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Cancer, Autoimmunity and Transplant Immunology > Pathogens and Cancer > Flashcards

Pathogens and Cancer Flashcards

1
Q

give examples of what pathogens can cause cancer:

A

EBV
Hep B/C virus
Kaposi’s sarcoma herpes virus
HPV
Merkel cell polyomavirus

Helicobacter pylori

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2
Q

how is HIV linked to cancer?

A

HIV is a cofactor for cancer as it causes immunosuppression:
- Virus replicates in CD4 cells – loss of CD4 immunity
- Patients can then develop AIDS
- Opportunistic infections likely in AIDS such as herpes virus, EBV, KSHV can cause cancer
HIV increases risk of cancer due to loss of immunity

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3
Q

what was the first virus found to be associated with cancer?

A

EBV first virus found to cause cancer

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4
Q

what does EBV infect?

A

Infects B cells
- Remains latent for lifetime in B cells
- Can transform B cells into immortalised proliferating cell lines using EBV in vitro

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5
Q

what cancers can EBV cause?

A

EBV can cause a whole range of cancers, not just one or 2 – , Burkitt’s, Hodgkin’s, B cell cancer, head and neck epithelial cancer, gastric carcinoma, NK/T cell lymphoma, leukaemias

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6
Q

what cancers do different viruses cause?

A
  • HBV/HCV = hepatocellular carcinoma
  • HPV = carcinoma of cervix, vagina, penis
  • KSHV = Kaposi’s sarcoma, B cell lymphoma (primary effusion)
  • MCV (Merkel Cell Polyomavirus) = Merkel cell carcinoma
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7
Q

how do viral-induced cancers differ across the world?

A

Viral-induced cancers have different global distribution:
- High prevalence in china, sub-Saharan Africa, south America
- These places have poor screening programs – high rates of cervical cancer caused by HPV
- Cofactors can drive virally-induced cancer e.g. food storage, nitrosamines

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8
Q

what are the features of polyomaviruses?

A
  • enveloped
  • circular dsDNA
  • a small virus - 5000bp
  • genome replication and virion assembly occurs in host nucleus
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9
Q

what is an example of a polyomavirus?

A

Merkel Cell Polyomavirus

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10
Q

what important proteins does MCV have?

A
  • 3 capsid proteins VP1-3 to enable receptor-mediated entry
  • capsid contains viral nucleic acids – dsDNA
  • Nucleic acids contain late proteins (capsid proteins) and early, non-structural proteins (large T, small T, middle T and AGNO protein)
  • Large T and Small T can manipulate cell cycle and drive cancer
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11
Q

what is contained within the genome of MCV?

A
  • origin of replication - important for Large T to enable replication of viral genome
  • regulatory region contains gene promoters and origin of replication
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12
Q

what does Large T control?

A

Large T controls replication of the viral genome

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13
Q

why does MCV depend on the host to replicate?

A

It is a small virus so doesn’t encode its own replicative enzymes
- manipulates host cell cycle before the cell can recognise that it has been infected
- they use the host DNA synthesis machinery to produce their viral proteins during S-phase

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14
Q

what genes of MCV function prior to DNA replication (early gene expression)?

A

Genes that function prior to DNA replication:
- Large T
- Middle T
- Small T

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15
Q

how does Large T induce replication?

A

Large T is transcribed and binds the replication origin to recruit host RNA pol II which recognises the regulatory region promoter of the viral genome
- Synthesis of T antigens followed by DNA replication
- Large T unwinds DNA drives the cell cycle

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16
Q

what occurs during late gene expression in MCV?

A

Occurs from new DNA template
- Capsid proteins synthesized in cytoplasm
- Capsid proteins bind DNA in nucleus
- Cell lysis - viral particles are released

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17
Q

what normally leads to cell cycle progression?

A

Mitogenic signal binds to surface receptor
- transmits signal to nucleus to upregulate cyclin D
- Cyclin D activates CDK4/6
- phosphorylation of Rb and release of E2Fs for S-phase gene transcription

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18
Q

how does MCV manipulate resting cells?

A

Polyomaviruses manipulate resting cells to enter the cell cycle
- This is mostly achieved through the action of Large T
- Large T directly binds Rb allowing entry into S phase without the need for mitogenic signals

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19
Q

what happens when Large T binds Rb?

A

Large T binds Rb
- This detaches the E2F TFs
- Phosphorylation of Rb is no longer needed to liberate E2Fs, meaning the cell enters cell cycle
- enables rapid replication of viral DNA

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20
Q

what happens when Large T promotes cell cycle progression?

A

Inappropriate entry into S-phase is detected, so p53 is activated
- virus needs to inactivate p53 to avoid arrest or apoptosis

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21
Q

how does MCV inhibit cell cycle control?

