L17-19: Immunity to Viruses

Question 1

Lytic viruses include

Answer 1

Influenza, HSV - results in death of infected cell by lysis

Question 2

Non-lytic viruses

Answer 2

LCMV - virions are released by budding or exocytosis

Question 3

Latency viruses

Answer 3

HSV, EBV

Question 4

Barriers to Infection

Answer 4

Mechanical: Keratinised epithelium, tight junctions between cells; Secretions - mucous, tears; cilia; air flow or fluid flow.
Chemical: Low pH (skin, gut); Enzymes [pepsin, lysozyme]; Fatty acids.
Soluble proteins: Defensins; Collectins; Complement.
Microbiological (normal flora): virome
Cellular: Phagocytes – Macrophages, neutrophils

Question 5

Defensins role and mechanism

Answer 5

Role in protection against enveloped viruses

Disrupts the membranes of enveloped viruses by binding to viral glycoprotein gp120

Question 6

Collectins role and mechanism

Answer 6

Collectins are soluble PRRs and have a key role in the first line of defence against viruses
Collectins bind to virions, resulting in:
- Aggregation - facilitates uptake by phagocytes (macrophages)
- Neutralisation
- Complement activation and virus or cell lysis

Question 7

Role of macrophages in viral immunity

Answer 7

Macrophages in the tissues can capture viruses
Viruses that enter the tissues can enter the lymphatic vessels and drain to the lymph nodes, or may enter the blood system and be delivered to the spleen.
Viruses are captured by specialised subsets of resident macrophages - subcapsular sinus macrophages located in the LN or marginal zone macrophages in the spleen.
These macrophages can prevent further virus spread around the body (‘Flypaper’)
Macrophages then release IFN-I and cytokines that limit viral replication (and also help prime the adaptive immune response)

Question 8

Viral PAMPs are detected by

Answer 8

Cell surface and endosomal Toll-like receptors (TLRs),

Cytosolic RIG-I like receptors (RLRs), NOD-like receptors (NLRs) and dsDNA sensors

Question 9

TLR activation-induced downstream effects

Answer 9

TLR signalling through MyD88 (apart from TLR3) activates IRF3/IRF7 leading to activation of type I IFNs or NFkB activation to induce pro-inflammatory cytokine production

Question 10

RIG-I-like receptors role and mechanism

Answer 10

Cytosolic sensors of viral RNA and activate NFkB to produce IL-1 as well as indirectly triggering inflammasome activation by activating NLRP3

Question 11

Inflammasome role and mechanism

Answer 11

Sense cytoplasmic PAMPs and promote release of proinflammatory cytokines (IL-1β and IL-18)

Question 12

viral dsRNA is recognized by

Answer 12

cytoplasmic RLRs (e.g. RIG-I or MDA), leading to the production of type I IFNs via the adaptor protein MAVS and the transcription factors, NFkB, IRF3 and IRF7.

Question 13

IFN response

Answer 13

IFN can signal to cells in the environment and activate an antiviral state which involves activation of the PKR pathway. This results in inhibition of viral protein synthesis by inactivating translational factors required for translation of host proteins through activation of RNAase L which degrades viral RNA.
Activated MX GTPases inhibit viral gene expression and virion assembly.

Question 14

Viral proteins that interfere with host cell function

Answer 14

Influenza virus non-structural protein-1 (NS-1) inhibits RIG-I sensing of viruses by binding to dsRNA and thereby inhibiting IFN production, as well as inhibiting the PKR and 2’-5’ OAS pathways

Question 15

Autophagy

Answer 15

enable cells to digest their cytoplasmic contents in lysosomes.
Sequestosome 1-like receptors (SLRs) recognise viruses and can direct xenophagy (autophagy of viruses in the cytoplasm)

Question 16

Viral interference in autophagy

Answer 16

HSV-1 ICP34.5, Influenza virus M2 and HIV-1 nef: inhibit autophagy by targeting Beclin-1

Question 17

Viral mechanisms for evading immune system

Answer 17

Viral mimicry of host cytokines: EBV - IL-10; Pox virus - soluble cytokine receptor
Autophagy interference: HSV-1 inhibit autophagy by targeting Beclin-1
Influenza NS-1 inhibits host cell IFN α/β production by binding to dsRNA and inhibiting RIG-I sensing of viruses, Interferes with the induction of the antiviral state by inhibiting PKR and 2’-5’ OAS pathways, Promotes translation, Inhibit viral RNA destruction
Pox viruses encode a IFN receptor to ‘mop-up’ type I IFNs

Question 18

NK cell mechanism of action

Answer 18

NK cells readily kill virus-infected cells;
NK cells are a major source of IFN-g;
Express activating receptors (NKG2D, CD16, Ly49 and natural cytotoxicity receptors [NCRs]).
Recognise viral glycoproteins expressed on infected cells e.g. influenza virus haemagglutinin
Recognise downregulation of MHC class I molecules induced by viruses
Inhibitory receptors expressed by NK cells block cytotoxicity when they recognise MHC-I molecules.

Question 19

Mechanism of T cell exhaustion

Answer 19

Antiviral T cells begin to upregulate inhibitory receptors which dampen the their responses (PD-1, CTLA-4)
Induction of TREG cells can suppress antiviral T cell function
Immunoregulatory cytokines such as IL-10, TGF-β are produced in higher amounts and inhibit function of T cells
Antigen-presenting cells can be infected by viruses and also chronic production of cytokines can suppress their function leading poorer activation of T cells

Question 20

Antivirals

Answer 20

NA inhibitors: Relenza, tamiflu

M2 channel blockers: amantadine