MIC252_2024_Lec26.pdf

MIC252: VIROLOGY Dr Tasnim Suliman [email protected] Lec 26: Viral pathogenesis How viruses enter the human body, spread to other organs, and cause disease Lec 27-31: The stages of the virus life cycle in an individual cell...

MIC252: VIROLOGY Dr Tasnim Suliman [email protected] Lec 26: Viral pathogenesis How viruses enter the human body, spread to other organs, and cause disease Lec 27-31: The stages of the virus life cycle in an individual cell Entry Genome replication (DNA and RNA viruses) Gene expression Assembly and release Lec 42: Viruses that cause cancer  Virology Textbook Louten, J. Essential Human Virology, 2016, Elsevier. ISBN: 978-0-12-800947-5 e-book is available FREE via UWC library https://uwc.primo.exlibrisgroup.com/permalink/27UWC_INST/22rg9v/alma993292381703721 Log in with your campus name and password Note: The slides I will provide are not an exact replica of the textbook. There may be information in the textbook that is not in my slides, and there may be information in my slides that is not covered in the textbook. Use the content of the slides as a guide for what you are expected to know, but reading further will never hurt you. 2  MIC252 Lecture 26: Viral Pathogenesis 12 September 2024 Dr Tasnim Suliman [email protected]  Learning Objectives Students should to be able to: Explain how viruses cause disease Explain how viruses enter the human body Describe how viruses spread in the human body List the different modes by which viruses can be transmitted Explain how Koch’s postulates modified when applied to viruses 4 Textbook Reading Essential Human Virology: Chapter 5 5.1: Portals of virus entry 5.2: Dissemination within a host 5.3: Portals of virus exit 5 Quick refresher on viruses Viruses are: Very small (10-400nm) Infectious Obligate intracellular parasites Made of genetic material (RNA or DNA) surrounded by a protein capsid and sometimes a membrane Viruses lack protein synthesis machinery and cannot reproduce on their own. Viruses are NOT cells! Viruses are NOT bacteria! 6 Koch’s Postulates The four criteria designed to establish a causal relationship between a microbe and a disease. 1. The organism must be regularly associated with the disease and its characteristic lesions. 2. The organism must be isolated from the diseased host and grown in culture. 3. The disease must be reproduced when a pure culture of the organism is introduced into a healthy, susceptible host. 4. The same organism must be re-isolated from the experimentally infected host. 7  But these rules don’t work for viruses……. 1. The organism must be regularly associated with the disease and its characteristic lesions. Not all infected individuals show signs of disease. E.g. only 1% of polio infections result in paralysis (i.e. many sub-clinical infections) Infections with different viruses may result in the same disease 2. The organism must be isolated from the diseased host and grown in culture. 3. The disease must be reproduced when a pure culture of the organism is introduced into a healthy, susceptible host. Many viruses cannot be grown in culture And a suitable animal model that mimics human disease may not exist 8  Modified Koch’s Postulates (for the 21st Century) 1. A nucleic acid sequence belonging to a putative pathogen should be present in most cases of an infectious disease. 2. Fewer, or no, copy numbers of pathogen-associated nucleic acid sequences should occur in hosts or tissues without disease. 3. With resolution of disease, the copy number of pathogen-associated nucleic acid sequences should decrease or become undetectable. With clinical relapse, the opposite should occur. Fredricks and Relman. Sequence-Based Identification of Microbial Pathogens: a Reconsideration of Koch’s Postulates. Clinical Microbiology Reviews, 1996, 9, 18-33. 9  Viral Pathogenesis VIRAL PATHOGENESIS The process by which viruses cause disease VIRAL DISEASE Disease consists of both the effects of virus replication and the immune response of the host i.e. disease is influenced by both viral and host genes Many virus infections are subclinical or asymptomatic, meaning that the host immune response controls the infection and there is no development of disease Some viruses have mechanisms to block the immune response, resulting in more severe disease. Sometimes it is the immune response that is responsible for the symptoms 10 Cycle of virus infection Entry Shedding Localized PRIMARY SITE infection Local Spread Lymphatic Neuronal Blood (viremia) SECONDARY SITES Shedding Disseminated/Systemic infection 11 Overview 12 Successful virus infection depends on 3 things: 1. Sufficient virus to be able to initiate infection 2. Cells at site of infection must be accessible and be BOTH susceptible (virus is able to enter) and permissive (virus is able to replicate) for the virus 3. Local immune responses must be absent or initially ineffective 13 Viral Entry Common sites of virus entry are: 1. Respiratory tract