A

Large T can bind and inhibit Rb

Small T inhibits p53 by upregulating MDM2

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22
Q

what is MDM2?

A

an E3 ubiquitin ligase which can induce the degradation of p53 at the proteosome

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23
Q

how does small T function to inhibit p53?

A

Small T cannot bind to the host DNA itself, but can interact with TF complexes MycL and EP400
- these TFs will bind to the host DNA and upregulate MDM2
- MDM2 can then induce the degradation of p53 via ubiquitination

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24
Q

why is Large T indispensible for MCV replication?

A
  • Large T binds to the origin of replication of the viral DNA.
  • Acts a helicase to unwind the DNA.
  • Recruits host DNA polymerase complex to this site and initiates DNA replication
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25
Q

what normally happens when a virus induces its replication in the host cell?

A

Virus antigens are replicated e.g. viral DNA, capsid
- Usually, new infectious virions will be released from the cell and kill the cell due to bursting

  • So how does the host cell become cancerous?
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26
Q

what is Merkel Cell Carcinoma?

A
  • rare but aggressive skin cancer of Merkel cells
  • higher incidence in immunosupressed: 10x in AIDS, 5x in transplant patient
  • present on exposed areas of body susceptible to UV - similar appearance to melanoma
  • increased risk with age due to immunosenescence
  • tumours mostly appear on head and neck
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27
Q

what is a merkel cell?

A

Light touch receptor –mechanoreceptor that synapses with somatosensory afferent nerves – can receive and signal fine contact
- Found just under the skin epidermis

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28
Q

how did scientists discover MCV?

A

digital transcriptome subtraction:
- Took tissue from healthy area and carcinoma region
- generated cDNA and sequenced the transcriptome
- subtracted the healthy transcriptome from the cancer transcriptome, with the remainder being the genome of the virus
- left 2400 sequences which showed homology to a monkey polyomavirus
- the viral DNA was found clonally integrated into the host cell genome
- this virus was found in >80% of merkel cell carcinoma

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29
Q

what are the key domains of Large T, identified by sequencing of MCV?

A

Large T has an Rb binding domain, origin binding domain and helicase domain to unwind DNA
- the helicase domain assembles on the origin and opens the origin sequence to allow initiation of cellular polymerase-mediated replication
- Enables replication of host cell genome

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30
Q

what is the model for MCV cause of cancer?

A
  • most people are infected with the polyomavirus, but is kept under tight immune control so it doesn’t replicate
  • If it does replicate, it destroys infected cells – no cancer
  • If under immune suppression due to HIV, transplant or senescence, there is increased viral replication
  • first insult may be UV, which induces dsDNA break in genome allowing virus to integrate into host genome via non-homologous recombination
31
Q

what does sequencing of Large T in merkel cell carcinoma show? how does this affect its function?

A

Large T sequences from MCC samples showed that these consistently had mutations
- truncating mutations via stop codon insertion
- Rb-binding domain remains intact
- but helicase and origin binding domains are lost

Truncated large T can still bind Rb to induce progression into S-phase
- but Large T can’t unwind the DNA and transcribe the viral proteins, so virions are not generated and host cells don’t lyse
- mutations leads to excessive proliferation of infected cells - continual cell cycle where cells do not die, as viral replication has been disrupted

32
Q

how was mutant large T shown to be crucial to maintain merkel cell carcinoma proliferation?

A

Ablated large T expression with siRNA:
- All MCV positive MCC cell lines underwent growth arrest and senescence when large T expression was blocked.
- Indicates large T is required to maintain MCC continuous growth
- Strongly suggests MCV is the causative agent of MCC.

33
Q

what does human papilloma virus cause?

A

HPV can cause warts, verrucas, continual proliferation of keratinocytes without shedding, as well as cervical, head and neck cancer

34
Q

what is the genome size of human papilloma virus (HPV)?

A
  • small genome - 8000bp
35
Q

how does HPV infect and replicate?

A
  • HPV enters via microabrasions in the skin and infects basal epithelial cells
  • HPVs replicate as extrachromosomal plasmids or episomes – integration into host DNA is not a normal part of the life cycle
36
Q

why does the life cycle of HPV depend on basal epithelial cells?

A

The HPV life cycle critically depends upon the induction of terminal keratinocyte differentiation.
- Basal cells actively replicate to enable viral genome amplification, where the virions can assemble
- As basal cells differentiate and come out of cell cycle, they become keratinocytes at the top which are dead and shed off
- the differentiated, dead keratinocytes then release the virions

37
Q

how does HPV use the host machinery for replication?

A

Small virus, so doesn’t encode own DNA replication machinery
- it requires host cell for replication
- Infects basal epithelial cells as these actively replicate and can provide replicative enzymes

38
Q

what viral proteins does HPV express within basal epithelial cells?

