Lecture 22: Virus offence meets host defense: Innate Immunity
BSCI437
Flint et al. Chapter 15, pp. 531 – 584.
General points
• We literally swim in viruses and other microbes
• We’ve evolved numerous, overlapping 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
o Largest organ in body – >5 kg for adults
o Strong barrier to infection
o Inactivates viruses by desiccation, acids, skin cleansing mechanisms,
inhibitors made by commensals
 Other Epithelial surfaces: inactivates viruses via
o Secretions
o Mucus
o Tears
o Acid pH
Intrinsic cellular defenses – Intro
 Highly conserved, arose early in evolution
 Non-specific responses to stresses, e.g.
 Starvation
 Irradiation
 Infection
Apoptosis (Fig. 15.1)
 Programmed cell death
 Keeps “wrong” cells from proliferating
o “Sacrifice the one for the good of the many”
 Promoted by Capsases: Cysteine proteases that cleave after ASPartate residues
o Extrinsic pathway: triggered from outside
o Intrinsic pathway: triggered from inside
 Viruses can alter gene expression inside and outside of cell
 Viruses can activate either pathway
Viral inhibition of apoptosis (see 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
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Autophagy
o Cells cannibalize themselves!
o Induced by starvation, viral infection
Nuclear domain 10 (NSD10) bodies
o Prevent transcription of “foreign DNA” in nucleus
o Defense against DNA viruses
RNA silencing (siRNAs, RNAi)
o System recognizes and degrades dsRNAs
o Defense against RNA viruses
Immune defenses – overview (Fig. 15.3.)
 Highly coordinated
 Depends on interplay of secreted proteins, receptor-mediated signaling, and cellto-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
o Natural Killer (NK) cells
o Neutrophils, Basophils, Macrophages, other granulocytes.
 Pattern recognition receptors
o Detection of “non-self”
 Toll-like receptors.
 Expressed inside and outside of cells
 Very ancient
o 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
o e.g. IL-1, Tnf, IL-6, IL-12
 Anti-inflammatory – return system to basal activity
o e.g. IL-10, IL-4, Tgf-
 Chemokines – Recruit immune cells early in immune response
o 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. (Table 15.6)
 Viroreceptors: mimic host cytokine receptors. Serve as sinks for cytokines,
prevent cytokine activities. (Table 15.7)
Interferons – early warning (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
o Apoptosis of infected cells
o Apoptosis of nearby cells – firebreak to infection
o Block cell proliferation
o Enhances NK cell activity
o Alters MHC expression…and many more effects
 Very non-specific and toxic…Not the “magic bullet”
o 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) 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.
 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
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Proteins tagged with ubiquitin are targeted to the proteosome for degradation
Viral gene products that counter IFN response (see Table 15.9)
 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
Non-specific cellular response (Figs. 15.9, 15.10)
 Dendritic cells and macrophages
o Sentinel cells: patrol local area for bad guys
o Phagocytotic
o Present foreign antigen to T-cells
 NK cells
o Recognize and kill virus infected cells
o 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 (Fig. 15.11)
“Complemented by antibody”
3 pathways: classical, alternative, mannan-binding
Poke holes in infected cells, target cells for degradation
Short Interfering RNAs (siRNA)
No cellular dsRNAs, but RNA viruses produce these
Ancient mechanism against parasitic dsRNAs.
Two host cellular enzyme complexes
1. Dicer: recognizes and cleaves dsRNAs into small pieces (20 – 23 nt)
2. RISC complex: anneals small RNAs to target (viral) RNA, and then
cleaves the target.
Viral defenses against siRNA
Best known examples are in plants
• Coat protein of Turnip Crinkle Virus binds to and inactivates Dicer (see Lect. 7).
• Carnation Italian ringspot virus (CIRV) p19 protein.
– Specifically binds 21 nt dsRNA fragments.
– Acts as a molecular caliper to specifically select siRNAs based on the
length of the duplex region of the RNA.
– Sequesters siRNA away from RISC complex