Tumor inducing pathogens - Tumorviruses Flashcards
Tumor risk factors
Viral infections:
* Caused by tumorviruses
* (= oncoviruses, cancer viruses)
* 11.9 % being caused by viral infections (WHO)
* The majority of human and animal viruses do not cause cancer
-> Long-standing coevolution between virus and host
First discoveries of tumor viruses
First discoveries of tumor viruses:
1908: chicken leukemia virus, Ellerman & Bang
1911: Rous sarcoma virus, Peyton Rous (Nobel prize 55 years later)
chicken with sarcoma in breast muscle -> remove sarcoma and break up into small chunks of tissue -> grind up sarcoma with sand -> collect filtrate that has passed through fine pore filter -> inject filtrate into young chicken -> observe sarcoma in injected chicken
Viral structure
- Viral genome: DNA (single or double strand) or RNA (+/- strand or double strand)
- Capsid: protein coat, which surrounds and protects the viral genome
- Envelope (optional): lipid “envelope” derived from host cell membrane
Routes of body entry
- food and water
- skin lesions
- arthropod
- dog biting
- urogenital
- sexual contact
- alimentary
- respiratory
- Sufficient virus must be available to initiate infection
- Cells at the site of infection must be accessible, susceptible, and permissive for the virus
- Local host anti-viral defense systems must be absent or initially ineffective
Cellular entry
Viruses have evolved strategies to overcome cellular barriers:
a. Receptor-mediated endocytosis followed by pH-dependent/ independent fusion from endocytic compartments
b. pH-independent fusion at the plasma membrane, coupled with receptor-mediated signaling and coordinated disassembly of the actin cortex
Infection strategies of viruses
- strategy: once established in the host, a virus can cause acute infection
-> constantly infect cells of the same host (mumps)
-> capacity to rapidly infect a new host (rabies)
-> survive in the environment
-> HIGH COPY NUMBER - strategy: starting as acute infections which then progress to latent or persistent forms
-> maintain viral genome without cytopathic effect
-> without being detected by the host immune system
-> maintain a strategy for transmission
-> LOW COPY NUMBER/GENOME IS EPISOMAL OR INTEGRATED
- Acute infection (e.g. influenza virus)
- persistent infection (e.g. lymphocytic choriomeningitis virus)
- latent, reactivating infection (e.g. herpes simplex virus)
- slow virus infection (e.g. human immunodeficiency virus)
Baltimore classification of viruses
- a virus classification system developed by David Baltimore that groups viruses into families, depending on their type of genome
Class I: dsDNA
Class II: ssDNA -> dsDNA
Class III: dsRNA
Class IV: (+)ssRNA -> (-)ssRNA
Class V: (-)ssRNA
Class VI: ssRNA-RT -> DNA/RNA -> dsDNA
Class VII: dsDNA-RT
- Viruses in the group 1, 2, 6 and 7 highly depend on replication machinery of the host for their reproduction (e.g. DNA repair enzymes, polymerases, kinases, ligases)
- Most viruses from group 3, 4, 5 provide own replication machinery
DNA vs RNA virus replication
- Depending on the genome type, the virus requires the replication machinery of the host
- The localization of viral replication depends on the molecule type of the genome
DNA viruses: require host DNA polymerases -> Replication in the nucleus
Exception: Pox viruses require own replication system -> replication in the cytoplasm
RNA viruses: require own DNA polymerases -> Replication in the cytoplasm
Exception: Orthomyxo, Borna viruses use splicing mechanisms in the nucleus
Retro viruses: host genome integration
Viral genome integration
DNA tumor viruses:
- not necessary for viral replication cycle
- Hypothesized: Strategy to hide from host immune system
- Is often described for tumor viruses -> chronic infections
RNA tumor viruses (retroviruses):
- viral genome integration into host genome is part of viral life cycle
- The initial integration event likely takes place in regions where the viral and host DNA
are in close proximity - Genomic signature of HPV integration events have identified only a handful of recurrent loci in the host genome:
- Common fragile sites
- Transcriptionally active regions
- Regions of micro-homology (10 bp) between viral and human genomic sequences
- AT-rich regions which have the potential to form stem-loop structures that promote the formation of stalled replication forks during replication stress
Oncogenic potential of viral genome integration
direct -> introduction of new “transforming gene” into the cell -> induction of non-genotoxic mechanisms (loss of normal growth regulation processes, affection of DNA repair mechanisms, genetic instability) -> mutagenic instability
indirect -> alteration of expression of pre-existing gene -> induction of non-genotoxic mechanisms (loss of normal growth regulation processes, affection of DNA repair mechanisms, genetic instability) -> mutagenic phenotype
Cervical cancer
Nobelprice 2008:
* discovery of human papilloma viruses causing cervical cancer
* DNA from cervical carcinomas (lanes 2, 4, 5, 7, 9), dysplasia (lane 6), cervix carcinoma in situ (lane 1, 5) and vulva carcinoma (lane 3), cleaved by BamHI restriction digestion
* DNA hybridization at low stringency conditions to screen for novel HPV types
HPV risk groups
HPVs can be roughly divided into two groups
-> Low risk (HPV types: 6, 11, 42, 43, 44) -> genital warts or benign lesions, not cervical cancer
-> High risk (HPV types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) -> all types isolated in cervical cancer
- U.S.: among adults ages 18-59 in 2013-2014, about 45% of men and 40% of women had HPV infection
- U.S.: high-risk genital HPV infection affected about 25% of men and 20% of women
-> Not all infected people develop cancer - HPV high risk types were identified in 95-98 % of cervical cancers
-> Members of the high risk group are associated with cervical cancer
Proportion of cervical cancers caused: 16 > 18 > 33 > 45 > 31 > 58 > 52 > 35 > 59 >56 >51 > 39 > 73 > 68 > 82
Organization of the HPV genome
E: early expressed genes
L: late expressed genes
LCR: long control region
L1: major capsid protein
L2: minor capsid protein
E5: genome amplification, cellular proliferation
E4: genome amplification, interaction with cytoskeleton/keratin
E2: Transcriptional control, tethering of viral episome, viral DNA replication
E1: DNA helicase, viral DNA replication
E6/E7: Oncoproteins
- Necessary cellular DNA polymerases and replication factors are only produced in mitotically active cells
- Expressions of the viral E6 and E7 oncogenes promote cellular proliferation and abrogates cell cycle checkpoints
-> enables replicative potential for the virus
Viral gene expression in cervix carcinogenesis
- High risk HPV viruses infect basal layer cells
- Depending on the differentiation state of the cell, the virus induce the expression of different viral genes
HPV genome integration is frequent in cancer
- HPV integration occurs in >80% of HPV-positive cervical cancers
- 76% of HPV16-positive samples have integrated HPV, whereas integration is evident in all HPV18-positive samples
- Disadvantage for the virus: integration is a dead end for the virus, as it is no longer able to form a small, circular genome that can be packaged and transmitted to a new host
- Advantage: Persistence in the host without recognition by the host immune system
