Infectious Agents Flashcards
Give examples of early work on viruses and cancer?
1908 - Ellerman and Bang
= identify infectious leukaemia in chickens
1911 - Rous
= shows virus could induce sarcomas in chickens
= RSV - Rous sarcoma virus
1933
= Rabbit papillomavirus identified
1936
= mouse mammary tumour virus discovered (MMTV)
= spread through breast feeding
1950s
= mouse leukaemia / polyoma viruses identified
1960s
= adenovirus / SV40 shown to induce tumours in rodents
What is the Rous experiment?
- Chicken with sarcoma in breast muscle
- Remove sarcoma and break up into small pieces + grind up with sand
- Collect filtrate passed through fine pore filter
(does NOT let cells through - only viruses) - Inject filtrate into young chicken
- Observe sarcoma in injected chicken
(over just few weeks)
What is RSV ? What is it’s structure?
= Rous Sarcoma Virus
= retrovirus
env = encodes surface glycoprotein
gag = encodes proteins that comprise the coat
pol = encodes reverse transcriptase that plays an essential role in lifecycle
(lipid bilayer = acquired from infected cell)
What is the retrovirus lifecycle?
- Attachment and entry
= retrovirus attach to receptors on surface of host cells, and then enter the cells through fusion or endocytosis - Reverse transcription
= retrovirus release its RNA genome
= enzyme reverse transcriptase converts it into DNA
= DNA (known as provirus) integrated into host cell’s DNA - Transcription and translation
= integrated provirus can remain latent
= eventually transcribed and translated into viral proteins - Assembly and budding
= viral proteins and RNA assemble at host cell membrane to form new virus particles
= they bud off and released into extracellular space - Infection of new host cells
= newly released virus particles go on to infect new host cells
= life cycle repeated
What does RSV infection cause? What does it require?
= aberrant growth
(e.g. cells in petri dish form focus)
= requires presence of active viral proteins (for cancerous phenotype)
= transformation of cell
= is temperature sensitive = suggests protein involved (when temp raised, transformed phenotype lost)
What does the src gene do?
Src
= additional gene in RSV genome
(found to be avian in origin)
= oncogene
s-src = non-receptor tyrosine kinase
v-Src lacks Tyrosine-527
= therefore is permanently switched on
= proliferation
= in active form (compared to inactive) kinase site NOT occluded and so phosphorylation continues downstream = proliferation
What is ALV?
= avian leukosis virus
(induces leukaemia)
= slowly transforming retrovirus
(carcinogenesis takes longer)
= provirus inserts randomly into the host genome
= very occasionally (1 in 10 million) inserts upstream of c-myc
(myc = transcription factor that drives expression of proliferation genes)
= induction of cancer is rare
What are some examples of Human Cancer Viruses?
EBV - Epstein Barr Virus
= dsDNA herpesvirus
= Burkitt’s lymphoma, nasopharyngeal carcinoma (+some Hodkins / Non-hodgkins lymphoma)
HBV - Hepatitis B Virus
= ssDNA and dsDNA hepadenovirus
= hepatocellular carcinoma
HTLV-I - Human T-lymphotrophic virus-I
= + strand, ssRNA retrovirus
= adult T cell leukaemia
HPV - High-risk Human Papillomaviruses
= dsDNA papillomavirus
= cervical, penile, anal and head and neck cancers
HCV - Hepatitis C virus
= + strand, ssRNA flavivirus
= hepatocellular carcinoma
KSHV - Kaposi’s Sarcoma Herpesvirus
= dsDNA herpesvirus
= Kaposi’s sarcoma
= primary effusion lymphoma
= multicentric castlman’s disease
MCV - Merkel Cell Polyomavirus
= dsDNA polyomavirus
= merkel cell carcinoma
EXTRA READING
HHV-8 - Human herpesvirus 8
= herpes virus
= associated with Kaposi’s sarcoma, especially in HIV/AIDS patients
BKPyV - Polyomavirus BK
= DNA virus
= associated with kidney / bladder cancer
Adenovirus
= some types linked to adenocarcinomas of lung and GI tract
What is the link between HPV and cervical cancer?
