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Flashcards in Host Responses to Viral Infection Deck (17):

Explain what Type I and Type II interferons are how they act in host defense against viruses

Type I interferons
o Result of infection, host cells release Type I INF
o Two subtypes (α & β) but bind to same host receptor = act the same

Type II interferons
o Secreted by immune cells (lymphocytes)

Both = antiviral role
o Diffuses to adjacent cells
o Bind IFN receptors on uninfected cells → signal transduction cascade → expression of INF regulated genes:
Protein Kinase R (PKR)
• Phosphorylates initiation factor eIF2α
• Result: cells can’t initiate protein synthesis of BOTH cell or viral proteins
Ribonuclease L (RNAase L)
• Nuclease that digests mRNA in cells (BOTH cellular and viral)
Oligo-2’-5’ adenylate synthetase
• Regulatory protein
• Binds to influenza virus polymerase = blocks function

NOTE: system is tightly regulated!
• PKR and RNAase L synthesized in inactive form
Activated when cell infected:
o PKR activated by binding dsRNA
o RNAase L activated by dsRNA and 2’-5’ oligoadenylate (made by oligo 2-A synthase which is induced by IFN & activated by binding dsRNA)
dsRNA = high levels in virally infected cells
o INF = NOT specific for any virus, but INF is species specific (ex: human IFN will not work in mice)


Describe the roles played by the following cells in a viral infection: CD4+, CD8+, NK, neutrophils, macrophages, APC, and B cells.

Virus infects epithelial cells

Binds to TLRs → triggers synthesis of Type I IFN, proinflammatory cytokines, Antimicrobial peptides (AMPs)
o IFN released = acts on adjacent cells, activates NK cells
o Intracellular proteins Rig-1 and MDA5 = recognize viral RNA → induce IFN
o Pro-inflammatory cytokines (IL-6, IL-8, MIP-1α) diffuse away = attract cellular components (neutrophils)
AMPs: small molecular weight peptides
• Made by host cells, alpha and beta-defensins, and cathelecidins
• Form pores in bacterial membranes
• Bind to viruses → block attachment/entry or disrupt envelopes

PMNs infiltrate site
o Attack infected cells = phagocytose
o Release more cytokines = attract T cells

APCs (dendritic, Langerhans, macrophages, B cells) pick up viral antigens = traffic to draining lymph node
o Present antigen to B and T cells

B cells begin making Ab’s
o Begins with IgD on B cell surface
o Production of IgM
o Isotype switching to IgA or IgG
o Viral infection can also generate IgE’s

T cells activated = migrate to site
o Helper T cells (CD4+) = Class II MHC restricted (exogenous antigen)
o Killer T cells (CD8+) = Class I MHC restricted (endogenously synthesized or endocytosed antigens)

Depending on virus: CD4+ and/or CD8+ cells attack
CD8+ T cells → perforins form pores; granzymes activate apoptosis
CD4+ T cells = Delayed type
• Migrate to site of infection
• Secrete cytokines: INF-γ = antiviral effects; can synergize with Type I IFNs

Infection = cleared or persistent infection established


Describe the ways in which antibodies contribute to the defense against viruses

Ab binds to viral surface → Virus neutralization
• Block attachment or uncoating

Ab binds to infected cell = suppresses gene expression

• Increases phagocytosis

Fc-mediated events
• Complement activation = form membrane attack complexes
• Binding of cells with Fc receptors (macrophages and neutrophils)


Antibody enhancement

o Non-neutralizing Abs bind to virus = exposes Fc portion
o Cells with Fc receptors take up virus
o Result: infection of cell that may normally be non-permissive (expands tropism)
o Ex: Dengue fever/Hemorrhagic fever
• Allows infection of new cell type (macrophages)
o Prevents binding of neutralizing Abs via steric hindrance
• Ex: HIV



Different types available:
• Killed: influenza, Polio, Rabies, HPV
• Subunits: Hepatitis B virus sAg
• Live attenuated: MMR, Polio, Yellow Fever, Smallpox, FluMist

Principle mechanism = induction of serum Abs
o Most prevent development of symptoms but do NOT prevent from getting infected
o Problem for protection against persistent viral infections


Overview of the mechanisms by which viruses interfere with immune responses.

o Disrupt interferon binding to its receptor
o Bind to immune factor and sequester
o Viral proteins bind and degrade viral factors
o Alter phosphorylation status
o Stop host shut-off response


Describe the viral mechanisms to counteract IFN

Proteins that bind to signaling components or TF’s

Degrade signaling components or TF’s

Interfere with dsRNA activating signal (for PKR and RNAase L)

