11-18-09 Viral Pathogenesis Viral pathogenesis: process by which viruses cause disease. Occurs via three steps 1.

entry 2. local replication 3. dissemination 1. Describe the pathways by which viruses enter their hosts. Alimentary tract How: ingestion of contaminated food or water; into the lower GI via sexual intercourse What: poliovirus, Norwalk virus, rotavirus, HIV (technically) To what extent: Transcytosis: viruses taken up on the luminal side of the alimentary tract are transported virtually intact through the cytoplasm into the mucosal epithelium. After crossing the mucosal epithelium, the virus can enter lymphatic vessels and capillaries of the circulatory system. Replication in intestinal epithelial cells: some viruses stay in the epithelia and actively destroy cells there, causing mucosal inflammation and diarrhea Ex: Norwalk virus (cruise ships) and rotavirus. Fecal-oral transmission: replication of virus in the alimentary tract will result in the release of progeny virus into the feces. Example: poliovirus entry through alimentary tract Entry: ingestion of contaminated food Local replication: infection of intestinal epithelial cells Dissemination: release of virus into lymphatics, then the circulation (viremia) Infection of the CNS causing paralysis Respiratory tract How: aerosolized droplets produced by coughing/sneezing from infected individuals What: rhinoviruses, influenza viruses, coronaviruses, adenoviruses, (small)poxviruses To what extent: May be restricted to the epithelium of the respiratory tract Ex: rhinoviruses Or spread via lymphatics and circulation to other tissues Ex: smallpox viruses Most common route of viral entry!! Why? Alveoli places capillary and lymphatic vessels in close contact with inspired air Urogenital tract How: sexual activity, causing tears or abrasions in the urogenital tract to allow viruses to enter What: papillomavirus, HIV, herpes simplex To what extent: May be restricted to the urogenital epithelium

Ex: papilloma virus Or gain access to underlying tissues to infect the immune system Ex: HIV, herpes simplex

Skin How: in order for viruses to gain entry through skin, it must bypass the layer of dead keratinized cells that do a great job in protecting against viruses (this dead outer layer is also not amenable to supporting viral replication). Consequently, viruses may enter skin through minor abrasions. Other routes of entry include insect vectors, animal bites, and hypodermic needle punctures. What: arboviruses, rabies To what extent: often limited to the site of entry (in the case of abrasions) since the epithelium is devoid of lymphatics or blood. But can also initiate infection in the deeper tissues (in the case of hypodermic needles and tattoos) that allow for access to blood vessels, nervous systems etc.

A few notes on viral dissemination The most common way of disseminating virus is via the circulatory system Ex: poliovirus and hepatitis A Presence of viruses in blood is called viremia, and the deposition of viruses in organs from viremia is known as systemic infection. Many viruses can only infect specific organs, echoing the aforementioned concept of tissue tropism The less common way of disseminating virus is via the nervous system Ex: rabies virus and herpes simplex virus How: rabies virus enters nerve endings that are reached by an animal bite and subsequently spread to the CNS via neuritis (axons + dendrites) Within nerve cells, the viruses are actually shielded from the immune system. The viruses can also spread from the CNS to infect organs, causing systemic infection. Ex: salivary glands are a site of future transmission for the virus Incubation period is a consequence of virus dissemination. It is the period between exposure to the virus through the phase of dissemination, ending when the virus replicates in the target organ to cause symptoms. A few notes on viral transmission (virus shedding: the release of virus from their replication sites) Horizontal transmission: transmission of virus from a patient to a healthy individual Vertical transmission: transmission of virus from an infected mother to infants Congenital infection: infection of the fetus that occurs during maternal viremia, with viruses passing through the placenta. Can be observed with CMV* and rubellavirus. Examples: Hepatitis A is shed in feces Rhinoviruses are shed in respiratory tracts Arboviruses are shed into blood, a site for insect bites for further transmission Herpes simplex virus type 2 is shed into the genital tract

