Mechanisms of Viral Injury
Viruses can directly damage host cells by entering them and replicating at the host's expense. The predilection for viruses to infect certain cells and not others is called tissue tropism and is
determined by several factors, including (1) host cell receptors for the virus, (2) cellular transcription factors that recognize viral enhancer and promoter sequences, (3) anatomic barriers,
and (4) local temperature, pH, and host defenses. Each of these is described briefly.
A major determinant of tissue tropism is the presence of viral receptors on host cells. Viruses possess specific cell-surface proteins that bind to particular host cell-surface proteins. Many
viruses use normal cellular receptors of the host to enter cells. For example, HIV gp120 binds to CD4 on T cells and to the chemokine receptors CXCR4 (mainly on T cells) and CCR5
(mainly on macrophages). Rhinoviruses bind to the same site on ICAM-1 as LFA-1, an integrin on the surface of lymphocytes that is an important adhesion molecule for lymphocyte
activation and migration. In some cases, host proteases are needed to enable binding of virus to host cells; for instance, a host protease cleaves and activates the influenza virus
Another determinant of viral tropism is the ability of the virus to replicate inside some cells but not in others, and this is related to the presence of cell-type—specific transcription factors.
For example, the JC virus, which causes leukoencephalopathy ( Chapter 28 ), is restricted to oligodendroglia in the central nervous system because the promoter and enhancer DNA
sequences upstream from the viral genes are active in glial cells but not in neurons or endothelial cells. Physical barriers also 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 replicate only within the upper respiratory tract because they survive
optimally at the lower temperature of the upper respiratory tract.
Once viruses are inside host cells, they can kill the cells and/or cause tissue damage in a number of ways ( Fig. 8-5 ):
• Viruses may inhibit host cell DNA, RNA, or protein synthesis. For example, poliovirus inactivates cap-binding protein, which is essential for translation of host cell mRNAs, but
leaves translation of poliovirus mRNAs unaffected.
• Viral proteins may insert into the host cell's plasma membrane and directly damage its integrity or promote cell fusion (HIV, measles virus, and herpesviruses).
• Viruses may lyse host cells. For example, respiratory epithelial cells are killed by influenza virus replication, liver cells by yellow fever virus, and neurons by poliovirus and
• Viruses may manipulate programmed cell death (apoptosis). Some virus-encoded proteins (including TAT and gp120 of HIV, adenovirus E1A) can induce cell death. In contrast,
some viruses encode one or more genes that inhibit apoptosis (e.g., homologues of the cellular bcl-2 gene), suggesting that apoptotic cell death may be a protective host response to
eliminate virus-infected cells. It has been hypothesized that viral antiapoptotic strategies may enhance viral replication, promote persistent viral infections, or promote virusinduced
• Viral proteins on the surface of the host cells may be recognized by the immune system, and the host lymphocytes may attack the virus-infected cells. Acute liver failure during
hepatitis B infection may be accelerated by cytotoxic T lymphocyte (CTL)-mediated destruction of infected hepatocytes (a normal response to clear the infection). FAS ligand on
CTLs, which bind to FAS receptors on the surface of hepatocytes, also can induce apoptosis in target cells.
• Viruses may damage cells involved in host antimicrobial defense, leading to secondary infections. For example, viral damage to respiratory epithelium predisposes to the
subsequent development of pneumonia by Streptococcus pneumoniae and Haemophilus influenzae. HIV depletes CD4+ helper lymphocytes and thereby causes opportunistic
• Viral killing of one cell type may cause the death of other cells that depend on them. For example, denervation by the attack of poliovirus on motor neurons causes atrophy and
sometimes death of distal skeletal muscle supplied by such neurons.
• Some viruses can cause cell proliferation and transformation (e.g., EBV, HBV, human papillomavirus, or HTLV-1), resulting in cancer. The mechanisms of viral transformation
are numerous and are discussed in Chapter 7 .
Figure 8-5Mechanisms by which viruses cause injury to cells.
TABLE 8-8-- Pathogens with Significant Antigenic Variation
Influenza virus Influenza
Neisseria gonorrhoeae Gonorrhea
Borrelia hermsii Relapsing fever
Borrelia burgdorferi Lyme disease
Trypanosoma brucei African sleeping sickness
Giardia lamblia Giardiasis
Plasmodium falciparum Severe malaria
neutrophils and macrophages. The carbohydrate capsule on the surface of all the major bacteria that cause pneumonia or meningitis (pneumococcus, meningococcus, Haemophilus
influenzae) makes them more virulent by shielding bacterial antigens and by preventing phagocytosis of the organisms by neutrophils. For example, E. coli with the sialic acid-containing
K1 capsule causes meningitis in newborns. Sialic acid will not bind C3b, which is critical for activation of the alternative complement pathway, so the bacteria escape from complementmediated
lysis and opsonization-directed phagocytosis. Many bacteria make toxic proteins that kill phagocytes, prevent their migration, or diminish their oxidative burst. Bacteria also can
circumvent immune defenses by covering themselves with host proteins. S. aureus are covered by protein A molecules that bind the Fc portion of antibodies and so inhibit phagocytosis.
Neisseria, Haemophilus, and Streptococcus all secrete proteases that degrade antibodies. Another successful strategy for circumventing phagocytic defense mechanisms is to replicate
within phagocytic cells. A number of viruses, rickettsias, some intracellular bacteria (including mycobacteria, Listeria, and Legionella), fungi (e.g., Cryptococcus neoformans), and
protozoa (e.g., leishmania, trypanosomes, toxoplasmas) can multiply within phagocytes.
Viruses can produce molecules that inhibit innate immunity.   Some viruses (e.g., herpesviruses and poxviruses) produce proteins that block complement activation. Viruses have
developed a large number of strategies to combat interferons (IFN), an early host defense against viruses. Some viruses produce soluble homologues of IFN-a/b or IFN-g receptors that
inhibit actions of extracellular IFNs, or produce proteins that inhibit intracellular JAK/STAT signaling downstream of IFN receptors or inactivate or inhibit dsRNA-dependent protein
kinase (PKR), a key mediator of the antiviral effects of IFN. Viruses also can produce homologues of chemokines or chemokine receptors, and these can function as antagonists and inhibit
recruitment of inflammatory cells to favor survival of viruses. Viruses also can produce soluble cytokine mimics (e.g., EBV produces a homologue of the immunosuppressive cytokine IL-
10) or soluble cytokine receptor homologues.
Some microbes can decrease recognition of infected cells by CD4+ helper T cells and CD8+ cytotoxic T cells. For example, several DNA viruses (e.g., herpesviruses, including HSV,
HCMV, and EBV) can bind to or alter localization of MHC class I proteins, impairing peptide presentation to CD8+ T cells  ( Fig. 8-6 ). Downregulation of MHC class I molecules
might make it likely that virus-infected cells would be targets for NK cells. However, herpesviruses also express MHC class I homologues that act as effective inhibitors of NK cells by
engaging killer inhibitory receptors ( Chapter 6 ). Similarly, herpesviruses can target MHC class II molecules for degradation, impairing antigen presentation to CD4+ T helper cells.
Viruses also can infect lymphocytes and directly compromise their function. HIV infects CD4+ T cells, macrophages, and dendritic cells, and EBV infects B lymphocytes.
Date: 2016-04-22; view: 720