Synthesize short RNAs that bind IFN induced proteins without activating them
• Result: prevents activation of PKR and oligo2A synthetase, RNAase L
• Ex: Epstein-Barr virus, adenovirus

Phosphorylate PKR → inactivation
• Ex: herpes simplex

Proteins that bind to PKR or RNAase L → inhibit
• Ex: influenza virus NS5 protein binds PKR

Synthesize cytokine receptor decoys
• Prevent cytokines from binding to host cells

Encodes analogous host genes for immunosuppressive cytokines
• IL-10, IL-4
• Ex: Epstein-Barr virus has IL-10 homolog

Viral glycoproteins that act as Fc receptors
• Abs bind backwards on cell → expose Fab portions
• Prevents Fc receptor cells from recognizing infected cell
• Also blocks complement activation

Encode glycoproteins that bind and block complement
• Ex: herpes simplex glycoprotein C binds C3b

Directly infect T cells
• Ex: measles = infected T cells become non-functional

Directly kill T cells → immune suppression
• Ex: HIV kills CD4+ T cells
• HIV also has gp120 that binds CD4 receptors on T cells induces apoptosis (so doesn’t need to be infected to die)

Interfere with antigen processing and presentation:
• Targets HLA molecule
• Viruses may be protease-resistant
• Ex: EBV EBNA 1 protein
• Viruses block peptide transport to ER (ex: herpes)
• Viruses block loading of peptides onto MHC protein
• Ex: Human CMV
• Viruses trap MHC protein in ER
• Viruses down-regulate expression of MHC proteins (host shut-off response)
• Reduce transcription
• Induce endocytosis of cell surface MHC proteins

Down-regulate co-stimulatory molecule expression

Immune exhaustion
• Viruses force host to use up all available antigen specific cells

Escape variants
• Virus just mutates
• Ex: Hepatitis C, HIV = high mutation rate


Describe the roll of Toll-like Receptors in viral infection.

o Pattern-recognition receptors
o Bind to molecular components in pathogens

Intracellular TLRs = TLR-3, 7, 8, & 9
• All involved in recognizing viral infections
• Activated by nucleic acid structures in viruses

TLR binding → signal transduction cascade → gene expression
• MyD88 → NFκB → enters nucleus for gene activation
• Production of chemokines and cytokines
• Ex: Type I interferons, IL-6 (chemotactic)


Describe the roll of RIG-1 in viral infection.

RIG-1 (retinoic acid-inducible gene 1)
o Binds non-capped RNA = recognizes viral infection
o Tends to detect picornaviruses, Epstein-Barr virus


Describe the roll of MDA5 in viral infection.

MDA5 (melanoma differentiation associated gene 5)
o Detects dsRNA (replication intermediate non-specific to many viruses)


Describe the roll of APOBEC in viral infection.

Deaminate cytidines in 1st strand of DNA of HIV → mutations and degradation of genome prior to integration


Describe the roll of TRIM5α in viral infection.

o Binds HIV capsid
o Accelerates uncoating = inhibits reverse transcription


Describe the roll of Tetherin in viral infection.

o Located in plasma membrane
o Prevents release of virions from cells


Type I Hypersensitivity Responses

o Anapylaxis
o IgE-mediated = IgE bound to mast cells reacts with antigen
o Triggers histamine, serotonin release
o Can also skew type of Ab released toward IgE

Ex: Respiratory virus infection
• Can exacerbate or cause asthma
• Viral induced cytokines attract mast cells and eosinophils into lung


Type II Hypersensitivity Responses

o Ab-mediated
o Abs bind infected cells
o Fc portions of Ab bind to Fc receptors on NK cells, macrophages, and PMNs → kill infected cells
o “ADCC” = antibody mediated cell-dependent cytotoxicity
o When happens to uninfected cell = bystander damage


Type III Hypersensitivity Responses

o Immune complex = mediated by Ab and Complement
o Antigen-Ab complexes in blood deposit in tissues
o Activation of complement → damages tissues (even though tissues not infected)

Usually seen in chronic infections:
• Glomerular nephritis with Hepatitis B virus
• Arteritis with HIV (due to circulating gp120)


Type IV Hypersensitivity Responses

Delayed type
o Mediated by CD4+ T cells
o Antigen → cells release cytokines → increased cell infiltration = causes direct damage

Ex: herpes simplex keratitis
• Virus infects epithelial cells → pro-inflammatory cytokines released
• Triggres PMN infiltration → production of more cytokines, PMN-mediated damage
• Infiltration of CD4+ cells → release other cytokines = amplification of inflammation
Result: damage → blindness (cornea becomes cloudy)
• Cell infiltration
• Edema
• ECM deposition (scarring)
• Cytokine interference with cell physiology