Tumour Viruses Flashcards
1
Q
Rous Sarcoma Virus
A
- Had 4 genes: 3 for replication and fourth for transforming cells
- Discovered by Peyton Rous: 1879-1970. Isolated the first tumour causing animal virus (in chickens)
- Awarded Nobel prize 55 years later in 1966,
- 20% of human cancers associated with viruses
2
Q
Oncogenes
A
An oncogene is a gene coding for proteins that can cause cell transformation:
- Some viruses carry their own oncogenes (e.g. RSV)
- Some viruses disrupt the host’s regulation of normal cellular genes involved in control of cell growth which can then act as oncogenes (proto-oncogenes) –> uncontrolled proliferation
- We can use experimental infections with these DNA and RNA viruses to identify genes involved in cancer development
3
Q
Normal Cell Cycle
A
- The cell cycle is normally tightly regulated.
- Specific checkpoints control progression through the cell cycle.
- If certain criteria are not met, then checkpoints block progression through phases and apoptosis occurs (programmed cell death).
- Cells of skin & intestinal lining are almost always in growth phase
- Liver/ lung cells are mainly in the G0 phase but can enter growth phase when required
- Cells of heart muscle & CNS, don’t have resident tissue stem cells- heal by fibrosis/ scarring rather than tissue regeneration
4
Q
Cell Transformation
A
Characterized by: Uregulated Cell growth, Loss of Contact Inhibition, Altered Cell morphology
- Tumours are the result of unregulated cell proliferation,
- Caused by altered expression of genes that are involved in growth control:
- Genes that are stimulatory for growth and which cause cancer when hyperactive (oncogene)
- Tumour suppressor genes which are responsible for controlling the checkpoints (inhibit cell growth) are switched off –> dysregulation of cell checkpoints
5
Q
Papilloma Viruses
A
- Papillomaviridae
- Non-enveloped, dsDNA virus
- Species Specific
- Resisitant to diverse environmental insults
- Over 118 types
6
Q
Retroviruses
A
- Retroviridae
- Enveloped, RNA virus
- Possess unique enzyme reverse transcriptase- converts RNA–> DNA
7
Q
Papillomaviruses
(Pathogenesis)
A
- Entry via lesion in epithelium (skin or mucosa) & infect dividing basal cells below
- First theres expression of early proteins (oncogenes) in basal epithelial cells uncontrolled proliferation
- Differentiate & are sloughed off towards the surface epithelium, late structural proteins are expressed
- Virus transmission via exfoliated cells
8
Q
BPV Genome
(papillomaviruses)
A
divided into:
1. Early genes: non-structural proteins (in basal epithelium and transformed cells)
2. Late genes: structural proteins (differentiated cells)
9
Q
Diseases caused by Papilloma viruses
A
- Low Risk –> warts/verruca (HPV-1)
- High Risk –> cell transformation & malignant tumour growth e.g. Cervical Cancer (HPV-16/ HPV-18)
10
Q
Bovine Papilloma Virus
A
- In cattle 10 BPV recognised to date
- Usually benign skin tumours (papillomas) particularly on head, neck, shoulder and udder
- Most frequently in calves and yearlings
- BPV-1/5/ 6 –> fibropapillomas on teats, BPV-1 benign penis tumors, BPV-1/2 benign facial tumors
- In most cases tumours regress spontaneously after ~ 6 months, may persist if immunocompromised
11
Q
How early gene e5 contributes to transformation
(papilloma virus)
A
- Virus protein E5 binds to receptor for platelet-derived growth factor (PDGF)–> cell proliferation
- E5 inhibits the formation of gap junctions between cells –> ↓ communication of the infected cell with neighbouring cells and lack of growth inhibitory signals from those cells
- E5 downregulates MHC1 expression- helps virus evade host immunosurveillance
12
Q
Malignant Tumors
(papilloma)
A
