CTE3 - virus-host interactions

Question 1

virus-infected cell clearance - innate

Answer 1

o Natural killer (NK) cells –> granule exocytosis releases proteins adjacent to the target cells.
Perforin, facilitates the entry of granzymes,
 The granzymes are proteolytic enzymes that initiate apoptosis
o They can mediate ADCC activity via their Fc receptor
o Their nonspecific cytotoxic activity is increased by interferon and interleukin-2 (IL-2);
o They can produce a number of different cytokines including interferon when stimulated with virus or virus-infected cells

Question 2

virus-infected cell clearance - adaptive

Answer 2

Cytotoxic T cells
 The principal mechanism through which cytotoxic T cells act is by the calcium-dependent release of specialized lytic granules (perforin and granzymes) upon recognition of antigen on the surface of a target cell –> apoptosis

Question 3

NK cell activation

Answer 3

In general, the activating receptors recognize ligands on infected and injured cells, and the inhibitory receptors recognize ligands on healthy normal cell
o NK cell–activating receptors are called killer cell Ig-like receptors (KIRs)
o A second important group of activating NK receptors are similar to the family of C-type lectins
o FC receptor (CD16) binds IgG antibodies  antibody-dependent cell-mediated cytotoxicity
o Inhibitory receptors of NK cells recognize class I MHC molecules, which are cell surface proteins normally expressed on all healthy nucleated cells in the body

Question 4

antibodies in viral infections

Answer 4

• Antibodies can bind to extracellular viruses and neutralise them  prevent infection by blocking VAPs
• Antibodies can bind to viruses and opsonize them for phagocytosis
• Antibodies can mediate ADCC  bind to antigens presented in MHC-1 and mark the infected cells for destruction
• Antibodies can mark infected cells for complement mediated lysis via the classical pathway
  o C3b etc cause inflammation and chemotaxis
  o MAC formation on virus surface to cause lysis

Question 5

PRRs and COVID

Answer 5

Normally sensed by endosomal TLRs (3, 7,8 and9) and RLRs (RIG-1 and MDA-5) and possibly by

leads to IFN expression and acute inflammation

Question 6

type 1 IFN response

Answer 6

• Infected cells (or immune cells) produce type 1 IFNs (alfa – 13 proteins - and beta IFN) to stop the spread to neighbouring cells –> paracrine action
  1. IFN alfa and beta bind to IFN receptor
  2. STAT1 and 2 and IRF9 transcription factors activated
  3. Activate 2 antiviral genes:
• A protein kinase (PKR  dsDNA activated), catalyses the phosphorylation of a ribosomal protein and an initiation factor necessary for protein synthesis, so greatly reducing mRNA translation
• 2′,5′-oligoadenylate synthetase catalyses the formation of a short polymer of adenylic acid which activates a latent endonuclease (RNase L); this in turn degrades both viral and host mRNA
• Type I IFNs promote sequestrating of lymphocytes in LNs, maximizing the opportunity to encounter microbial antigens  via CD69 signalling
• Type I IFNs increase cytotoxicity of NK cells and cytotoxic T cells and promote the differentiation of naive T cells to the Th1 cells
• Type 1 IFNs increase MHC-1 expression

Question 7

covid and IFN signalling

Answer 7

• SARS-Cov2 produces antagonists that inhibit the IFN response at several stages of the response:
  o Innate sensing –> nsp14 and 16 prevent detection of RNA via RIG-1 and MDA5
  o Cell signalling –> N and M proteins and nsp1 and 6 (STAT inhibition)
  o The production of type I IFN –> ORF3b
  o IFN signalling –> ORF6

Question 8

covid and cytokine storm

Answer 8

IL6 is a major player in the inflammatory profile of covid19
Sustained infection leads to large and prolonged release of cytokines which stimulates more leukocytes and epithelium which leads to more cytokines etc.

inhibiting the IL6 or leukocytes (dexamethason) might improve symptoms by alleviating the inflammation and reducing tissue damage

Question 9

casirivimab and imdevimab

Answer 9

monoclonal IgG1 antibodies that bind and block the spike glycoprotein which leads to the blocking of viral entry into host cells
o Non-competing (different targets)

seronegative people benefit from the antibodies since they do not yet have their own (testing these things is becoming harder since very little people are still seronegative)

Question 10

evasion of Abs by mutations

Answer 10

1. Amino acid substitutions that alter the epitope
2. Increasing receptor-binding avidity
   a. Increased the likelihood of binding to ACE instead of Ig
3. Changes in glycosylation
   a. Glycans can shield epitopes from Ig binding
4. Deletions and insertions
   a. Chang shape of epitope much like AA substitution
5. Allosteric structural effects
   a. AA substitution outside of epitope might affect the shape of the epitope

Question 11

opportunistic infection HIV

Answer 11

depletion of CD4 cells will lead to opportunistic infections

tuberculosis –> intracellular bacterium so loss of Th1 will increase susceptibility
candidiasis –> fungus so loss of Th17 will increase susceptibility
cancer –> loss of Th1 increases risk since they aid in CD8 activation (they can kill cancer cells)

Question 12

effects of early cART

Answer 12

• CNS: cytokines back to base level
• Blood: CTL memory differntiation / reduces B cell activation / mitigates cytokine storm / inhibits depletion of CD4 cells
• LNs: reduces CD8 activation
• GI: increase in memory CD4 cells and memory B cells