Pathogens (Jeremy Lecture 2)

Question 1

How does influenza shut down host protein synthesis?

Answer 1

1) Viral polymerase steals 5’ guanine cap from host mRNA preventing their translation
2) NS1 blocks host mRNA nuclear export
3) NS2 facilitates viral mRNA nuclear export
4) Down regulated the expression of Nup98 (nucleoporin essential for mRNA export)

Question 2

What % of human cancers are attributed to viral infection?

Answer 2

~20%

Question 3

What type of cancers are commonly caused by viral infectiom?

Answer 3

Liver and cervical

Question 4

Where is HPV replication at its highest?

Answer 4

In highly differentiated epithelial cells

- can not replicate in less differentiated cells

Question 5

Why does HPV induce increased host cell replication and differentiation?

Answer 5

Because it can replicate more effectively in highly differentiated host cells

Question 6

How does HPV induce increased host cell replication and differentiation?

Answer 6

1) E6 protein
- binds to p53 resulting in ubiquitination
- Ubiquitination targets p53 to proteasome, causing its degradation
- p53 is cell cycle inhibitor, breakdown increases cell cycle
- Also prevents apoptosis
2) E7 protein
- degrades pRb, a cell cycle regulator protein

Question 7

How does the Ebola virus spread from the site of infection throughout the body?

Answer 7

By causing vascular leakage

• Ebola virus infects macrophages, resulting in large scale production of cytokines (cytokine storm) that increase vascular leakage
• Production of some cytokines i.e IL-10 associated with fatal disease
• Soluble Ebola glycoproteins down-regulated host cell adhesion molecules i.e tight junctions between endothelial cells, increasing vascular permeability
• Ebola can enter blood and spread throughouut body

Question 8

Describe the structure of sialic acid?

Answer 8

Sialic acid is a sugar, covalently linked to either a protein or a lipid
Bond between the 2 is mainly either a alpha2-3 or alpha2-6 linkage

Question 9

Where are the 2 types of sialic acids mostly found?

Answer 9

alpha2-6 found mainly in upper respiratory tract

alpha2-3 found mainly in lower respiratory tract

Question 10

What influenza virus cell surface component binds to sialic acids?

Answer 10

Hemagglutinin (HA)

Question 11

Which sialic acids do avian influenza strains (H5N1) preferentially bind to?

Answer 11

• alpha2-3 sialic acid
• Found in lower respiratory tract
• Causes more serious disease (pneumonia)

Question 12

What occurs for the influenza virus to exit the epithelial cells?

Answer 12

Virus cell surface Neuraminidase (NA) cleaves host cell sialic acids so that it does not re-attach

Question 13

Why does sialic acid cleavage by NA often give way to more serious disease?

Answer 13

Cleavage of sialic acid exposes receptor for streptococcus pneumoniae

• greater adherence of s. pneumoniae
• bacterial super-infection is a leading cause of sever disease in influenza

Question 14

Name some ways that viruses can kill host cells

Answer 14

• Inhibition of critical cell processes
• Cleavage of cytoskeleton causing disruption to cell intergrity
• Mitochondrial damage
• Inducing Apoptosis
• Autophage

Question 15

Name the ways in which influenza virus kills cells through inducing apoptosis?

Answer 15

1) PB1-F2 (high pathogenicity strains i.e H5N1d) causes mitochondrial permeability, the release of cytochrome c and induction of apoptosis
2) NS1
3) M2 protein induces incomplete autophagy causing apoptosis
4) Cellular antiviral response triggers apoptosis

Question 16

What is the benefit of inducing apoptosis for influenza?

Answer 16

Apoptotic signalling produces large amounts of caspases that can be utilised by the virus
They affect:
- Viral RNP nuclear export
- Virion assembly
- Cell survival
- Airway integrity

Question 17

How does the M2 protein induce incomplete autophagy?

Answer 17

Prevents the fusion of the autophagosome and the lysosome (prevents autolysosome formation)

Question 18

How does poliovirus utilise incomplete autophagy?

Answer 18

• Prevents fusion of the autophagosome and the lysosome
• Poliovirus then causes the phagolysosome to fuse with the plasma membrane to release it from the cell
• Known as autophagosome-mediated exit without lysis (AWOL)
• Useful for a non-enveloped virus such as poliovirus

Question 19

Name some ways that HIV causes CD4+ T cell death

Answer 19

1) Env binds to CD4 and induces caspase-3 activity (apoptosis)
2) Tat upregulates Fas and Fas-L, increasing caspase-8 activity (apoptosis)
3) Nef upregulates Fas and Fas-L
4) Vpu increases susceptibility to Fas-induced death
5) Vpr causes cell cycle arrest after G2 resulting in apoptosis

Question 20

What is insertional mutagenesis

Answer 20

Mutagenesis by insertion of one or more bases into DNA

- e.g. implanting viral genome into host cell chromosome

Question 21

What is a potential by product of insertional mutagenesis by a virus?

Answer 21

Insertion into an oncogene or tumour supressor gene can cause cancer

Question 22

How is the HIV genome integrated into the host chromosome?

Answer 22

1) HIV encodes reverse transcriptase
2) In the cytoplasm, HIV uses reverse transcriptase to make a cDNA copy of its RNA genome
3) DNA replication to give double stranded cDNA
4) Viral cDNA transported to the nucleus
5) Viral protein integrase intergrates ds DNA into host genome