Virus Pathology Flashcards
Viral Pathogenesis
Virulence
Process by which a viral infection leads to disease
Virulence = capacity of virus to cause disease
- virus strain, dose or inoculum of virus, inoculation route, host factors
GEneral principles
Viruses are often asymptomatic
Incubation period (length depends on virus, host factors, route of entry dose etc)
Symptoms linked to immune response - more so than bacteria becuase by the time you have symptoms you have cleared the virus
Different patterns of virus infection in people
Acute (common)
- influenza, rhinovirus
- virus infects host and replicates quickly before being cleared by immune system
- GI and respiratory tract
Chronic (ongoing for years or months)
- less common, lasts for many years with ongoing virus replication
- hepB, C HIV
Latent, relapsing
- varicella, zoster, HSV1,2
- reactivated years later
Also transforming infection where the virus immortalizes the cell, giving rise to cancer
Patterns of viral infections in vivo: acute infection
Acute, self limited, virus cleared by immune response (influenza, many RNA viruses)
May be symptomatic or more often asymptomatic
Rapid production of virus
Rapid resolution and clearing of infection
Well suited for rapid spread- by the time the patient is symptomatic, virus has already replicated and spread to new hosts
Viruses that cause acute infections may modify innate immune responses; rarely adaptive immune response
What do viruses that cause acute infections do to host cell protein synthesis?
Shut it off to make as much virus as possible
- poliovirus cleaves cellular EF4 preventing host mRNA translation, has RNA structures that support ribosomes binding only viral proteins produced
- influenza steals 5’ caps from cellular mRNAs so they cant be translated, uses the caps for viral mRNA only viral proteins produced
Viruses that cause acute infections are cytopathic
Replicate quickly, killing cell and producing new visions
Cytopathic effects observed: inclusions, syncytia, cell stealing, cell death from apoptosis, cytomegalovirus, negribody in rabies neurons
Some cytopathic viruses induce cell fusion (syncytia)
Virus infects cell
Viral fusion protein delivered to surface
Infected cell fuses with adjoining cell
Viruses that cause acute infections have to deal with innate immunity, especially type 1 interferons
IFN production!
IFN-B, alpha
Induced by dsRNA, ssRNA, and other less defined signals, TLRs
Can be produced by virtually all cell types
IFN–> anti-viral state
What does interferon do (IFN)?
Released, binds to its receptors on neighboring cells and induces an antiviral state
Proteins induced by IFN:
- PKR: phosphorylates elongation factor 2 alpha - inhibits translation
- Rnase L: degrades all mRNA in a cell
- Max protein: inhibits transcription and inhibits virus assembly
Viruses that cause acute infections usually inhibit IFN production or the response to IFN. Many mechanisms are employed. Examples: decoy substrates; PKR degradation, etc.
Viruses also have to deal with the fact that infection triggers apoptosis of the host, what mechanisms are employed to inhibit apoptosis?
Death receptors, FAS ligand, p53 activation–> caspases–> cell death
- many viruses interdict apoptotic pathways
Patterns of chronic infections in vivo
Virus particles or products made for prolonged periods often but not always caused by DNA viruses (hep B, C, HIV)
Infection may be ultimately cleared but some viruses remain for the entire lifetime of the host
Viruses are usually non cytopathic- symptoms usually come from the immune response
Evasion of host immune defenses is de rigueur and is characteristic of larger DNA viruses
Viruses Have to deal with innate immune response and apoptosis so must avoid adaptive immune response
Viruses that cause chronic infections in vivo have to exist in the face of an evolving adaptive immune response
What are the there mechanisms employed to avoid adaptive immune response?
Virus can mutate and evolve, staying a step ahead of the immune response (HIV, hep C)
Virus can produce proteins that modify the immune response (many viruses) eg disrupt class I antigen presentation
Establish a latent infection and wait for the immune response to subside (3rd pattern of infection, reemerge when immune response has subsided ) eg herpes hides out for life and comes up when you are stressed
Chronic infections & MHC Class I? How do viruses modify immune response?
