virus blocks synthesis of IL-12, thereby reducing an effective Th-1 response. Ebola virus synthesizes two proteins, one of which blocks the induction of interferon, whereas the other blocks its action. Collectively, these viral virulence factors are called virokines.

A third important way by which viruses evade our host defenses is by having multiple antigenic types (also known as multiple serotypes). The clinical importance of a virus having multiple serotypes is that a patient can be infected with one serotype, recover, and have antibodies that protect from infection by that serotype in the future; however, that person can be infected by another serotype of that virus. The classic example of a virus with multiple serotypes is rhinovirus, which has more than 100 serotypes. This is the reason why the “common cold” caused by rhinoviruses is so common. Influenza virus also has multiple serotypes, and the severe worldwide epidemics of influenza are attributed to the emergence of new antigenic types. HIV and hepatitis C virus have multiple serotypes, which contribute to the difficulty in obtaining a vaccine against these viruses. Note that only some viruses have multiple serotypes. Many important human pathogens (e.g., measles virus, rubella virus, varicella-zoster virus, and rabies virus) have only one serotype, and some have only a few serotypes (e.g., poliovirus has three serotypes).

Persistent Viral Infections

In most viral infections, the virus does not remain in the body for a significant period after clinical recovery. However, in certain instances, the virus persists for long periods either intact or in the form of a subviral component (e.g., the genome). The mechanisms that may play a role in the persistence of viruses include (1) integration of a DNA provirus into host cell DNA, as occurs with retroviruses; (2) immune tolerance, because neutralizing antibodies are not formed; (3) formation of virus–antibody complexes, which remain infectious; (4) location within an immunologically sheltered “sanctuary” (e.g., the brain); (5) rapid antigenic variation; (6) spread from cell to cell without an extracellular phase, so that virus is not exposed to antibody; and (7) immunosuppression, as in acquired immunodeficiency syndrome (AIDS).

There are three types of persistent viral infections of clinical importance. They are distinguished primarily by whether virus is usually produced by the infected cells and by the timing of the appearance both of the virus and of the symptoms of disease.

Chronic-Carrier Infections

Some patients who have been infected with certain viruses continue to produce significant amounts of the virus for long periods. This carrier state can follow an asymptomatic infection as well as the actual disease and can itself either be asymptomatic or result in chronic illness. Important clinical examples are chronic hepatitis, which occurs in hepatitis B and hepatitis C virus carriers, and neonatal rubella virus and CMV infections, in which carriers can produce virus for years.

Latent Infections

In these infections, best illustrated by the herpesvirus group, the patient recovers from the initial infection and virus production stops. Subsequently, the symptoms may recur, accompanied by the production of virus. In herpes simplex virus infections, the virus enters the latent state in the cells of the sensory ganglia. The molecular nature of the latent state is unknown. Herpes simplex virus type 1, which causes infections primarily of the eyes and face, is latent in the trigeminal ganglion, whereas herpes simplex virus type 2, which causes infections primarily of the genitals, is latent in the lumbar and sacral ganglia. Varicella-zoster virus, another member of the herpesvirus family, causes varicella (chickenpox) as its initial manifestation and then remains latent, primarily in the trigeminal or thoracic ganglion cells. It can recur in the form of the painful vesicles of zoster (shingles), usually on the face or trunk.

Slow Virus Infections

The term slow refers to the prolonged period between the initial infection and the onset of disease, which is usually measured in years. In instances in which the cause has been identified, the virus has been shown to have a normal, not prolonged, growth cycle. It is not, therefore, that virus growth is slow; rather, the incubation period and the progression of the disease are prolonged. Two of these diseases are caused by conventional viruses, namely, subacute sclerosing panencephalitis, which follows several years after measles virus infections, and progressive multifocal leukoencephalopathy (PML), which is caused by JC virus, a papovavirus. PML occurs primarily in patients who have lymphomas or are immunosuppressed. Other slow infections in humans (e.g., Creutzfeldt-Jakob disease and kuru) may be caused by unconventional agents called prions (see Chapter 28). Slow virus infections are described in Chapter 44.

PEARLS

The Infected Cell

• Death of infected cells is probably caused by inhibition of cellular protein synthesis. Translation of viral mRNA into viral proteins preempts the ribosomes preventing synthesis of cellular proteins.

• Inclusion bodies are aggregates of virions in specific locations in the cell that are useful for laboratory diagnosis. Two important examples are Negri bodies in the cytoplasm of rabies virus–infected cells and owl’s eye inclusions in the nucleus of cytomegalovirus-infected cells.

• Multinucleated giant cells form when cells are infected with certain viruses, notably herpesviruses and paramyxoviruses such as respiratory syncytial virus.

• Cytopathic effect (CPE) is a visual or functional change in infected cells typically associated with the death of cells.

• Malignant transformation occurs when cells are infected with oncogenic viruses. Transformed cells are capable of unrestrained growth.

