Skills to Develop
- Briefly describe at least 4 ways viruses can damage infected host cells.
- Briefly describe at least 3 different ways viruses can evade host immune defenses.
Animal viruses may cause cytopathic effect or CPE that damages infected host cells in a variety of means, including:
- Inhibiting normal host cell DNA, RNA, or protein synthesis. This can cause structural or functional defects in the infected host cell leading to cytolysis or altered cell functions.
- Causing nicks or breaks in the host cell's chromosomes, as seen in congenital rubella syndrome.
- Viral proteins and glycoproteins changing the antigenic surface of the host cell's cytoplasmic membrane resulting in its being recognized as foreign and destroyed by the body's immune defenses (see Fig. 9, Fig. 10, Fig. 11A and Fig. 11B). This will be discussed further in Unit 6.
- Depleting the host cell of cellular materials essential for life or normal function.
- Stimulating body cells to release inflammatory cytokines and chemokines.
- Stimulating body cells to release inflammatory vasoactive peptides, bradykinins, histamines, etc. resulting in vasodilation and increased mucous secretion.
- Inducing adjacent host cells to fuse together forming giant multinucleated cells or syncytias (see Fig. 1, Fig. 2, Fig. 3A, and Fig. 3B) as seen with cytomegalovirus (CMV), varicella-zoster virus (VZV), and HIV.
- Playing a role in normal cells becoming malignant (cell transformation by oncogenic viruses ).
- Causing cytolysis of the infected host cell (see Fig. 13C ).
Evading Host Immune Defenses
As will be seen in Unit 6, one of the major defenses against free viruses is the immune defenses' production of antibody molecules against the virus. The "tips" of the antibody (the Fab portion; see Fig. 4A) have shapes that have a complementary shape to portions of viral attachment proteins and glycoproteins called epitopes found on the viral surface. When antibodies react with these attachment proteins, they block viral adsorption to host cell receptors and, therefore, block viral replication.
In addition, Antibodies such as IgG function as opsonins and stick viruses to phagocytes.
- The influenza viruses undergo what is called antigenic drift and antigenic shift.
- With antigenic drift, mutations cause a gradual change in the hemagglutinin antigen that adsorbs to receptors on host cells.
- Antigenic shift is caused by a human influenza virus acquiring a new genome segment from an influenza virus capable of infecting other animals such as a ducks or swine. This new genome segment causes a major change in the hemagglutinin antigen.
- Likewise HIV, because of its high rate of mutation and its intracellular recombination with other strains of HIV, as mentioned earlier in this unit, produces altered gp120 to which antibodies made against the earlier strains of HIV can no longer bind.
- The hepatitis C virus (HCV) frequently through mutation produces viral variants ("escape mutants") to resist antibodies.
Another major defense against viruses, as we will see in Unit 6, is the killing of virus-infected host cells by cytotoxic T-lymphocytes (CTLs). Virus-infected host cells naturally bind viral epitopes to a host molecule called MHC-I and place the MHC-1 with bound viral epitope on the surface of the infected cell (see Fig. 5) where they can be recognized by CTLs having a T-cell receptors on its surface with a complementary shape. In this way the CTL can kill the infected cell by apoptosis , a programmed cell suicide (see Fig. 11A and Fig. 11B).
For a preview of CTLs killing virus-infected cells from Unit 6, Cell-Mediated Immunity, see the two animations below.
- Epstein-Barr virus (EBV) and cytomegalovirus (CMV) inhibit proteasomal activity so that viral proteins are not degraded into viral peptides. (see Fig. 5A)
- Herpes simplex viruses (HSV) can block the TAP transport of peptides into the endoplasmic reticulum (see Fig. 5B).
- Numerous viruses, such as the cytomegalovirus (CMV) and adenoviruses can block the formation of MHC-I molecules by the infected cell. As a result, no viral peptide is displayed on the infected cell and the CTLs are no longer able to recognize that the cell is infected and kill it (see Fig. 5C).
- Epstein-Barr virus (EBV) down regulates several host proteins involved in attaching viral epitopes to MHC-I molecules and displaying them on the host cell's surface (see Fig. 5D).
