Lec 11 Outline - Viruses and Cancer - Fall 2024 PDF

Viruses, their life cycle and cancer THE TREE OF LIFE: VIRUSES Morris text, 4th ed, Chapter 19 & 11 The Coronavirus Pandemic The human population has recently experienced a global pandemic caused by a virus. In early 2020,...

Viruses, their life cycle and cancer THE TREE OF LIFE: VIRUSES Morris text, 4th ed, Chapter 19 & 11 The Coronavirus Pandemic The human population has recently experienced a global pandemic caused by a virus. In early 2020, cases of COVID-19 reached pandemic levels. As of April 2024, 7 million people had died from COVID-19 worldwide. VIRUSES? https://universe-review.ca/I10-02-TreeOfLife1.jpg  WHAT ARE VIRUSES? Viruses Microscopic infectious agents Contain DNA or RNA as genetic material Genome is surrounded by protein coat called capsid Some have an envelope – outer membranous layer containing glycoproteins Replicate solely when the nucleic acid has been delivered to a host cell Metabolically inert and use the host cells’ proteins and machinery https://blujayscience.wikispaces.com/file/view/cell_2.jpg/115852905/cell_2.jpg  WHAT ARE VIRUSES? Viruses infect all forms of life; every living organism has a virus that can infect it Estimate for how many viruses there are on the planet: 10 31 - As in over 10 million times more viruses than stars in the universe! Each virus typically infects a few specific species = host range Within the hosts, only a limited number of cell types will be infected by the virus = tropism Host range Tropism http://www.nature.com/nri/journal/v9/n9/images/nri2623-f1.jpg  VIRUSES = LIFE? Viruses are on the boundary of what is considered “life” by biologists - contain genetic material; composed of protein capsids - cannot replicate and use this genetic information outside of a living host cell; host cell carries out all steps for viral DNA or RNA à viral proteins  VIRUSES = LIFE? Large viruses have been discovered that now possess many of the molecules needed for translation! E.g. Mimivirus https://www.newscientist.com/data/images/archive/2544/25441401.jpg  VIRUSES = LIFE? Mimivirus = Giant virus Contain 7 of the 67 universal genes that are shared across the 3 domains of life Encodes various proteins needed for translation and protein modification Translation factors, tRNAs, enzymes “relics of a more complete ancestral protein-translation apparatus, gradually lost through a genome reduction process” http://web.stanford.edu/group/virus/mimi/2005/phylotree2.jpg  VIRUSES: A 4TH DOMAIN OF LIFE? Origin: - viruses are merely “escaped genetic fragments”. - Viruses evolved by hijacking genes from "true" organisms and encapsulating them in protective protein shells Prediction: Important enzymes in viruses should resemble those of their hosts Observation: DNA-replicating enzymes in many viruses have no relationship whatsoever to the host cell enzymes. Hypothesis: Viruses evolved from an ancient fourth domain of life (that has since disappeared). “Although most biologists would argue that viruses are not alive, some argue that viruses should be included in the tree of life.” -Raoult, D. & Forterre, P. Redefining viruses: lessons from Mimivirus. Nature Reviews Microbiology 6, 315– 319 (2008). VIRUS CLASSIFICATION http://www.nlv.ch/Virologytutorials/graphics/classificationtotal.jpg VIRUS CLASSIFICATION: CAPSIDS VIRUS CLASSIFICATION: ENVELOPES https://classconnection.s3.amazonaws.com/976/flashcards/392976/png/screen_sh ot_2012-09-29_at_25610_am1348912583918.png VIRUS CLASSIFICATION: GENOMES Virus life cycles: bacteriophage (virus that infects bacteria)  Virus life cycles: non- enveloped virus (poliovirus) http://amhistory.si.edu/polio/virusvaccine/how.htm http://amhistory.si.edu/polio/virusvaccine/how.htm Virus life cycles: enveloped virus (HIV or Zikavirus) https://ka-perseus-images.s3.amazonaws.com/cf8eb719a6d67560f7f763c92f08eb60d2dba9c9.png  https://aidsinfo.nih.gov/images/glossaryimages/HIV- Virus-Spanish-800.jpg http://www.pharmacology2000.com/Antiviral/images/fusion1.JPG  http://66.media.tumblr.com/4f0adaa8642fe8542c76b1181e6f751a/tumblr_inline_oa8tzkE png http://webappsr2.swau.edu/biology/faculty/nclasses/classes/B&V_Viral_Replication_files/image006.jpg