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Immune Responses To
Viruses

Steps Needed To Establish Infection

• Penetrate The Epithelial Barriers-Not Easy
– Skin
– GI Lining
– Respiratory Lining
• Compete With Normal Flora For Binding Sites
– Lactobacillus Acidophilous
– Bifidobacterium Bifidus
• Evade Innate Immunity
– M
– Neutrophils
– NK cells

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Innate Immunity
• Innate Immunity Cells Express Receptors That
Recognize Bacterial Molecules
• TLR-4 (Recognizes LPS, gram negative bacteria)
• TLR-2 (Recognizes peptidoglycan, gram positive
bacteria)
• TLR-3,7,9 (viral nucleic acids)
• Viruses Induce Production of Interferons (IFN-,
IFN- and IFN)
• Interferons produce an anti-viral state

Pathogens Often Succeed

• Pathogens Use Several Tricks To Avoid Immune
System
– Start Living Inside Cells
– Induce specific type of immunity that allows it to survive
– Continuous variation of antigens. Ex. HIV
– Express antigens that resemble our own genes
• Infections Are Prevalent In Developing Countries
– 4,000,000 of deaths due to respiratory infections

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Viral Infections
• The Immune Response Against Virus Is Primarily
Mediated Through Interferons
– Double stranded RNA induces production of IFN
– Main producers of IFN and IFN are pDCs
– TLR-3 (dsRNA); TLR-7 (ssRNA)
– Interferons produce an anti-viral state
• A state that inhibits viral replication
• A state that inhibits viral infection

Plasmacytoid dendritic cells (pDCs) are innate immune cells that circulate
in the blood and are found in peripheral lymphoid organs. They constitute <
0.4% of peripheral blood mononuclear cells (PBMC).

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Toll-like receptor (TLR) signaling plays an essential role in the

innate immune response. Activation of TLR signaling through
recognition of pathogen-associated molecular patterns leads to
the transcriptional activation of genes encoding for pro-
inflammatory cytokines, chemokines and co-stimulatory
molecules.

Variations in TLR ligands initiate specific immunological responses:

TLR2 recognizes bacterial LAM, BLP, and PGN following their initial interaction with
CD14.
TLR4 forms a homodimer complex with the MD-2 protein after the initial binding of
bacterial LPS to CD14.
TLR5 activation occurs following interaction with bacterial flagellin.
TLR1 and TLR6 function as co-receptors to TLR2 to promote unique signaling
mechanisms based on specific pathogen binding.
TLR1, TLR2, TLR4, TLR5, and TLR6 are all receptors located on the cell surface; other
TLR receptors located within the endosome recognize additional pathogens.
TLR3, TLR7, TLR8 and TLR9 are activated by viral dsDNA, viral ssRNA,
and bacterial CpG, respectively.
TLR7 and TLR8 can be activated by the imidazoquinoline compounds imiquimod and R-
848.

IFN Signaling
• Upon Ligand Binding The Following Events Occur
– Expression of oligo adenylate synthetase [2-5 (A)
Synthetase]
– Activation of RNAase L
– Degradation of viral RNA
• In Addition Activation of dsRNA-dependent Protein
Kinase (PKR)
– Phosphorylates eIF-2
– Protein synthesis is inhibited
– Viral replication is inhibited
• IFN Signaling Activates NK cells
– Start eliminating virally infected cells

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Antibody Protection Against Viruses

• Antibodies Bind To Viral Surface Antigens
– Protect againts re-infection
– Huge amounts of secretory IgA in lumen block viral
attachment
• Viral Entry Into Cells Is Mediated Through Receptors
– Influenza virus binds to sialic acid on glycoproteins
– Rhinovirus binds to ICAMs (intercellular adhesion
molecules )
• If Receptor Is Blocked, Infection Is Blocked
• Oral Polio vaccine Relies On IgA Production