- Adenoviruses and Epstein-Barr Virus (EBV) code for proteins that blocks apoptosis , the programmed cell suicide mechanism triggered by various defense mechanisms in order to destroy virus-infected cells.
3. Another defense cell that is able to kill virus-infected cells is the NK cell. NK cells recognize infected cells displaying stressed-induced proteins and not displaying MHC-I molecules on their surface and kill these cells (see Fig. 7).
MHC-I molecules are the molecules on host cells that display viral epitopes to cytotoxic T-lymphocytes (CTLs). Some viruses suppress the production of MHC molecules by host cells, preventing CTLs from recognizing the infected cell as foreign and killing it. NK cells, however, can recognize cells not displaying MHC-I and kill them anyway.
See the three animations below for a preview of NK cells from Unit 5, Innate Immunity.
- The cytomegalovirus (CMV) can also trigger its host cell to produce altered MHC-I molecules that are unable to bind viral epitopes, and, therefore, are not recognized by CTLs. However, NK cells are also unable to kill this infected cell because it is still displaying "MHC-I molecules" on its surface.
- CMV also produces microRNAs (miRNAs), small non-coding RNA molecules that down-regulates the production of stress-induced proteins that the killer-activating receptor of NK cells first recognizes. The miRNAs do this by binding to the host cell's mRNA coding for stress-induced proteins (see Fig. 14). Without this binding there is no kill signal by the NK cell.
4. Some viruses cause infected host cells to secrete molecules that bind and tie up cytokines , preventing them from binding to normal cytokine receptors on host cells.
- Poxviruses cause infected host cells to secrete molecules that bind interleukin-1 (IL-1) and interferon-gamma (IFN-gamma).
- Cytomegaloviruses (CMV) cause infected host cells to secrete molecules that bind chemokines.
5. Some viruses suppress immunocompetent cells.
- Epstein-Barr virus (EBV) produces a protein that is homologous to the cytokine interleukin-10 (IL-10). IL-10 inhibits the activation of dendritic cells and macrophages , antigen-presenting cells that are needed to present antigens to T-lymphocytes for their activation. EBV also produces microRNAs (miRNAs ), small non-coding RNA molecules that inhibit an interferon response by infected cells. The miRNAs do this by binding to the host cell's mRNA coding for interferon (see Fig. 14).
- The human immunodeficiency virus (HIV) infects immunocompetent dendritic cells and T4-lymphocytes leading to their death or disfunction.
6. Some viruses block apoptosis of infected host cells enabling the infected host cell to survive and produce new viruses.
- Cytomegalovirus (CMV) and herpes simplex type 1 virus (HSV-1) produce microRNAs (miRNAs ), small non-coding RNA molecules that block protein involved in apoptosis, a programmed cell suicide. The miRNAs do this by binding to the host cell's mRNA coding for apoptosis-inducing proteins (see Fig. 14).
Exercise: Think-Pair-Share Questions
Describe four different ways viruses may resist immune responses.
Medscape article on infections associated with organisms mentioned in this Learning Object. Registration to access this website is free.
- Alteration of host cell function and/or death of the host cell occurs as a result of viruses using an infected host cell as a factory for manufacturing viruses.
- The body’s immune defenses recognize infected host cells as foreign and destroy infected cells.
- The body’s adaptive immune defenses produce antibodies against viruses that block viral adsorption to host cells or result in opsonization of the virus.
- The body’s adaptive immune defenses produce cytotoxic T-lymphocytes (CTLs) against viruses that bind to infected host cells and induce cell suicide (apoptosis).
- The body’s innate immune defenses produce NK cells that can induce apoptosis of stressed, virus-infected host cells.
- Viruses can develop resistance to antibodies and cytotoxic T-lymphocytes by altering the order of the amino acids and, therefore, the shape of viral antigens so the antibodies and CTLs no longer fit.
- Viruses can alter infected host cells in such a way that NK cells no longer kill them.
- Some viruses block apoptosis of infected host cells enabling the infected host cell to survive and produce new viruses.
Dr. Gary Kaiser (COMMUNITY COLLEGE OF BALTIMORE COUNTY, CATONSVILLE CAMPUS)