A

During cell proliferation and viral genome amplification, HPV expresses of early viral proteins in basal cells e.g. E1, E2, E4, E5

39
Q

What is the role of the HPV E2 protein?

A

E2 protein inhibits the expression of E6 and E7 in basal cells
- In the normal virus life cycle, expression of E6 and E7 is tightly regulated by E2 in replicating cells
- when basal cells begin to come out of cycle and differentiate, HPV expresses E6 and E7

40
Q

how do low risk and high risk HPV differ?

A

low risk:
- E6 and E7 expression stimulates cell cycle entry in the upper epithelial cell layers allowing genome amplification

High risk:
- E6 and E7 expression stimulates cell cycle entry and cell proliferation in the lower and middle and upper epithelial layers to allow genome amplification and leading to neoplasia

41
Q

how does E7 induce neoplasia?

A

Similar mechanism of polyomavirus and HPV
- E7 binds Rb and displaces E2Fs
- When cells begin to come out of cycle, E7 is expressed and causes cells to enter S-phase by inactivating Rb
- this activates p53

42
Q

how does HPV inhibit p53 to enable cell cycle progression?

A

HPV encodes E6 to recruit E6AP ubiquitin ligase:
- Ubiqutinates and degrades p53 to avoid cell cycle arrest
- Lack of p53 leads to accumulation of DNA mutations which cant be detected – accumulation of mutations with no apoptosis = cancer

43
Q

why does the expression of E6 and E7 become deregulated when HPV integrates into the host DNA?

A

Integration of HPV genome into host DNA disrupts E2 control of early promoter
- 4 cut sites in the viral genome block E2 activity once integrated, leading to upregulation of E6 and E7 oncoproteins
- continuous expression of E6 and E7 proteins retained in cancers = uncontrolled cell cycle progression
- necessary for malignant progression

44
Q

what does loss of E6 and E7 induce in cancers?

A

knockdown of E6 and E7 in cancer cells leads to senescence/apoptosis
- important to maintain the transformed phenotype

45
Q

what are the risk factors for cervical carcinogenesis?

A
  1. HPV persistence at the cervix - virus isn’t cleared
  2. HPV genome integration - deregulation of E6 and E7
  3. co-factors e.g. smoking
46
Q

what are the features of herpesviruses?

A
  • Larger viruses – 230kbp genome
  • Encode a large array of enzymes involved in: nucleic acid metabolism, DNA synthesis and processing of proteins
  • encodes sufficient enzymes for DNA replication - doesn’t rely on host cell polymerases
  • relies on host cell for energy and nucleotides, not enzymes
  • viral DNAs and capsid assembly occurs in nucleus - gain envelope as they bud from plasma membrane
  • when they leave, they destroy the host cell
47
Q

what are the 2 life cycles of herpesvirus?

A

Lytic cycle

latent cycle

48
Q

what is the lytic cycle of herpesvirus?

A

viruses actively replicating
- Encodes its own enzymes to replicate DNA during lytic cycle – doesn’t rely on the host cell for replication enzymes at this point, just relies on host energy and nutrients

49
Q

what is the latent cycle of herpesvirus?

A

Latent cycle - enter latency one they have infected a cell
- persists for entire lifetime and hides from immune system
- Downregulates viral protein expression – become less immunogenic so aren’t detected

50
Q

what occurs during herpesvirus latency?

A

Upon infection of a cell the viral genome can circularise to form an episome
- Few if any viral genes are expressed from the viral episome
- Some viral genes may be expressed to facilitate establishment of latency
- No viral particles are produced in this state - no longer immunogenic
- However the virus has the capacity to reactivate from this form and produce new infectious particles when the B cell differentiates

51
Q

what is an example of a herpesvirus?

A

Kaposi’s sarcoma herpes virus (KSHV)

52
Q

what are the features of KSHV?

A

Encodes up to 86 genes, 22 of which have immunomodulatory capacity
- Even when the virus expresses multiple antigens, they can stop MHC trafficking, stop peptides shuttling through TAP, keep peptides from leaving ER
- overall reduces antigen presentation

53
Q

how is KSHV transmitted and what does it infect?

A

Virus appears to be saliva transmitted but evidence for other routes also exists

KSHV infects B cells and endothelial cells
- can establish latency in B cells

54
Q

what diseases can KSHV cause?

A

Kaposi’s sarcoma - endothelial tumours

Primary effusion lymphoma - B cell malignancy

Multicentric castleman disease - B cell pathology

55
Q

how is KSHV distributed?

A

Seroprevalence correlates with disease incidence
- KSHV is necessary but not sufficient to cause KS
- highest rates in Africa and South America

56
Q

what viral proteins does KSHV encode in Kaposi’s sarcoma?

A

Lana
V-cyclin
V-flip
kaposin

57
Q

what is LANA in KSHV?