Cervical cancer
= 4th most common cancer in women worldwide
= 86% in developing world
= 2nd most common cancer in young women
HPV
= dsDNA virus
= many subtypes = most innocuous (cause warts)
= show tissue tropism
= high risk HPV 16 and HPV 18 cause cervical cancer
EXTRA READING
= other types that cause cervical cancer
= HPV31, 33, 45, 52, 58 (less common)
What is the HPV lifecycle?
- Entry
= HPV enters through small breaks in skin / mucus membrane (sexual contact) - Attachment
= virus attaches to surface of epithelial cell - Internalisation
= virus enters cell, begins to replicated DNA - Early gene expression (e.g. E6, E7)
= virus produces several early genes involved in viral replication and evasion of host immune system - Genome amplification
= virus replicates its DNA and amplifies its genome within epithelial cells - Late genome expression
= virus produces late genes involved in production of viral capsid proteins - Capsid assembly
= viral capsid protein assemble to form mature virions - Release
= mature virions are released from infected cell, infect other cells - Shedding
= infected cells shed from surface of skin / mucus membrane = transmission
What are episomes? How do they relate to HPV?
= circular DNA molecules
HPV 16/18
= integrate into host’s cell chromosome as episomes
= disrupts normal cell functioning
= leads to production of viral proteins that promote cell growth and division
= eventually leads to cervical cancer
= this episomal DNA is more stable
= can replicate independently of host cell’s genome = leads to production of more viral DNA = increases likelihood of cancer
What does E7 / E6 do? What are their tumour-promoting effects?
E7 = binds to RB = targets it for degradation
= allows cell cycle entry (S phase), uncontrolled proliferation
= also binds to RB-related proteins, inhibiting their function too
E6 = tags p53 with Ub for degradation by proteasome
= damaged DNA continues to divide and replicate
= reason why cervical cancer does NOT have high rate of p53 mutations
Both E6/E7 have further tumour promoting effects:
= E6 = depresses expression of hTERT (component of telomerase)
= E6 = stimulates expression of VEGF (angiogenic factor)
= E6 + E7 = stimulate genomic instability
= E6 + E7 = can promote all stages of carcinogenesis (aberrant proliferation, extended proliferation, indefinite life span, cellular transformation)
EXTRA READING
= also involved in MAPK pathways, PI3K.Akt pathways
What are some other examples of infections linked to cancer?
Southeast Asian Liver fluke
= Opisthorchis viverrini
= liver cancer
Bilharzia
= Schistosoma hematobium
= bladder cancer
Heliobacter pylori
= stomach cancer
EXTRA READING
= some E.coli = colorectal cancer
= fungi = Aspergillus spp. = lung cancer
= chronic inflammation
What is Helicobacter pylori?
= bacteria (NOT virus)
= estimated to cause up to 90% of stomach cancers
= causes chronic inflammation:
(chronic superficial gastritis = atrophic gastritis = dysplasia = carcinoma)
= carcinogenesis driven partly by chronic inflammation and resultant genotoxic stress
= also some specific virulence factors
(e.g. CagA)
= induces number of pro-inflammatory carcinogenic changes in gastric cells
EXTRA READING
= CagA = injected by T4SS = leads to cellular changes = inflammation and tissue damage
= other virulence factors: VacA, LPS, Adhesins, Proteases, Urease
What does CagA do?
= virulence factor
- = allows H. pylori to bind to integrins on basolateral surface
- = Type IV secretion system injects peptidoglycan and CagA into cell
(T4SS encoded by cag pathogenicity island) - = pleiotropic effects:
(disrupts cytoskeleton, cell polarity, cell junctions, is mitogenic and inflammatory) - = stimulates inflammatory response
EXTRA READING:
= one key target of CagA = protein tyrosine phosphatases SHP-2
= also interacts with ZO-1 tight junction protein
= PAR1/MARK polarity protein
= receptor tyrosine kinase EGFR
