PMI 128: Lecture 11-13

What are “Anti-viral defenses”?

The various mechanisms, both innate and acquired, that the body uses to combat viral infections

What types of mechanisms are involved in Intrinsic Anti-viral defenses?

Physical, chemical, and physiologic defenses

Immune defenses require ____ of “non-self” pathogen.

Recognition

What is Innate immunity?

Preexisting or rapidly inducible host effector systems

What does Innate immunity do in anti-viral defense?

Provides time for development of specific antibody and T cell responses

What is Adaptive Immunity?

Inducible host effector systems targeted ro the specific viral agent

What does Adaptive Immunity do in anti-viral defense?

Clears viral infection, limits repeated infections with same virus

Why is recognition of “non-self” important for immune antiviral responses?

Recognition of “non-self” allows immune cells to distinguish pathogens from the body’s own cells, enabling a targeted and effective response without damaging host tissues

What is a key characteristic of non-immune antiviral defenses like physical, chemical, and physiologic defences?

They do not rely on recognition of a “non-self” pathogen, instead they act broadly and immediately to prevent viral entry or spread

What is apoptosis?

Cell-suicide

Form of programmed cell death

How does apoptosis help in antiviral defense?

When a cell is infected by a virus, it can undergo apoptosis to limit viral replication and spread.

Is a method of antiviral defense

What are the pathways of Apoptosis?

Intrinsic

Extrinsic

What triggers the Intrinsic pathway of Apoptosis?

Cellular stress

• DNA damage, Oxidative stress, Viral infection, Growth factor deprivation, Oncogene activation

State the order of the Intrinsic pathway of Apoptosis

Cellular stress→Pro-apoptotic BCL2 protein activation via BH3-only proteins→Cytochrome-c release→Apoptosome formation (APAF1, procaspase-9, dATP)→ Activation of executioner caspases

What triggers the Extrinsic pathway of Apoptosis?

Death receptors on the cell surface

• TNFR, CD95/FAS

State the order of the Extrinsic pathway of Apoptosis

Death receptors→ Death-receptor ligation→ Adaptor recruitment→ Procaspase-8 recruitment→ Caspase-8 activation→ activation of executioner caspases

What determines whether an adaptive response is triggered?

Pattern recognition receptors (PRRs)

What happens when a pathogen is recognized by the innate immune system?

Activation of dendritic cells and NK cells, cytokines and complement release, and triggering of the adaptive immune system

What happens if a pathogen is not recognized in the innate immune system?

No adaptive immune response

What are PRRs and what do they recognize?

Pattern recognition receptors, they recognize pathogens-specific molecules, aberrant localization of foreign or self molecules, or abnormal molecular complexes

What can PRR activation lead to besides infection resolution?

Inflammation diseases or autoimmunity

What are Humoral Factors?

Soluble molecules that circulate in the bloodstream and lymph, acting as intermediaries in the immune response

What Humoral factors did we go through in lecture?

Natural antibodies

Complement proteins

What are Natural Anitibodies (NAbs)?

Immunoglobins present in the blood of healthy individuals before exposure to an antigen or immunizations

What are Complement proteins?

Group of serum proteins involved in the control of inflammation, the activation of phagocytes, and the lyric attack on cell (or viral) membranes.

These colecules are produced by the liver

What are some pattern recognition receptors that we went over in lecture?

C-Type lectin receptors (CLRs)

Toll-like receptors (TLRs)

RIG-I-receptors (RLRs)

Nucleotide-binding oligomerization domain-like receptors (NLRs)

What are CLRs?

c-type lectin receptors

• Transmembrane proteins localized at the plasma membrane

• recognize glycine’s from the wall of fungi and some bacteria

What are TLRs?

Toll-like receptors

• Transmembrane proteins localized either at the plasma membrane or in endosomes

• Broad range of specificities recognized proteins, nucleic acids, and glycans

What are RLRs?

RIG-I-Like receptors

• Cytoplasmic sensors of viral RNA

• Signal via mitochondrial adapter proteins MAVS

• Trigger antiviral responses including the production of type 1 interferon

What are NLRs?

Nucleotide-binding Oligomerization domain-like receptors

• Cytoplasmic sensors

• Multiple subfamilies: NLPRs recognize bacterial, viral, parasitic, and fungal PAMPs AIM2 detects viral and bacterial DNA

• Form multiprotein signaling complexes known as inflammasomes

What transcription factors are activated by TLRs in response to viral PAMPs?

NF-kB

IRP3

IRF7

TLRs signal through ________

TIR domain-containing adaptors

• e.g. MyD88, TRIF

What adaptor is used by most TLRs to induce inflammatory cytokines?

MyD88

Which adaptor does TLR3 use to produce type 1 interferons?

