Porth's Essentials of Pathophysiology, 4e

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Mechanisms of Infectious Disease

C h a p t e r 1 4

The prion protein (PrP) is a human protein expressed on the cell surface. Its normal role is not well understood, but it is hypothesized to be involved in cell adhesion, cell binding, copper metabolism, or in synaptic function. Recent studies have shown that the prion proteins in disease (called PrP SC ) are actually altered or mutated forms of a normal host protein called PrP C . Differences in the posttranslational structure cause the two proteins to behave differently. The PrP SC is resistant to the action of proteases (enzymes that degrade excess or deformed proteins) and aggregates in the cytoplasm of affected neurons as amyloid fibrils. The normal PrP C is protease sensitive and appears on the cell surface. Prion diseases present significant problems to the medical community because their method of replica- tion is not clearly understood. Based on current mod- els, it is believed that PrP SC binds to the normal PrP C on the cell surface, causing it to be processed into PrP SC , which is released from the cell and then aggregates into amyloid-like plaques in the brain. The cell then replen- ishes the PrP C and the cycle continues. As PrP SC accu- mulates, it spreads within the axons of the nerve cells, causing progressively greater damage to host neurons and the eventual incapacitation of the host. In addition, because prions lack reproductive and metabolic func- tions, the currently available antimicrobial agents are useless against them. Viruses Viruses are the smallest obligate intracellular patho- gens. They have no organized cellular structures but instead consist of a protein coat, or capsid, surround- ing a nucleic acid core, or genome, of RNA or DNA— never both (Fig. 14-1 ). Some viruses are enclosed within a lipoprotein envelope derived from the cell membrane of the parasitized host cell. Enveloped viruses include members of the herpesvirus group and paramyxovi- ruses, such as influenza and poxviruses. Certain viruses, enveloped in buds pinched from the cell membrane, are continuously shed from the infected cell surface. The viruses of humans and animals have been cat- egorized somewhat arbitrarily according to various characteristics. These include the type of viral genome (single-stranded or double-stranded DNA or RNA), physical characteristics (e.g., size, presence or absence of a membrane envelope), the mechanism of replica- tion (e.g., retroviruses), the mode of transmission (e.g., arthropod-borne viruses, enteroviruses), target tissue, and the type of disease produced (e.g., hepatitis A, B, C, D, and E viruses), to name just a few. Viruses are incapable of replication outside of a living cell. They must penetrate a susceptible living cell and use the biosynthetic machinery of the cell to produce viral progeny. The process of viral replication is shown in Figure 14-2. Not every viral agent causes lysis and death of the host cell during the course of replication. Some viruses enter the host cell and insert their genome into the host cell chromosome, where it remains in a latent state for long periods without causing disease. Under the appropriate stimulation, the virus undergoes

A

Virion

Nucleic acid genome (DNA or RNA)

Capsid

B

Envelope

FIGURE 14-1. (A) The basic structure of a virus includes a protein coat surrounding an inner core of nucleic acid (DNA or RNA). (B) Some viruses may also be enclosed in a lipoprotein outer envelope.

active replication and produces symptoms of disease months to years later. Members of the herpesvirus group and adenovirus are the best examples of latent viruses. Herpesviruses include the viral agents of chickenpox and zoster (varicella-zoster), cold sores (herpes simplex virus [HSV], usually type 1), genital herpes (HSV, usu- ally type 2), infectious mononucleosis (cytomegalovirus or Epstein-Barr virus), and Kaposi sarcoma (human her- pesvirus 8). The resumption of the latent viral replica- tion may produce symptoms of primary disease (e.g., genital herpes) or cause an entirely different symptom- atology (e.g., shingles instead of chickenpox). Since the early 1980s, members of the retrovirus group have received considerable attention after iden- tification of the human immunodeficiency viruses (HIV) as the causative agent of acquired immunodeficiency syndrome (AIDS). The retroviruses have a unique mech- anism of replication. After entry into the host cell, the viral RNA genome is first translated into DNA by a viral enzyme called reverse transcriptase (see Chapter 16). The viral DNA copy is then integrated into the host chromosome where it exists in a latent state, similar to the herpesviruses. Reactivation and replication require a reversal of the entire process. Some retroviruses lyse the host cell during the process of replication. In the case of HIV, the infected cells regulate the immunologic defense system of the host and their lysis leads to a permanent suppression of the immune response. In addition to causing infectious diseases, certain viruses also have the ability to transform normal host cells into malignant cells during the replication cycle. This group of viruses is referred to as oncogenic and includes certain retroviruses and DNA viruses, such as