• Some virus-infected cells appear visually and functionally normal, yet are producing large numbers of progeny viruses.

The Infected Patient

• Viral infection in the person typically has four stages: incubation period, prodromal period, specific-illness period, and recovery period.

• The main portals of entry are the respiratory, gastrointestinal, and genital tracts, but through the skin, across the placenta, and via blood are important as well.

• Transmission from mother to offspring is called vertical transmission; all other modes of transmission (e.g., fecal–oral, respiratory aerosol, insect bite) are horizontal transmission. Transmission can be from human to human or from animal to human.

• Most serious viral infection are systemic (i.e., the virus travels from the portal of entry via the blood to various organs). However, some are localized to the portal of entry, such as the common cold, which involves only the upper respiratory tract.

Pathogenesis

• The symptoms of viral diseases are usually caused by death of the infected cells and a consequent loss of function. For example, poliovirus kills neurons, resulting in paralysis.

• Immunopathogenesis is the process by which the symptoms of viral diseases are caused by the immune system rather than by the killing of cells directly by the virus. One type of immunopathogenesis is the killing of virus-infected cell by the attack of cytotoxic T cells that recognize viral antigens on the cell surface. Damage to the liver caused by hepatitis viruses occurs by this mechanism. Another is the formation of virus–antibody complexes that are deposited in tissues. Arthritis associated with parvovirus B19 or rubella virus infection occurs by this mechanism.

• Virulence of viruses differs markedly from one virus to another and among different strains of the same virus. The genetic basis for these differences is not well understood. Strains with weakened (attenuated) virulence are often used in vaccines.

• Viruses can evade host defenses by producing multiple antigens, thereby avoiding inactivation by antibodies, and by reducing the synthesis of class I MHC proteins, thereby decreasing the ability of a cell to present viral antigens and blunting the ability of cytotoxic T cells to kill the virus-infected cells. Viruses also produce receptors for immune mediators, such as IL-1 and TNF, thereby preventing the ability of these mediators to activate antiviral processes.

Persistent Viral Infections

• Carrier state refers to people who produce virus for long periods of time and can serve as a source of infection for others. The carrier state that is frequently associated with hepatitis C virus infection is a medically important example.

• Latent infections are those infections that are not producing virus at the present time but can be reactivated at a subsequent time. The latent infections that are frequently associated with herpes simplex virus infection are a medically important example.

• Slow virus infections refer to those diseases with a long incubation period, often measured in years. Some, such as progressive multifocal leukoencephalopathy, are caused by viruses, whereas others, such as Creutzfeldt-Jakob disease, are caused by prions. The brain is often the main site of these diseases.

SELF-ASSESSMENT QUESTIONS

1. Viruses can cause changes in individual cells that are visible in the light microscope after suitable staining. Which one of the following is most characteristic of the changes seen in rabies virus–infected cells?

(A) Inclusion bodies in the cytoplasm of macrophages

(B) Inclusion bodies in the cytoplasm of neurons

(C) Inclusion bodies in the nucleus of neurons

(D) Multinucleated giants cells composed of neurons

(E) Multinucleated giants cells composed of macrophages

2. Many viruses use the upper respiratory tract (mouth, nasopharynx) as their important portal of entry. One feature of the portal of entry is that it is the site where the virus first infects and replicates. Which one of the following viruses is most likely to enter via the upper respiratory tract?

(A) Dengue virus

(B) Epstein–Barr virus

(C) Hepatitis A virus

(D) Hepatitis B virus

(E) Rotavirus

3. The term vertical transmission refers to:

(A) transmission by insect vector from reservoir to patient.

(B) transmission from a sex worker to a client.

(C) transmission from mother to child.

(D) transmission from one child to another at school.

(E) transmission from person to person within a family.

4. Some viruses are known for their ability to cause perinatal infections. Which one of the following viruses is most likely to cause perinatal infections?

(A) Cytomegalovirus

(B) Epstein–Barr virus

(C) JC virus

(D) Norovirus

(E) Poliovirus

5. Which one of the following viruses that causes human disease has an animal reservoir?

(A) Cytomegalovirus

(B) Hepatitis C virus

(C) Smallpox virus

(D) Varicella-zoster virus

(E) Yellow fever virus

6. Which one of the following best describes the mechanism by which immunopathogenesis occurs?

(A) Ability of antibodies to block pathogenesis by viruses

(B) Ability of cytotoxic T cells to block pathogenesis by viruses

(C) Ability of neutrophils to block pathogenesis by viruses

(D) Ability of cytotoxic T cells to cause pathogenesis by viruses

(E) Ability of eosinophils to cause pathogenesis by viruses

ANSWERS

1. (B)

2. (B)

3. (C)

4. (A)

5. (E)

6. (D)

PRACTICE QUESTIONS: USMLE & COURSE EXAMINATIONS

Questions on the topics discussed in this chapter can be found in the Basic Virology section of PART XIII: USMLE (National Board) Practice Questions starting on page 700. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.