Early Host Responses: Intrinsic cell response and Innate immunity

Intrinsic viral responses

Immediate preexisting cell responses within the infected cell that do not require protein synthesis

Innate viral responses

Require gene expression and protein synthesis following infection

What is the first line of defense against viral infection?

Anatomical and chemical barriers

What is the order of antiviral response/protection from first contact to days/weeks after infection?

1. Anatomical and chemical barriers - continuous protection

2. Intrinsic cell responses - act immediately to control virus replication

3. Innate immunity - minutes/hours after infection to keep viral replication in check and alert adaptive immune cells

4. Adaptive immunity - days/weeks after infection, provides highly specific and long-lasting immunity against the same virus

What are some examples of intrinsic cell responses to viral infection?

PKR mediates shutdown of protein synthesis, stress granules, RNAi, autophagy, apoptosis

What triggers intrinsic cell responses?

Viral alterations to host cells, such as metabolic stress, induction of autophagy, inhibition of transcription, etc.

Apoptosis

Programmed cell death 1 (PCD-1), which is an important and essential component of developmental pathways for maintaining organ size and integrity as well as providing an essential immune response to intracellular infection

Does apoptosis cause inflammation?

No, as long as the apoptotic bodies are cleared by macrophages

How is apoptosis triggered?

Through extrinsic and intrinsic pathways

Intrinsic - Cell responses to stress, such as viral infection

Extrinsic - through binding of transmembrane death receptors

How would an organism benefit from apoptosis?

Prevention of the spread of infection to other cells, as well as general maintenance of organ size and integrity

What enzymes are the primary responsible effectors for apoptosis?

Caspases

Why would a virus want to induce apoptosis (PCD - 1)?

To aid in the spread of infection late in replication

Why would viruses want to inhibit apoptosis?

To promote cell survival so that the virus can replicate efficiently

Why would a virus want to promote autophagy?

To aid in replication and viral releaseW

Why would a virus want to inhibit autophagy?

To prevent killing and evade the immune responses

How do infected cells and innate immune cells detect viral infections?

Pattern Recognition Receptors (PRRs) that bind to Pathogen Associated Molecular Patterns (PAMPs)

• Transmembrane PRRs - TLR, CLR

• Cytosolic PRRs - NLR, RLR

• Secreted PRRs - Complement proteins 

What happens when PRRs bind PAMPs?

Innate and adaptive immune response is activated

RLR PRRs - what are they and what do they activate?

Cytosolic PRRs present in all cells that recognize viral RNA PAMPs, activate IRF and NF-kB to upregulate Type 1 interferons and inflammatory cytokines

What genes do RLRs eventually upregulate gene expression of?

Type 1 interferons and inflammatory cytokines

Toll like receptors - what are they and what do they upregulate?

Transmembrane PRRs that are usually associated with immune cells, activate IRFs and NF-kB to upregulate Type 1 interferons, proinflammatory cytokines, AND immunoregulatory cytokines

Where are TLRs located?

• Immune cell surfaces to bind viral proteins/glycans

• Endosomes through autophagy

What are Type 1 interferons secreted by?

Infected cells and sentinel dendritic cells

What happens when Type 1 IFN (IFNa/B) binds to surface receptors?

JAK/STAT pathway is activated, which produces antiviral responses when cells are infected

What does activation of interferons do?

Block viral replication, activate immune cells and stimulate apoptosis

How do viruses block IFNs?

• Inhibit synthesis

• act as IFN receptor decoys

• interrupt IFN signaling

• block protein function

Blocking IFNs early infection is associated with ________ viral load

increased

What does complement activate/cause?

• Lysis of cell pathogens and disruption of viral envelopes

• Induction of inflammation

• Targets pathogen for phagocyte clearance

What are cytokines?

Small proteins that regulate the immune system through autocrine and paracrine action

Activation of the innate immune response causes what responses?

• Activation of phagocytes and natural killer cells

• Expression and secretion of interferons

• expression and secretion of pro-inflammatory cytokines

• Maturation of APCs

Binding of PAMPS in phagosomes causes what to occur?

Killing pathways in phagosomes to be activated, which triggers phagosomes to fuse with lysosomes and in some cases display antigens to activate adaptive immune system

What is inflammation?

A response to tissue damage that results in redness, heat, swelling, and pain

What causes inflammation?

• Binding of PAMPs and DAMPs to PRRs on sentinel tissue cells

• Activation of complement and Bradykinin pathway

What are some examples of cytokines?

IL-1, IL-6, TNF-a

What are chemokines?

Cytokines directly involved in regulating inflammation and the movement of leukocytes from capillaries to tissue sites

What are characteristics of chemokines?

Cysteine residues

What is an acute phase response?

When a systemic response is experienced dues to inflammation and pro-inflammatory cytokines enter circulation

What do IL-1, IL-6, and TNFa do?

Upregulate production of acute phage proteins in the liver to activate complement

What is a cytokine storm?

An unregulated immune response from an excessive amount of pro-inflammatory cytokines that leads to overwhelming inflammation

Where are cells that mediate innate and adaptive immunity generated?

Red bone marrow

What are some examples of innate immune cells?

• NK cells

• Macrophages

• Monocytes

• Dendritic cells

• Neutrophils

In general, how long do innate immune cells live?

Not long

Neutrophils

Most abundant leukocyte, that can ingest and kill pathogens, as well as induces NETosis to trap and kill microbes

Macrophages

Innate immune cells that are activated in response to PAMPs and DAMPs, to produce inflammatory cytokines and cause inflammation AND phagocytose pathogens

• Destroy complement covered microbes

• Process and present antigens to T cells on occasion

• Clean- up and repair

Dendritic cells

Major antigen presenting cells to activate T cells

• Take up viruses by phagocytosis, endocytosis, or pinocytosis

• Carries digested antigens to draining lymph nodes

What is special about dendritic cells?

They are the main antigen presenting cell to activate T cells

Natural killer cells - what are they and are they antigen specific?

Large granular lymphocytes that target and kill infected cells and cancer cells, NOT ANTIGEN SPECIFIC

How do NK cells kill?

They induce apoptosis through binding of activating receptors to stressed cell ligands

Name 3 viral sensors

TLRs, RLRs, CLRs

What transcription factors do viral sensors activate?

IRF3, IRF7, and NF-kB

What are interferons and how do they function?

Interferons are cytokines produces by infected cells that act in autocrine or paracrine ways to alter gene expression to promote inhibition of viral replication and prevent spread of viruses to new cells

What are some cells that are involved in innate immunity?

• Macrophages

• Dendritic cells

• NK cells

• Neutrophils