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

• 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

• 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 Fig. 15.1

Viral inhibition of apoptosis

Fig. 15.2

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

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

• 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• 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• 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

• (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 warningSee Table 15.8

• Produced by infected cells (and immature dendritic cells)• IFN-: produced by most nucleated cells in response to viral

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

infection, dsRNA• INF-: 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

Pkr (dsRNA activated protein kinase) Activated by dsRNA.

Phosphorylates eIF2-, shutting down translation.

Many viral proteins evolved to inactivate or misdirect Pkr.

RNase L + 2’-5’ Oligo(A) synthetaseWork together to degrade RNAs.

Both antiviral and apoptotic

Mx proteinsIn mice, specifically prevents “cap-snatching” by influenza

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

Antiviral IFN-induced proteins P200 proteinsBlock cell proliferation

Inhibit rRNA transcription and ribosome biosynthesis

Nitric oxide synthaseDirects synthesis of NO in NK cells

Cytotoxic

Inhibits poxvirus and herpesvirus replication

PMLPart of the ND10 bodies, prevents transcription of foreign

DNA

Ubiquitin-proteosome pathway componentsProteins tagged with ubiquitin are targeted to the

proteosome for degradation

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

• 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.

Non-specific cellular response (Figs. 15.9, 15.10)

Dendritic cell

NK cell

Complement

• “Complemented by antibody”• 3 pathways: classical, alternative, mannan-

binding• Poke holes in infected cells, targets cells for

degradation, activates inflammation

Complement

Pattern Associated Molecular Patterns- PAMPs