Microbiology 8 - Preventing Viral Replication PDF

Microbiology Preventing Viral Replication Microbiology| Preventing Viral Replication Contents : Virus-Infected Cells 3 Natural Killer Cells 8 Dendritic Cells 12 Microbiology| Preventing Viral Replication Virus-Infected Cells Take Drastic Measures to Prevent Viral Replication : The microbe-associated...

Microbiology Preventing Viral Replication Microbiology| Preventing Viral Replication Contents : Virus-Infected Cells 3 Natural Killer Cells 8 Dendritic Cells 12 Microbiology| Preventing Viral Replication Virus-Infected Cells Take Drastic Measures to Prevent Viral Replication : The microbe-associated immunostimulants on the surface of bacteria and parasites that are so important in eliciting innate immune responses against these pathogens are generally not present on the surface of viruses. The only general way that a host cell can recognize the presence of a virus is to detect unusual elements of the viral genome, such as the double-stranded RNA (dsRNA) that is an intermediate in the life cycle of many viruses which can be recognized by the Toll-like receptor (TLR9). Microbiology| Preventing Viral Replication Mammalian cells are particularly adept at recognizing the presence of dsRNA, and they can mobilize a program of intracellular responses to eliminate it. The program occurs in two steps. First, the cell degrades the dsRNA into small fragments (about 21–25 nucleotide pairs in length), using the enzyme Dicer. These double-stranded fragments bind to any singlestranded RNA (ssRNA) in the host cell that has the same sequence as either strand of the dsRNA fragment, leading to the destruction of the ssRNA. Microbiology| Preventing Viral Replication Second, the dsRNA induces the host cell to produce and secrete two cytokines — interferon-a (IFNa) and interferon-b (IFNb). The interferons activate a latent ribonuclease, which non-specifically degrades ssRNA. They also indirectly activate a protein kinase that phosphorylates and inactivates the protein synthesis initiation factor eIF-2, thereby shutting down most protein synthesis in the embattled host cell. Microbiology| Preventing Viral Replication Apparently, by destroying most of its RNA and transiently halting most of its protein synthesis, the host cell inhibits viral replication without killing itself. If these measures fail, the cell takes the even more extreme step of killing itself by apoptosis to prevent the virus from replicating, often with the help of a killer lymphocyte. Microbiology| Preventing Viral Replication Not surprisingly, many viruses have acquired mechanisms to defeat or avoid these intracellular defense processes. Influenza virus encodes a protein that blocks the recognition of dsRNA by Dicer. Many viruses, including most of those that are able to cause disease in healthy hosts, use various mechanisms to block the activation of the interferon pathway. Some viruses also inhibit host cell apoptosis, which can have the side-effect of promoting the development of cancer. Microbiology| Preventing Viral Replication Natural Killer Cells Induce Virus-Infected Cells to Kill Themselves : Interferons have other, less direct ways of blocking viral replication. One of these is to enhance the activity of natural killer cells (NK cells), which are part of the innate immune system. Like cytotoxic T cells of the adaptive immune system, NK cells destroy virusinfected cells by inducing the infected cells to kill themselves by undergoing apoptosis. Microbiology| Preventing Viral Replication The ways in which cytotoxic T cells and NK cells distinguish virus-infected cells from uninfected cells, however, is different. Both cytotoxic T cells and NK cells recognize the same special class of cell surface proteins to detect virus-infected host cells, The proteins are called class I MHC proteins. Microbiology| Preventing Viral Replication Cytotoxic T cells recognize peptide fragments of viral proteins bound to these MHC proteins on the surface of virus infected cells. By contrast, NK cells monitor the level of class I MHC proteins on the surface of all host cells: high levels inhibit the killing activity of NK cells, so that NK cells selectively kill host cells expressing low levels, which are mainly virusinfected cells and some cancer cells. Microbiology| Preventing Viral Replication The reason that class I MHC protein levels are often low on virus-infected cells is that many viruses have developed mechanisms to inhibit the expression of these proteins on the surface of the cells they infect, to avoid detection by cytotoxic T lymphocytes. Adenovirus and HIV, for example, encode proteins that block class I MHC gene transcription. Both NK cells and cytotoxic T lymphocytes kill infected target cells by inducing them to undergo apoptosis before the virus has had a chance to replicate. Microbiology| Preventing Viral Replication Dendritic Cells Provide the Link between Innate & Adaptive Immune Systems : Dendritic cells are crucially important cells of the innate immune system that are widely distributed in the tissues and organs of vertebrates. They display a large variety of pattern recognition receptors that enable the cells to recognize and phagocytose invading pathogens and to become activated in the process. The dendritic cells cleave the proteins of the pathogens into peptide fragments, which then bind to MHC proteins that carry the fragments to the cell surface. Microbiology| Preventing Viral Replication The activated dendritic cells now carry the pathogen-derived peptides, as complexes with MHC proteins, to a nearby lymphoid organ such as a lymph node, where they activate T cells of the adaptive immune system to join in the battle against the specific invader. In addition to the complexes of MHC proteins and microbial peptides displayed on their cell surface, activated dendritic cells also display special, cell-surface co-stimulatory proteins that help activate the T cells. Microbiology| Preventing Viral Replication The activated dendritic cells also secrete a variety of cytokines that influence the type of response that the T cells make, ensuring that it is appropriate to fight the particular pathogen. In these ways, dendritic cells serve as crucial links between the innate immune system, which provides a rapid first line of defence against invading pathogens, and the adaptive immune system, which provides slower but more powerful and highly specific ways of attacking an invader. Microbiology| Preventing Viral Replication