DD 02-24-14 11am-Noon Host Responses to Viral Infections - vanDyk Flashcards
Balances in viral infections
- Viruses are obligate intracellular parasites, so they must maintain a delicate balance with host in order to survive.
- Likewise, host must balance rejection of virus with collateral damage to self.
Three General Outcomes of Viral Infection of a cell
- Abortive infection or failed infection (no virus produced / no apparent effects on cell)
- Lytic infection (production of virus & death of infected cells)
- Persistent infection (chronic, latent, or transforming)
Factors determining different outcomes in viral infections
NOT hardwired.
Dependent on…
- virus
- host
- target tissue
- immune status at time & site of virus entry
EX: Virus that is cytolytic in epithelial cells may be latent in neurons (target tissue example)
EX: Virus that is latent in neurons may be reactivated upon immune suppression and thus resume productive lytic infection (immune status example)
Cytopathic effect in virus infection
Any detectable morphologic changes in host cell, including:
- Direct cell damage / death
- Indirect cell damage
Cytopathic effect of retroviruses
- usually do not cause cell death (released from cell via budding, not lysis)
- cause persistent infections
Cytopathic effects of Picronaviruses
- cause lysis and cell death in cells in which they replicate
- leads to fever, increased mucus secretion (Rhinoviruses), paralysis or death (Poliovirus)
Mechanisms of DIRECT cell damage / death
- diversion of cell’s energy
- shutoff of cell macromolecular synthesis
- competition of viral mRNA for cellular ribosomes
- competition of viral promoters & enhancers for cellular factors
- inhibition of interferon defense mechanisms
Types of cytopathic effects
MORPHOLOGICAL CHANGES:
- nuclear shrinking (pyknosis) & membrane proliferation
- nuclear membrane proliferation
- cytoplasmic vacuolization
- cell fusion (syncytia)
- chromosomal margination &breakage
- rounding & detachment of tissue culture cells
INCLUSION BODIES:
- virions & proteins in nucleus
- proteins & RNA in cytoplasm (Negri bodies)
- virus protein complexes & nascent virus in cytoplasm
- chromatin clumps in nucleus
Mechanisms of INDIRECT cell damage
- integration of viral genome
- induction of mutations in host genome
- inflammation
- host immune response (greatest impact)
Humoral vs. Cellular immunity roles in viral infections
Humoral = protects against reinfection Cellular = clears virus infection
Permissive vs. Non-permissive cells (for a particular virus)
Permissive cells provide the machinery & components required for completion of viral replication.
Non-permissive cells DO NOT.
A continuum from permissive to non-permissive.
Infection in non-permissive or semi-permissive cells does not result in efficient production of virus, and may not result in death of the infected cell.
Infection in non-permissive cell may result in latent or transforming infections.
Immortalization of infected cells
Some viral infections may lead to immortalization of cells either:
- directly by means of an oncogene
- indirectly by providing growth/survival advantages to infected cell
Viruses may encode genes involved in immortalization or may regualte cellular genes involved in immortalization.
Tissue tropism
Determined by…
- selective susceptibility of cells
- physical barriers
- local temp & pH
- host defenses
Selective susceptibility of cells due to…
- due to interaction of virus attachment protein with specific receptor molecule on cell
- also includes intracellular processes
Innate defenses: Soluble factors
Interferons
Cytokines
Complement
Chemokines
Innate defenses: Natural barriers
Skin Mucus Ciliated epithelium Gastric acid Tears Bile
Innate defenses: Cells
Macrophages
Neutrophils
Dendriticcells
NK cells
Intracellular restriction factors
= cellular proteins that block post-entry steps of certain virus infections
- NOT part of adaptive immune response (rather, innate), but specific for certain viruses
= potent, widely expressed, intracellular blocks to viral replication
- viruses have developed ways to antagonize restriction factors (evolve faster than hosts)
= an exciting new area of potential intervention
Examples of therapies using intracellular restriction factors
Trim5 blocks retroviruses
APOBEC blocks HIV HCV
Toll-like receptors (TLRs) and Helicases (RLHs)
- mechanisms by which innante immune response senses invasion of pathogenic microorganisms
- recognize specific molecular patterns present in viral & microbial components
TLRs - stimulation effect
- Stimulation of different TLRs induces distinct signaling pathways & patterns of gene expression
- -> leads to activation of innate immunity AND instructs development of Ag-specific acquired immunity
Retinoic acid-inducible gene I (RIG-I)-like Helicases (RLHs)
- also proteins that recognize viral nucleic acids w/in infected cells (like TLRs)
- coordinate many of the same signaling pathways & patterns of gene expression as TLRs do
Interferons - what are they & why produced
- production induced by viral infection of cells
- Most viruses can induce IFN production
- leads to “flu-like” syndrome (fever, chills, nausea, malaise…)
- interfere w/ infection of neighboring cells
- interact w/cells IFNs through receptors
- induce an “anti-viral state,” characteristic of cell bound & responsive to IFN (whether or not that cell has been infected!)
