Lecture 22 virus offence meets host defense
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Lecture 22: Virus offence meets host defense. Flint et al. Chapter 15, pp. 531 – 584. Note: immunopathology not covered General points We literally swim in viruses and other microbes We’ve evolved numerous, ovelapping active and passive defenses to enable us to ward off infection

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Lecture 22 virus offence meets host defense
Lecture 22: Virus offence meets host defense

  • Flint et al. Chapter 15, pp. 531 – 584.

    • Note: immunopathology not covered

      General points

  • We literally swim in viruses and other microbes

  • We’ve evolved numerous, ovelapping active and passive defenses to enable us to ward off infection

  • Successful pathogens have evolved gene products that modify, redirect and block host defenses

     For every host defense, there is a viral offense.


Primary physical and chemical defenses
Primary physical and chemical defenses

  • Skin

    • Largest organ in body – >5 kg for adults

    • Strong barrier to infection

    • Inactivates viruses by desiccation, acids, skin cleansing mechanisms, inhibitors made by commensals

  • Other Epithelial surfaces: inactivates viruses via

    • Secretions

    • Mucus

    • Tears

    • Acid pH


Intrinsic cellular defenses intro
Intrinsic cellular defenses – Intro

  • Highly conserved, arose early in evolution

  • Non-specific responses to stresses, e.g.

    • Starvation

    • Irradiation

    • Infection


Apoptosis

Programmed cell death

Keeps “wrong” cells from proliferating

“Sacrifice the one for the good of the many”

Promoted by Capsases: Cysteine proteases that cleave after ASPartate residues

Extrinsic pathway: triggered from outside

Intrinsic pathway: triggered from inside

Viruses can alter gene expression inside and outside of cell

Viruses can activate either pathway

Apoptosis

Fig. 15.1


Viral inhibition of apoptosis
Viral inhibition of apoptosis

Many viral proteins have evolved to inhibit apoptosis by intervening at any one of multiple steps in the pathway.

Fig. 15.2


Other intrinsic defenses
Other intrinsic defenses

  • Autophagy

    • Cells cannibalize themselves!

    • Induced by starvation, viral infection

  • Nuclear domain 10 (NSD10) bodies

    • Prevent transcription of “foreign DNA” in nucleus

    • Defense against DNA viruses

  • RNA silencing (siRNAs, RNAi)

    • System recognizes and degrades dsRNAs

    • Defense against RNA viruses


Immune defenses overview
Immune defenses – overview

  • Highly coordinated

  • Depends on interplay of secreted proteins, receptor-mediated signaling, and cell-to-cell communication

  • Three critical steps: recognition, amplification, control.

  • Can be non-adaptive (innate) or adaptive.


Innate immune responses
Innate immune responses

  • Cytokines – soluble proteins that act as signals

  • Sentinel cells – e.g. dendritic cells, patrol local areas

  • Complement – soluble proteins, poke holes in infected cells

  • Cytolytic “death star” cells

    • Natural Killer (NK) cells

    • Neutrophils, Basophils, Macrophages, other granulocytes.

  • Pattern recognition receptors

    • Detection of “non-self”

      • Toll-like receptors.

      • Expressed inside and outside of cells

      • Very ancient

    • Detection of “missing” or “altered self”

      • Used mainly by NK T-cells.

      • Also ancient: similar systems used by insects.


Cytokines
Cytokines

  • Rapid response team: one of the first indicators of infection

  • Infected cells make cytokines in response to multiple cues

    • e.g. uncoating of viruses, exposure to foreign DNA/viral proteins, stress such as ER overloaded viral proteins or too much transcription activity.

  • Divided into three classes:

  • Proinflammatory – promote immune activation

    • e.g. IL-1, Tnf, IL-6, IL-12

  • Anti-inflammatory – return system to basal activity

    • e.g. IL-10, IL-4, Tgf-b

  • Chemokines – Recruit immune cells early in immune response

    • e.g. IL-8


Cytokines viral responses
Cytokines – viral responses

  • (see Tables 15.6 and 15.7)

  • Cytokines interact with cells via cytokine receptors

  • Many viruses have evolved gene products to modulate the immune response

  • Virokines: Mimic host cytokines.

  • Viroreceptors: mimic host cytokine receptors. Serve as sinks for cytokines, prevent cytokine activities.


Interferons early warning see table 15 8
Interferons – early warningSee Table 15.8

  • Produced by infected cells (and immature dendritic cells)

  • IFN-a: produced by most nucleated cells in response to viral infection, dsRNA

  • IFN-b: produced by most nucleated cells in response to viral infection, dsRNA

  • INF-g: Produced by T-cells, NK cells in response to antigens, mitogens, IL-2, 12

  • Induce antiviral states

    • Apoptosis of infected cells

    • Apoptosis of nearby cells – firewall

    • Block cell proliferation

    • Enhances NK cell activity

    • Alters MHC expression…and many more effects

  • Very non-specific and toxic…Not the “magic bullet”

    • However, useful for treatment of many persistent viral infections, e.g. hepatitis B and C


Antiviral ifn induced proteins
Antiviral IFN-induced proteins

Pkr (dsRNA activated protein kinase)

Activated by dsRNA.

Phosphorylates eIF2-a, shutting down translation.

Many viral proteins evolved to inactivate or misdirect Pkr.

RNase L + 2’-5’ Oligo(A) synthetase

Work together to degrade RNAs.

Both antiviral and apoptotic

Mx proteins

In mice, specifically prevents “cap-snatching” by influenza

In humans ,can also prevent replications of VSV, Measles, parainfluenza and others.


Antiviral ifn induced proteins1
Antiviral IFN-induced proteins

P200 proteins

Block cell proliferation

Inhibit rRNA transcription and ribosome biosynthesis

Nitric oxide synthase

Directs synthesis of NO in NK cells

Cytotoxic

Inhibits poxvirus and herpesvirus replication

PML

Part of the ND10 bodies, prevents transcription of foreign DNA

Ubiquitin-proteosome pathway components

Proteins tagged with ubiquitin are targeted to the proteosome for degradation


Viral gene products that counter ifn response
Viral gene products that counter IFN response

  • Viruses have evolved many gene products to counter IFN. Types of modulation include:

  • Inhibition of IFN synthesis

  • IFN receptor decoys

  • Inhibition of IFN signaling

  • Block functions of IFN-induced proteins

  • See Table 15.9


Non specific cellular response
Non-specific cellular response

  • Dendritic cells and macrophages

    • Sentinel cells: patrol local area for bad guys

    • Phagocytotic

    • Present foreign antigen to T-cells

  • NK cells

    • Recognize and kill virus infected cells

    • Detect “altered” or “missing-self” molecules

      • Altered self: MHC I & II + non-self antigen

      • Missing self: Lack of MHC I or II, lack of activating receptors.



Complement

“Complemented by antibody”

3 pathways: classical, alternative, mannan-binding

Poke holes in infected cells, targets cells for degradation, activates inflammation

Complement




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