HIV is shed in both blood and semen *CMV is shed into milk

2. Contrast how viruses cause diseases directly by cytopathic effects and indirectly by stimulating the immune response. Cytopathic effect: viral infection causes cell DEATH (cytoPATH) Ex: poliovirus causes neuronal cell death that produces symptoms of poliomyelitis Etiology: shutoff of the cellular macromolecular synthesis of the virus, changing plasma membrane permeability, fusion of cells to form a giant cell known as a syncytium, or leakage of lysosomal enzymes into the cell causing autolytic digestion. Stimulating the immune system: viral infection generates an immune response that causes organ dysfunction Myocarditis: caused by coxachievirus B that infects cytotoxic T cells Hepatitis: caused by hepatitis B aor C Interferon is often involved, causing nausea, vomiting, anorexia, malaise and fatigue 3. Describe the relationship between the six human viruses and the cancers they cause. Viruses are implicated in 25% of all cancers. Viral oncogenesis is the process by which viruses cause cancer. The main mechanism for oncogenesis is: 1. somatic cells ordinarily do not divide and remain in a quiescent state. 2. Viruses have evolved to produce gene products to stimulate the quiescent cells to ender the S phase. In addition, retroviruses carry oncogenes that promote cell growth. It is the uncontrolled cell growth caused by a virus that can lead to the formation of a tumor. The 6 viruses that cause human cancers are: HTLV-1 (human T-cell leukemia virus type 1): i. What cancer: T cell leukemia (no shit) ii. Etiology: tax gene product protein stimulates cellular gene expression and promotes cell cycles HPV (human papilloma virus): i. What cancer: papilloma (aka warts, a benign tumor) and cervical carcinoma 1. over 90% of cervical carcinomas contain HPV DNA 2. warts will regress due to cellular immunity after a prolonged period ii. etiology: there are many different types of HPV, and only some can cause cervical carcinoma. These are referred to as the high risk types (i.e. HPV16 and HPV-18). Dysregulation of genes that promote cell growth leads to malignant transformation into cancer cells EBV (Epstein-Barr Virus): i. What cancer: Burkitts lymphoma and nasopharyngeal carcinoma ii. Etiology: immortalization of B cells via several viral gene products HBV (Hepatitis B virus):

What cancer: hepatocellular carcinoma Etiology: X protein accumulation that stimulates cellular gene expression and promotes cell growth 1. persistent infection with HBV causes chronic liver injury; keep in mind that liver can regenerate 2. mutations that occur during liver regeneration are responsible for transformation into cancer cells HCV (hepatitis C virus) i. What cancer: hepatocellular carcinoma ii. Etiology: identical to HBVhas gene products that induce cell growth, chronic liver injury, and liver regeneration that can lead to cancer KSV (Kaposis sarcoma virus, aka HHV-8 human herpes virus 8) i. What cancer: Kaposis sarcoma ii. Etiology: cancer originating from endothelial cells; seen only in AIDS patients, so Kaposis sarcoma is believed to be induced by the HIV-1 virus
i. ii.

4. Distinguish between antigenic shift and antigenic drift of influenza virus. Antigenic SHIFT: the appearance of new viral subtypes. It is caused by genetic reassortment that occurs with mixed infections of one host with a variety of animal and human subtypes. Antigenic DRIFT: the gradual antigenic change of surface glycoproteins. It is caused by point mutations primarily in the HA gene, such as AA substitutions in the head of the HA molecule (i.e. loss of viral epitope). Antigenic drift is why we need to have vaccines every year

Side note: H5N1: an Avian flu from this decade that had a 59% mortality rate!! Deadly but not transmitted easily amongst humans. Why? H5N1 vinds to NA with an alpha-2,3-linkage to galactose. This type of sugar linkage is absent in the upper respiratory tract, thus making transmission of the virus difficult. Moreover, H5N1 is very virulent and often kills the patient before s/he can effectively spread it to others.