A

Latency-associated nuclear antigen
- expressed in all KS cancer cells

58
Q

what is the function of LANA?

A

LANA tethers KSHV episome to host chromosomes:
- when cell replicates, LANA can bring host DNA machinery to KSHV origin
- when cells undergo mitosis, equal copies of viral genome are passed to daughter cells

LANA inhibits tumour suppressor function of p53 and Rb

LANA inhibits TGFb production – no CDKi activation – cell cycle dysregulation

59
Q

what is the role of V-cyclin in KSHV?

A

V-cyclin is a cyclin D homologue:
- V-cyclin destabilises cell cycle control
- No need for mitogenic signal at cell surface, as virus already expresses V-cyclin to replace cyclin D

60
Q

what is the role of v-FLIP in KSHV?

A

vFLIP is anti-apoptotic
- activates transcription factors associated with expression of pro-survival and proinflammatory genes
- e.g. BCL-2

61
Q

what is the role of Kaposin in KSHV?

A

Complex of proteins which stabilise mRNA of pro-inflammatory cytokines
- Chronic inflammation can cause epigenetic changes to cells which silence tumour suppressor genes

62
Q

what are the overall effects of KSHV on host cells?

A

KSHV can keep cell in cycle, inhibit CDKIs, can create inflammatory environment, can block apoptosis

63
Q

what is primary effusion lymphoma?

A

Aggressive malignancy seen in late stage AIDS patients
- Cells are of B lymphocyte origin transformed by KSHV - cancer of plasmoblasts
- In many cases these cells are co-infected with Epstein-Barr virus
- B lymphocyte shows features of a differentiated B lymphocyte/plasma cell
- Usually present as an effusion in peritoneum or pericardial spaces
-Few treatment options

64
Q

what viral proteins does KSHV encode in primary effusion lymphoma?

A
  • LANA
  • V-cyclin
  • V-FLIP
  • Kaposin
  • v-IL6
  • v- IRF3
65
Q

what is the role of V-IL6 in KSHV primary effusion lymphoma?

A

Cytokine shows homology to human IL-6
- Binds to human IL-6 receptor but bypasses regulatory receptor
- Important for promoting B cell proliferation
- Has proinflammatory activity

66
Q

what is the role of V-IRF3 in KSHV primary effusion lymphoma?

A

Viral interferon regulatory factor 3
- Inhibits components of the innate interferon anti-viral pathway
- Inhibits expression of class II MHC by interfering with transcriptional transactivators
- Promotes survival of primary effusion lymphomas

67
Q

what is Helicobacter pylori?

A
  • Colonizes the gastric mucosa of >50% population
  • Can cause gastritis, gastric atrophy, gastric ulcer, gastric cancer, MALT-lymphoma
  • Most infected people have an asymptomatic chronic active gastritis
  • Can be treated with antibiotics but resistance is increasing
68
Q

where is H. pylori most prevalent?

A

Predominately in developed countries
- Likely due to diet, and due to use of proton-pump inhibitors

69
Q

in what stages of gastric cancer is H. pylori present?

A

H. pylori is in the stomach of people with early gastritis and at the intestinal metaplasia stage:
- H. pylori changes pH and microbiome of stomach as the cells change
- This causes the microbiome to outcompete helicobacter – so not seen in the gastric carcinoma itself

70
Q

how does H. pylori induce gastric adenocarcinoma?

A

Helicobacter strains encoding the cytotoxin associated gene A (CagA) and VacA
- CagA strain are associated with increased risk of gastritis and gastric cancer
- Helicobacter can invade gastric glands and inject CagA into cells on the epithelium it colonizes

71
Q

what are the functions of CagA produced by H. pylori?

A
  • tethers to inner leaflet of plasma membrane via phosphatidylserine
  • inactivates p53 to prevent apoptosis
  • activates NF-KB to drive inflammation
  • triggers MAP/ERK pathway to drive proliferation and change epithelial polarity, leading to loss of E-CAD to drive EMT and invasion
72
Q

how does CagA drive EMT?

A
  • Disrupts adherens E-CAD junctions – lose cell polarity
  • Upregulates MMPs – detachment from ECM
  • Drives N-cad expression
  • epithelial cells become less polarised, more mesenchymal and migratory – can invade local tissue
73
Q

how do T cells respond to H. pylori?

A

Tumour infiltration of T cells correlated with increased survival time in gastric cancer

T reg thought to decrease likelihood of inflammation however may prevent clearance

Achieving a balance appears crucial

74
Q

how can H. pylori induction of gastric cancer be prevented?

A

Preventing infection may help or specifically targeting CagA expressing cells may be beneficial
- Antibiotics useful and can be screened for

Cancer, Autoimmunity and Transplant Immunology (15 decks)

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