BMOL30090 L6 IFN pathways

viruses

• infect host cells: RNA & DNA (single/double stranded) inside a protein capsid. some also have lipid envelope

• to replicate and produce new viral particles, they use host protein production machinery

• >200 viruses are known to infect humans

viruses example image

viral infection and replication

1 infected cell = many copies of a virus

attachment to host cell —> entry and release of genetic material —> viral genetic material replication and protein production —> assembly and release of new virions

viruses are flexible organisms that can mutate quickly to adapt to host

how the IIS senses viruses

• TLR3: dsRNAs, e.g. rotavirus (causes gastroenteritis)

• TLR7/8: ssRNAs, generated by viruses such as HIV

• TLR9: CpG DNA: cytosines connected to guanines by a phosphate bond (herped simplex virus type-1). not as frequent in vertebrate DNA

• RIG-I-like: viral DNA

how IIS senses viruses image

interferons (IFNs)

family of cytokines that respond to viral infection

IFNs production

• viral nucleic acids (RNA/DNA) activate PRRs (TLR3/7/8/9, RIG-I-like) & tigger release of interferons

• 2 types:

  • Type 1: IFN-alpha & IFN-beta

  • Type 2: IFN-gamma

• IFN expression mediated by IFN regulatory factors (IRFs): IRF3 and IRF7

• IRFs in cytosol are phosphorylated & translocate to the nucleus to promote IFN expression

• ‘interfere’ with viral replication to prevent spread

IFNs production image

Type 1 IFNs effects

• infected cells secrete IFN-alpha and IFN-beta

• binding of IFNs to IFNAR ½ heterodimers (nearby) activates STAT phosphorylation

• pSTATs translocate to the nucleus, assoc. with IRF9 & promote the prod of enzymes that block viral replication

  • PKR - dsRNA-activated Ser/Thr protein kinase: inhibs viral protein synthesis

  • RNAse L: degrades viral RNA

type 1 IFNs effects image

the paths of innate immunity

virus infection: IFNs and NKs function

IFNs - stop viral replication

NKs - kill cells that are already infected

NK cells eliminate infected cells

NK cells respond to the balance between tolerance and alarm signals. Can recogn. & eliminate infected cells

1. recognition: NK cells survey host cells for signs of infection/cellular stress (tumour cells)

2. activation: infected cells lose expression of receptors that induce tolerance in NK cells & gain expression of receptors that alert NK cells. This combo leads to NK activation

3. response: release cytotoxic molecules such as gramzymes, causing target-cell death. can also release cytokines, incl. IFNs, to amplify IR

NK cells eliminate infected cells image

what is a barrier?

• cell lining

• cell diversity

  • goblet cells: mucus

  • paneth cells: anti-bac

  • stem cells: barrier renewal

  • M cells: surveillance

  • cornified epithelium (in skin): sealing

innate immune response (IIR) ORDER

1. PRR recognition

2. release of inflam mediators

3. vascular & endothelial changes

4. leukocyte recruitment

5. phagocytosis & bac killing

6. resolution & repair

Step 1. IIR

PRR recognition: unspecified recogn. of conserved molecular patterns by resident cells

Step 2. IIR

release of inflam mediators: release of cytokines, chemokines, vasoactive mediators to activate the IR

Step 3. IIR

vascular & endothelial changes: vasoactive mediators: histamine and PGs

Step 4. IIR

leukocyte recruitment:

• capture and rolling (selectins)

• chemokine activation

• firm adhesion and crawling

• diapedesis

Step 5. IIR

phagocytosis & bacterial killing:

• NPs: arrive rapidly, phagocytosis, degranulation (ROS), bacterial killing

• Monocytes: differentiate to MPs (mainly) and DCs, phagocytosis of microbes, cytokine prod, resolution and tissue repair

Step 6. IIR

resolution and repair: reduce pro-inflam cytokines prod & Ag presentation. ECM prod to replace lost/damaged tissue

activity: selectin vs. integrin

early-release cytokines (TNF & IL-1alpha/beta) summary

paths of inname immunity image