Interferon types
Type I IFNs: alpha- and beta- IFN
= antiviral cytokines transiently produced & secreted by most infected cells w/in hours of infection
Type II IFNs: gamma-IFN
= produced ONLY by T cells & NK cells
IFN receptors
IFN receptors signal through Jak/Stat pathways
Control genes whose transcription is regulated by…
- ISREs (interferon-stimulated response elements) for Type I (alpha/beta) IFNs
- GAS (gamma activated site) elements for Type II (gamma) IFNs
IFNs - Anti-viral state - how it works
- optimal state to block viral replication
- alters transcription of >100 cellualr genes (both increasing and decreasing transcription)
- faciliated by dsRNA
dsRNA - action with IFNs, production
- facilitates IFNs anti-viral state
- activates several IFN responsive genes (PKR, OAS, etc.)
- produced or is an intermediate in the replication cycle of come viruses
- thus, ensure IFNs are only active under conditions of viral infection
Results of IFNs anti-viral state
Results in…
- temporary blockade of cell proliferation
- reduced cellular metabolism
- potentiates NK cell activity, including gamma-IFN production
- increases expression of APCs
- may lead to apoptosis
- etc
Treatment with IFNs
- Large amounts of IFNs have dramatic consequences (significant side effects)
- BUT, successful in the treatment of some persistent infections Hep C) and some tumors
Major mediators of IFN-induced anti-viral state
- PKR
- OAS
PKR action in IFN-induced antiviral state
= protein kinase
- phosophorylates / inactivates cellular translation initiation factor
- results in decreased protein synthesis
OAS action in IFN-induced antiviral state
= 2’-5’ Oligoadenylate synthetase
- activates cellular ribonuclease that degrades mRNA)
Interaction between viral dsRNA and PKR / OAS
PKR / OAS begin as inactive precursors (PKRa, OASa)
Activated by dsRNA
Once activated, the gene products shut down translation of both cellular & viral mRNAs.
Summary of IFN cellular effects (4)
- w/ PKR and OAS (and dsRNA), shut down translation of both cellular & viral mRNAs
- induce synthesis of gene products to arrest cell cycle (p21, inhibitor of G1/S phase), thus blocking viral replication
- induce pro-apoptotic state (e.g. procaspases)
- induce synthesis of proteins involved in processing / presenting virus proteins to cytotoxic T lymphocytes (CTLs) (e.g. MHC class I proteins, the proteosome & peptide transporter molecules)
Cells of innate defense
- Mononuclear phagocytes
- Dendritic cells
- NK cells
- Granulocytes (inflammatory cells = PMNs, basophils, eosinophils)
Action of mononuclear phagocytes
phagocytosis
release of inflammatory mediators
antigen presentation
Action of dendritic cells
- found in every tissue except brain
- present antigens to T cells (esp. important)
- stimulate B cell differentiation & proliferation
- key modulators in development of adaptive immune response during viral infections
- secrete large variety of antiviral & immunoregulatory cytokines
Action of NK cells
- activated in response to IFNs or macrophage-derived cytokines
- CONTAIN virus infection while immune response generates Ag-specific cytotoxic T cells that can clear the infection
Cytokines of Innate Defense
- Small proteins (~25 kDa) released by various cells in response to activating stimulation (suc h as infection or ligand-binding receptor) which bind specific receptors and act in autocrine/paracrine manner (some endocrine)
- e.g. IFNs, IL-1, TNF-alpha, IL-6, IL-12, IL18
Chemokines of Innate Defense
= chemoattractant cytokines for leukocytes
- recruit monocytes, neutrophils, other effector cells from blood to sites of infection
- with integral membrane protein receptors containing seven membrane-spanning helices
e. g. IL-8, IP10, MIP1-alpha
Innate vs. Adaptive immune actions in viral infections
Adaptive immunity harnesses many of teh same effector mechanisms used in the innate system, but is able to target them with greater precision
- antigen-specific T cells activate microbiocidal & cytokine-secreting properties of macrophages harboring pathogens
- Antibodies activate complement, opsonize microbes for phagocytes, and stimulate NK cells to kill infected cells
- uses cytokines & chemokines to induce inflammatory responses that promote influx of Abs & effector lymphocytes to infection site
Humoral response
- B lymphocyte effectors
- surface-bound immunoglobulins function in B cell presentation to T cells
- secreted immunoglobulins are antibodies
Abs produced during primary infections
- usually of lower affinity than those produced later
- usually IgM isotype (unswitched)
secretory IgA action against viruses
- inhibits virion/host attachment
- neutralizes toxins & enzymes
IgG actions against viruses
- inhibits fusion of enveloped viruses with host membranes
- enhances phagocytosis (along with IgM)
- facilitates complement lysis of enveloped viruses (along with IgM)
IgM actions against viruses
- coats & agglutinates some virions
- enhances phagocytosis (along with IgG)
- facilitates complement lysis of enveloped viruses (along with IgG)
Other ways to categorize Abs in viral infections:
Group by recognition or function
Group specific
- see epitopes shared by all of a virus group
Type specific
- see epitopes defining a virus group subset
Neutralizaing Abs
- binds virus attachment proteins or others that interfere w/ binding & fusion to host cells or prevents productive infection
- critical for preventing re-infection
- can also bind viral proteins & target virions or infected cells for complement-mediated lysis, or for enhanced killing by NK cells & phagocytes, as in Ab-dependent cell mediated cytotoxicity (ADCC)
Humoral response is critical for…
…recognition of virions.