Antibody Protection Against Viruses

• Antibodies Are Efficient In Preventing Infection
• Once Infection Has Occurred, Only Cell Mediated
Immunity Can Eliminate Infected Cells
• Examples Of Cell Mediated Immunity
– TH1, CTL Are the major participants
• TH1 Produce IFN-, IL-2, and TNF-
– IL-2 expands CTL-P (cytotoxic T lymphocyte precursors)
– IFN- induces antiviral state
– IL-2 and IFN- activate NK cells (first line of defense)
• CTL (cytotoxic lymphocytes)
– Peaks 7-10 days post infection
– Eliminate virally infected cells

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Evading The Immune System

• HCV (Hepatitis C Virus) Evades Anti-viral Effect
Of IFNs By Inhibiting Action Of PKR
• HSV (Herpes Simplex Virus) Decreases Expression
Of MHC I, Avoids CTL Elimination
• CMV (Cytomegalovirus) Also Decreases
Expression Of MHC I
• HIV (Human Immunodeficiency virus) Decreases
MCH II Expression, No TH1 Support for CTL
• Influenza Virus, Keeps Changing Antigens
– Antigenic Drift
– Antigenic Shift

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Differences Between Antigenic Shift and Antigenic Drift

Influenza Virus are remarkable because of the frequent antigenic change
that occurs in HA (hemagglutinin) or NA (neuraminidase). The two
surface antigens of influenza undergo antigenic variation independent of
each other. They are Antigenic Shift and Antigenic Drift.

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Influenza Virus
• Size of Virion Is 90-100 nm
• Surrounded By Plasma Membrane Of Host
– 2 glycoproteins on surface
• Hemagglutin (HA) and Neuroaminidase (NA)
• HA is responsible for viral attachment to sialic acid found on glycoproteins
• NA is responsible for detaching from sialic acid (budding)
• Matrix Protein Beneath Lipid Bi-layer
• Nucleocapsid contains 8 ssRNA
– ssRNA associates with RNA polymerase and protein
– Each ssRNA encodes for one or more proteins
• Types of Influenza Virus Are Based On Protein Matrix Composition
and nucleoprotein composition
– Type A, B, C
– Type A is responsible for major pandemics in humans
– Antigenic variation in HA (13 variants) and NA (9 variants) determines subtype
• Ex. H1N1

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Phase 3: In phase 3, the virus continues to spread. Groups of human beings have
contracted the virus in one community. There is potential for spread of the virus if others
outside that community come into contact with those humans who are infected. At this
point, the illness may be considered to be an epidemic in that community, but it is not yet
pandemic.
Phase 4: In phase 4, the virus spreads even more. Human-to-human and animal-to-human
virus transmission is causing outbreaks in many communities and more people are getting
sick in those communities. More communities report outbreaks and the possibility of a
pandemic is becoming more likely, although the development of a pandemic is not yet a
guarantee.
Phase 5: In phase 5, human-to-human transmission is taking place in at least two countries
in one WHO region. WHO has a network of 120 National Influenza Centers in 90 different
countries. At phase 5, a majority of countries have not yet been affected, but a pandemic is
considered imminent. Phase 5 signifies that governments and health officials must be ready
to implement their pandemic mitigation plans.
Phase 6: The last stage is stage 6. At stage 6, a global pandemic is underway. Illness is
widespread and governments and health officials are actively working to curtail the spread
of the disease, and to help their populations deal with it using preventive and stop-gap
measures.
Post-pandemic: Post-pandemic is the period after the pandemic has occurred. After the
increase in activity, the disease-spreading activity will begin to wane. Prevention of a
second wave is key at this point.

The time frame of these phases varies greatly, as it could range from months to years.

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Antigenic drift = slight antigenic change

Antigenic shift = radical antigenic change

Mediated cell attachment

Antibody to HA are protective

Internal
antigens are
relatively stable

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Host Response To Influenza Infection

• Humoral Response Is Strain Specific
– If Antigenic Drift Occurs Protection Is Lost
• Antibodies Are NOT Essential For Recovery
– In Mice Infected With Influenza And Ab Production Is
Suppressed There Is Recovery
– However Can Be Re-infected
• NK, pDC , CTL Are Responsible For Viral
Elimination

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