TRIF

What is SARM and what does it do?

An adaptor that inhibits TRIF-dependent signaling

What the two main pathways downstream of TLR4?

MyD88 and TRIF

What does it mean when PRR signaling is “divergent”?

One receptor recruits multiple adaptors, leading to distinct cellular outcomes depending on adaptor use or cell types

What does it mean when PRR signaling is “convergent”?

Multiple receptors use the same adaptor, leading to a similar cellular response

What kind of immune response does the RIF-I and MDA5 signal pathway trigger?

Antiviral innate immune response

Double-stranded DNA in the cytoplasm is detected by what?

Cyclic GMP-AMP (cGAMP) synthase (cGAS), which synthesizes cGAMP (2’-5’) as its second messenger molecule

What does cGAMP (2’-5’) do after its synthesized?

Binds and activates the endoplasmic reticulum (ER)-resident receptor STING (stimulator of interferon genes)

What can STING do once its activated?

Translocated to a perinuclear Gogli compartment, where it binds to TBK1 (TANK-binding kinase 1) to activate IRF3 and induce NF-kB activation

What are the systemic effects of inflammatory cytokines?

Feaver, Fatigue, lethargy

Hematopoiesis, Mobilization of lymphocytes

What does type 1 interferon synthesis and paracrine signaling result to?

Synthesis of interferon stimulated genes

What are the Type 1 Interferon receptors shown in lecture?

IFN-αs and IFN-β

What are the Type 2 Interferon receptors shown in lecture?

IFN-Υ

What are the Type 3 Interferon receptors shown in lecture?

IFN-λs

How is IFN-λ produced?

By intestinal epithelial cells (IECs) and signals via the IFN-λ receptor (IFNλR) on these cells

Dendritic cells provide ______ to naive T cells

Cytokine signals and peptide antigens

What can NK cells help distinguish?

Normal healthy cells from infected cells missing self receptors

What is the purpose of virus-encoded mechanisms that modulate NK-cell activity?

To evade immune detection and killing by natural killer (NK) cells by interfering with NK-cell recognition or activation pathways

What is Strategy 1 used by viruses to evade NK cells?

Inhibition by a viral protein with homology cellular MHC class 1 proteins

What is Strategy 2 used by viruses to evade NK cells?

Inhibition of production or cell surface localization of human MHC class 1, resulting in an increase in the quality of host HLA-E (or HLA-C) on the target surface

What is Strategy 3 used by viruses to evade NK cells?

Release of virus-encoded cytokine-binding orteins that block the action of NK-cell-activating cytokines

What is Strategy 4 used by viruses to evade NK cells?

Inhibition of action of NK-cell-stimulating cytokines by binding these cytokines or by producing a chemokine antagonist

What is Strategy 5 used by viruses to evade NK cells?

Effect of newly produced virus particles, which can engage the NK cell, block an inhibitory NK-cell receptor, or infect the NK cell itself to disrupt various effector functions or even kill the cell.

What natural antibodies did we go over in lecture?

• IgM, IgG or IgA

• Poly-specific low-affinity antibodies

• They also react with proteins, lipids or carbohydrates

What is Opsonization?

Enhanced phagocytosis by coating of the viral surface with C’ (complement receptor) or antibody (Fc receptor)

What is Chemotaxis?

Process whereby chemicals (C’) direct cell movement and orientation

How can the complement system be activated?

By three pathways: classical, lectin, and alternative

What does the Classical pathway in the complement system use?

Antibody complex

What does the Lectin pathway in the complement system use?

MBL-carbohydrate

What does the Alternative pathway in the complement system use?

C3b-microbe

What does the Complement system enhance and activate?

Enhances chemotaxis and phagocytes

Activates immune cells

What does Factor H do?

Part of the regulation of the complement cascade

• Inhibits factor B binding to C3b

• Accelerates the decay of C3bBb

• Cofactor for factor 1 in cleaving C3b to iC3b

  • Inhibits phagocytosis and kills by MAC

What are Macrophages?

Long-lived phagocytic cells involved blood and tissues derived from bone marrow

Engulf, internalize and destroy viruses

Present antigens to T cells to elicit adaptive anti-viral immunity

How are macrophages formed?

Begin as stem cell in bone marrow, stay 10-20 hrs in circulation, leave blood to tissues and transformed into large macrophage cells, and life span is up to few months in tissues

What are the different types of macrophages?

Kupffer, Microglia, Reticular, tissue history ties, alveolar cells

How do the different types of macrophages differ?

Organs in which they reside

Phagocytosis is part of the _______

Innate immune system

What is the primary role of innate immunity?

To limit the viral infection

What can adaptive immunity do?

Prevent, limit, and reduce infection

Clear viral infections