Chapter 19 Active Lecture Slide 38 SARS-CoV-2 SARS-CoV-2 is a (+)ssRNA virus. The spike, envelope, and membrane proteins of SARS- CoV-2 are all glycoproteins and give the virus the appearance of a “crown” surrounding the virus. SARS-CoV-2 is one of many types of coronaviruses that infect humans. Chapter 19 Active Lecture Slide 39 Infection by SARS-CoV-2 VIRUSES ARE HUMAN PATHOGENS https://www.researchgate.net/profile/Sarah_Temmam/publication/258043379/figure/fig2/AS:2675617827389 48@1440803108275/Figure-3-The-human-virome-in-non-pathogenic-conditions-distribution-of-the-viral.png Viruses can spread through direct or indirect contact  VIRUSES CAN CAUSE CANCER ~20%* of all human cancers = viruses contribute to their development Cancer results due to a host’s response to the viral infection or impact of viral genes on the host cell http://schoolbag.info/biology/humans/humans.files/image248.jpg *Biochim Biophys Acta. 2008 Mar; 1782(3): 127–150. http://cancerprogressreport.org/2015/Pages/prevention.aspx?Page=3  ONCOGENESIS = DEVELOPMENT OF CANCER Cancer is a genetic disease – Mutations in genes that control cell growth & division Oncogenesis results in tumours – composed of unregulated, rapidly dividing cells – may invade neighbouring tissues – Can be brought about by: Inherited mutations DNA damage caused by environmental agents (carcinogens) Viruses  ROUS SARCOMA VIRUS (RSV) IN CHICKENS Cancer can be caused by a viral infection!  RSV AND THE V-SRC GENE v-Src: Viral gene in RSV that is essential for oncogenesis In the lab, mutants of v-Src were identified - showed that protein-protein interaction was important - v-Src likely interacted with many host cell proteins Normal avian cells carry a gene that is similar to v-Src = c-Src! - sequences of c-Src and v-Src were different = mutants? - protein function of c-Src was very different from v-Src and its expression did not lead to cancer Normal function of c-src A kinase = enzyme that phosphorylates its targets http://www.nature.com/nrm/journal/v2/n6/fig_tab/nrm0601_467a_F4.html v-Src and c-Src differ in sequence v-Src is a mutant version of c-Src that was “captured” by RSV from the host cell genome Activation of v-SRC is no longer controlled by phosphorylation/de- phosphorylation http://www.nature.com/nrc/journal/v4/n6/images/nrc1366-f1.jpg v-Src: a mutated version of a normal cellular gene, c-Src, that can promote uncontrolled cell division à Oncogenesis v-Src = oncogene c-Src = proto-oncogene http://www.nature.com/nrm/journal/v2/n6/fig_tab/nrm0601_467a_F4.html  CANCER Oncogene: cancer-causing gene Proto-oncogenes: normal genes important in promoting cell division that have the potential to become cancerous if mutated Tumor suppressors: genes that encode proteins whose normal activities inhibit cell division HUMAN PAPILLOMAVIRUS CAN CAUSE CERVICAL CANCER http://hpvawakening.org/wp-content/uploads/2011/12/hpv.jpg CELL CYCLE (EUKARYOTES) Interphase M phase  FIG. 11.24 Cell cycle checkpoints. 1. Cell big enough? DNA undamaged? 2. DNA replicated? 3. Chromosomes attached to spindle? DNA Damage Checkpoint: p53 Regulation FIG. 11.25 DNA damage checkpoint controlled by p53. Cell big enough? DNA undamaged? DNA replicated? Chromosomes attached to spindle? https://upload.wikimedia.org/wikipedia/commons/3/3f/Figure_28_02_08.JPG  HPV ENCODES PROTEINS THAT INACTIVATE TUMOUR SUPPRESSORS IN CELLS P53 = tumour suppressor – activated in response to DNA damage à stops cell division of damaged cells HPV E6/7 proteins – bind and inactivate p53 à cells with damaged DNA go ahead and divide à oncogenesis http://www.virology.ws/w3310/019_W3310_12.pdf  Multiple-Mutation Model for Cancer Development Most human cancers develop from the accumulation of multiple mutations in proto-oncogenes and/or tumor suppressor genes. Cancers can be benign or metastatic.  2 take home thoughts How might viruses fit into the tree of life? How has the study of virus-induced cancers enhanced our understanding of the cellular mechanisms of this disease? http://www.virology.ws/w3310/019_W3310_12.pdf Raoult, D. & Forterre, P. Redefining viruses: lessons from Mimivirus. Nature Reviews Microbiology 6, 315–319 (2008).