Mucosal 2. Alimentary tract lining 3. Urogenital tract 4. Outer surface of eye 5. Skin (requires a breach e.g. scratch, needle stick, insect bite) 14  Respiratory tract infection Most common route of virus entry Breathing introduces 6L of air per min! Viruses enter in aerosolized droplets expelled from a cough or sneeze. Large droplets are deposited in the nose; small droplets end up in the alveoli (lungs) Host defenses: Mucus coats the resp. tract & traps virus particles Ciliated cells “sweep” the mucus (and virus) up to throat Macrophages in the alveoli destroy virus particles (eat them!) 15  Viruses infecting the gut: Alimentary tract infection Enteroviruses Reoviruses Noroviruses Common route of virus entry via ingestion of Rotaviruses foods, drinks, hands in mouth etc. Astroviruses Extremely hostile place for viruses - low pH in stomach - high pH in intestine - bile, digestive enzymes (proteases) This restricts the type of virus that can enter the gut Intestinal tract is covered with epithelial cells densely packed with microvilli, coated with mucus = barrier for viruses 16  Viral Spread Virus particles can remain localized at site of entry or spread to other tissues Disseminated infection: spreads beyond primary site of infection Systemic infection: many organs become infected A key determinant of whether a virus remains localized or becomes systemic is directional release of virus from polarized cells Virus released from the apical surface is outside the host. These e.g. lining viruses cause localized infections. of alveoli or intestine Virus released from the basal surface is inside the host. These viruses tend to cause disseminated infections that Polarized epithelial cells may become systemic. 17  Viral Spread through the Blood Viremia: infectious virus particles in the blood Virus can disseminate from a local site by entering the blood via the lymphatic system Virus particles may be free in the blood or carried by infected immune cells e.g. HIV in macrophages and T lymphocytes Primary viremia: when virus first enters the blood. Low viral load Secondary viremia: when virus has disseminated to other organs, replicated, and re-entered the blood. High viral load. 18  Rabies virus Viral Spread through Neurons Some viruses spread from the site of infection by entering nerve endings at initial site of infection e.g. rabies virus, herpesviruses. Neurotropic virus: infects neural cells Neuroinvasive virus: enters the CNS (spinal cord, brain) Neurovirulent virus: causes disease of nervous tissue, neurological symptoms, death Herpes virus 19  Organ invasion Virus in the blood can spread to other organs and re-establish infection in these new tissues. Viruses must cross the blood vessel/tissue barrier. Skin: manifests as rash e.g. measles, varicella/chicken pox Liver: manifests as hepatitis e.g. hepatitis A, B, C viruses Brain: encephalitis e.g. herpes simplex, varicella, measles, Japanese encephalitis virus, rabies Heart muscle: myocarditis e.g. adenovirus, enterovirus (and others) Fetus: congenital viral infections e.g. cytomegalovirus, rubella virus, HIV 20  Virus Tropism Most viruses are restricted to specific cell types (cellular tropism) of certain organs (tissue tropism). Enterotropic virus: replicates in gut Neurotropic virus: replicates in nervous system Hepatotropic virus: replicates in liver Pantropic virus: replicates in many cells and tissues Tropism depends on the presence of receptors for entry (makes cells susceptible to virus) and the requirement of other cellular proteins to support virus replication (makes cells permissive to virus infection). Susceptible and permissive cells must also be accessible to the virus. 21 Virus Transmission Transmission is the process whereby viruses spread between hosts Direct transmission (close contact with infected person) 1. Direct contact (skin-to-skin contact, kissing, sexual intercourse) 2. Droplet spread (large, short-range aerosols e.g. sneeze, cough, talking) Indirect transmission 3. Airborne (small aerosols that remain suspended in air) 4. Vehicle borne (contaminated food, water, blood, cups, needles etc. – inanimate objects) 5. Vector borne (insects, animals e.g. mosquito bite, dog bite) 22 Additional Virology Resources A free podcast about viruses - the kind that make you sick http://www.microbe.tv/twiv/ One episode a week Weekly topics based on what’s hot in the news, or sometimes it’s devoted to Virology 101 (basic virology concepts) – see http://www.virology.ws/virology-101/ Hosted by Prof. Vincent Racaniello from Columbia University Web-resource for all viral genus and families, providing general molecular and epidemiological information, along with virion and genome figures. https://viralzone.expasy.org/ Public health World health organization https://www.who.int/ websites Centers for Diseases Control and Prevention https://www.cdc.gov/ (search for virus of interest) 23 National Institute for Communicable Diseases https://www.nicd.ac.za/