Cell-mediated response
- T-lymphocyte effectors
- bind specific structural epitopes made up of hsot MHC class I or II together with viral peptides in APC surface
- Th, CTLs, and activated NK cells secrete IFN-gamma
T helper cells
- generally bind MHC class II
- produce cytokines that regulate the proliferation & activity of other cells
Cytotoxic T cells
- generally bind MCH class I
- can kill virus-infected cells (lyse)
Actions of macrophages & activated NK cells against viruses
- kill infected cell directly
OR - kill by antibody-dependent cell-mediated cytotoxicity (ADCC)
Th1 vs. Th2
Th1 skews immune response toward cell-mediated immunity and inflammation.
Th2 skews immune response toward humoral response.
Cell-mediated response is critical for…
…recognizing & eliminating virally infected cells
(once inside cells, viruses are not accessible to antibodies, and can only be eliminated by the destruction of the infected cells on which they depend… by cytotoxic CD8 T cells)
Protective immunity
- consists of preformed immune reactants (cells, Ab, cytokines) and immunological memory
- Ab levels & effector T cell activity gradually decline after infection is clear
- Early reinfections are rapidly cleared by these immune reactants (there are few symptoms, but levels of immune reactants are increased)
- Later reinfections lead to rapid increase in Ab & effector I cells owing to immunological memory (anamnestic response) –> infection mild or inapparent
Control of viral infection by host immune system
- may be accomplished with or without clearance of the virus
Virus strategies to evade host defenses (8)
- Antigenic variation
- Immune tolerance
- Restricted expression of viral genes
- Production of viral molecules that act as inhibitors or decoys of host defense molecules
- Down-regulation of host proteins
- Infection of immunoprivileged sites (brain)
- Direct infection of the immune system
- Inhibition of apoptosis & cell cycle control
Antigenic variation mechanisms
- point mutations in antigenic drift (e.g. HIV, influenza A)
- genome shuffling in antigenic shift (e.g. influenza A)
= rapid genetic changes that allow viruses to become unrecognizable to specific immune receptors
Immune tolerance
= molecular mimicry or infection prior to competent immune system
- virus proteins that closely resemble host proteins may escape recognition
Restricted expression of viral genes
- going invisible to host defenses in latent infection (e.g. HIV)
Production of viral molecules that act as inhibitors or destroy host defense molecules
- Viruses produce proteins which can bind & block cellular mediators or can mimic cellular receptors
- those that mimic may have evolved to moit certain function of their cellular counterparts (suc has stimulatory function) and retain only those function which benefit them (suppressive functions)
= may destroy host defense molecules such as cytokines, receptors, Ab’s (e.g. Pox, Herpesvirus)
Down-regulation of host proteins
- down-regulate host proteins such as MHC class I or adhesion molecules (e.g. Pox and Herpesviruses)
- Class I is required for CTL recognition, thus downregulation protects these virus-infected cells from detection
- Class I down-regulation, however, is a trigger for NK cell detection
- So some sophistocated viruses also express a viral homolog of Class I molecuels to avoid NK recognition
Direct infection of the immune system
by HIV and EBV, for example
Inhibition of apoptosis & cell cycle control
- SV40 large T antigen and Adenovirus E1A
- affected by many viruses
- these two pathways are also often involved in tumorigenesis
