Described next are some of the mechanisms whereby viruses and bacteria damage host tissues.
Viruses can directly damage host cells by entering them and replicating at the host’s expense. The manifestations of viral infection are largely determined by the tropism of the virus for specific tissues and cell types. Tropism is influenced by a number of factors.
Host receptors for viruses. Viruses are coated with surface proteins that bind with high specificity to particular host cell surface proteins. Entry of many viruses into cells commences with binding to normal host cell receptors. For example, HIV glycoprotein gp120 binds to CD4 and CXCR4 and CCR5 on T cells and macrophages (Chapter 5). Host proteases may be needed to enable binding of virus to host cells; for instance, a host protease cleaves and activates the influenza virus hemagglutinin.
Specificity of transcription factors. The ability of the virus to replicate inside particular cell types depends on the presence of lineage-specific transcription factors that recognize viral enhancer and promoter elements. For example, the JC virus, which causes leukoencephalopathy (Chapter 23), replicates only in oligodendroglia in the CNS because the promoter and enhancer DNA sequences regulating viral gene expression are active in glial cells, but not in neurons or endothelial cells.
Physical characteristics of tissues. Host environment and temperature can contribute to tissue tropism. For example, enteroviruses replicate in the intestine in part because they can resist inactivation by acids, bile, and digestive enzymes. Rhinoviruses infect cells only within the upper-respiratory tract because they replicate optimally at the lower temperatures characteristic of this site.
Once viruses are inside host cells, they can damage or kill the cells by a number of mechanisms (
Fig. 9.7
Direct cytopathic effects. Viruses can kill cells by preventing synthesis of critical host macromolecules, by producing degradative enzymes and toxic proteins, or by inducing apoptosis. For example, poliovirus blocks synthesis of host proteins by inactivating cap-binding protein. HSV produces proteins that inhibit synthesis of cellular DNA and mRNA and other proteins that degrade host DNA. Viral replication also can trigger apoptosis of host cells by cell-intrinsic mechanisms, such as perturbations of the endoplasmic reticulum during virus assembly, which can activate caspases that mediate apoptosis.
Anti-viral immune responses. Viral proteins on the surface of host cells may be recognized by the immune system, and lymphocytes may attack virus-infected cells. Cytotoxic T lymphocytes (CTLs) are important for defense against viral infections, but CTLs also can be responsible for tissue injury. Hepatitis B infection causes CTL-
Fig. 9.7 Mechanismsbywhichvirusescauseinjurytocells.Virus Receptor Entry, uncoating Viral genome replication, mRNA synthesis Viral protein synthesis Virus assembly Viral antigens Neoplastic transformation Cell lysis or fusion Reduced host cell DNA, RNA, protein synthesis Metabolic derangements Host T cell–mediated injury Viral inclusions VIRAL PROTEINS mediated destruction of infected hepatocytes, a normal response that is attempting to clear the infection.
• Transformation of infected cells. Different oncogenic viruses (e.g., HPV, EBV) can stimulate cell growth and survival by a variety of mechanisms, including hijacking the control of cell cycle machinery, anti-apoptotic strategies, and insertional mutagenesis (in which the insertion of viral DNA into the host genome alters the expression of nearby host genes). Mechanisms of viral transformation are discussed in Chapter 6.