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
Fig. 15.1
• Viruses can activate either pathway
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
• 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 warning
See 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
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 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
• 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)
NK cell
Dendritic cell
Complement
• “Complemented by antibody”
• 3 pathways: classical, alternative, mannanbinding
• Poke holes in infected cells, targets cells for
degradation, activates inflammation
Complement
Pattern Associated Molecular Patterns- PAMPs