- BPV-4 infection usually–> benign papillomas in GIT, but can –>malignant tumours in upper GIT & bladder in cattle grazing on bracken fern (contains mutagens & immunosuppressants)
13
Q
BPV in Horses–> SARCOIDS
(papilloma)
A
- BPV-1/2 E5 expression is associated with–> equine sarcoids
- locally invasive skin tumours
- Frequently recur after surgical removal & in some cases more severely
- Vary in gross appearance: verrucous, fibroblastic, occult, mixed
- Can mistake for ringworm/ granulation tissue
- Transmission from horse to horse has been shown experimentally
- Biting flies now thought to be involved in viral transmission
- The infection transformation of fibroblast (mesenchymal) cells in the dermis (not epithelial cells)
14
Q
Canine Oral Papillomavirus
A
- Benign tumours on lips, tongue, palate- Usually spontaneously regress
15
Q
Equine Papillomavirus
A
Causes benign skin tumours- Usually self-limiting
16
Q
Jaagsiekte Sheep Retrovirus
A
- Causes: Ovine pulmonary adenocarcinoma (tumour in lung epithelial cells)
- Similar arrangement of genome to FeLV but env (a structural protein) is the oncogene
- Pneumocytes line the alveoli:
Type 1 pneumocytes- where gaseous exchange occurs
Type 2 pneumocytes –>surfactants (progenitor cells of the lung)
- When sheep inhale JSRV infects type 2 pneumocytes –> env protein is expressed–> cell transformation
- Symptoms: ‘driving sickness’- respiratory distress, some weight loss, exercise intolerance
- Diagnosis: Wheelbarrow Test- lift hind legs higher than head & fluid produced by virus will leak out of nose
- Transmission: Virus–> fluid of lungs and is coughed up & spread on
17
Q
Retroviruses
A
Retroviruses commonly cause immunological disease, neurological disease, cancer
- Alpha Retroviruses –> RSV
- Beta Retroviruses–> JSRV (causes lung cancer in sheep), ENTV-1/2 (enzootic nasal tumour virus- sheep)
- Gamma Retroviruses–> FeLV
- Lentiviruses–> FIV & EIAV
18
Q
Retroviral Replication
A
- Bind to specific receptor–> cytoplasm
- Reverse transcription occurs: RNA–> ds DNA (DNA-RNA hybrid forms in between)
- (In some cases, cell must replicate for virus to gain entry through nuclear membrane- Can be an important limiting factor)
- Viral DNA integrates with host genome at random–> provirus
- Viral mRNA produced using host cell’s RNA polymerase
19
Q
Organization of Retroviral Genome
A
- LTR - (Long Terminal Repeats) at either end- regulate gene expression, can ↑ expression of host genes
- GAG - (Group specific antigen)- Codes for capsid
- POL- Codes for polymerase (reverse transcriptase)
- ENV- Codes for envelope proteins
22
Q
FeLV Pathogenesis
A
- Initial viral replication in the lymphocytes/ macrophages of hosts tonsils –> Primary viraemia
- Cat may show pyrexia/ generalised lymphadenopathy or maybe clinically normal
- Outcome of infection depends on: Age of animal & host immune response
Possible Outcomes:
- 20-30 % will seroconvert without becoming detectably viraemic.
- 30-40 % show transient viraemia & remain latently infected with provirus in the bone marrow cells. May reactivate if animal immunosuppressed but rare.
- 30% will become persistently viraemic: Virus infects dividing cells in the BM & integrates –> stem cells, large quantities released from bone marrow, infects epithelial cells in salivary glands & intestine & released. Clinical signs of immunosuppression, anaemia & lymphoma
- FeLV often integrates near c-myc gene –> uncontrolled expression of myc (protein regulates transcription) cell proliferation
- Tumours can originate in any organ: May be multicentric (involving lymphoid tissues at various sites) or may involve predominantly one site such as the thymus, alimentary tract or in rare cases: skin/ kidney
- Immunosuppression due to malfunction of lymphocytes –> secondary infections (which are most common cause of death in cats with FeLV)