In chronic infections, viruses can encode proteins that down regulate MHC Class I, disrupt antigen presentation
- in infected cell, some viral proteins are degraded by proteosome and resulting peptides are transported into the ER via the TAP proteins and loaded onto Class I MHC molecules
- once loaded MHC Class I is transported to the surface and CD8 cells with cognate receptors will bind to and then lyse the offending cell
- viruses can make proteins that block peptide transport, bind to and degrade class I, block transport of class I, cause class I to be downregulate from cell surface etc
Latent Infections
Can last for years or even life of the host cell
- eg herpes viruses
- latently infected cell either makes no virus proteins, or only a few that keep it in a latent state
- no protein production = cell is not seen as being infected by the immune system
- virus can be reactivated, by things like stress, decrease in immune surveillance
Classic examples of latent infections
Herpes simplex virus ‘cold sores’ come back when stressed ** reactivated when stressed, make new viruses and infect new cells leading to symptoms ***
Varicella zoster causes chickenpox in a young child–> latent infection in sensory neurons–> reactivation many years later leads to shingles
What are the steps of virus infection and dissemination
- Source of virus (most human infx are caused by viruses that only infect humans so humans are the source, except rabies or hantavirus which come from animals or dengue and west Nile via insect vector)
- Transmission mechanism - virus typically establishes a primary, local infection, can spread from this site and spread to other people
- some never leave the primary site of infection eg GI dont leave GI tract
- other viruses disseminate within the host via hematogenous spread, lymphatic spread, neural spread etc –> replication can then occur at distant sites
How does a virus infect the host?
Infect cells at one or more body surfaces
Be introduced by parenteral inoculation (needle, wound, bite)
Routes of Viral Transmission
Conjunctivitis: herpes-measles Respiratory tract: rhino-, corona-, measles, RSV, influenza, adenovirus-, herpes- Alimentary tract: picorna-, reovirus-, rotavirus Urogenital tract; HIV, HBV, HPV Anus: Skin: HPV Arthropod: flavi, bunya Capillary Scratch, injury: pox, herpes, rabies Skin: HPV
Vertical transmission, transfusions, transplants
Virus dissemination
May be disseminated as individual virus particles or may be transmitted as cell associated visions
While viruses cant move on their own, they usurp host pathways to get them to where they need to go between tissues, cells, within cells quickly
Passive dissemination: hematogenous and lymphatic spread
May enter bloodstream via capillaries, replication in endothelial cells, inoculation by a vector bite
Viremia: presence of infectious virus particles in the blood, virus load is the amount of virus in the blood (measure HIV virus load in the blood - measur eof how well therapy is going)
Polio moves through lymphatics to reach regional lymph nodes draining into blood stream and reaching the CNS
Cleared by neutralizing antibodies, cells of the reticuloendothelial system, binding and infection of new target cells
Viruses cant move by themselves (non motile) so they induce the host to move them around, hitch rides on cells, move along cell surface, move along microtubules within a cell, and come up with ways to efficiently move from an infected cell to an adjoining uninflected cell
Active dissemination: hitching a ride on migratory cells
Lymphatic dissemination via association with cells: transport of HIV by dendritic cells
- viruses infect migratory cells like lymphocytes and then these cell transport the virus to distant sites eg HIV
Dendritic cells are first HIV encounters–> infect–> regional lymphnodes–> HIV returned to cell surface and is surrounded by T cells it can infect
Viral surfing: active dissemination
Some viruses bind to cell surface with this transduction get signals that cause the cell to move the virus (viral surfing) along the surface until it reaches point wher eit can enter the cell
Bind to cell receptor–> intracellular signaling–> cell cytoskeleton to move the receptor along the surface–> by surfing viruses can move along plasma membrane to the base of microvilli where virus can enter or be endocytosed
Why evolve the ability to move along the cell surface?
Surface of epithelial cells is inhospitable place for a virus
By surfing virus can move to the base of cilia where it can be endocytosed
Active dissemination/ more ways cells can move
Endocytosis
Viruses have to be taken up by host cells–> some viruses trigger signals to induce cell to engulf the virus and drugs that stop this also block function
Eg poxviruses not only surf along surface of filopodia but when they reach the cell surface they transduce signals that cause the cell to internalize the virus via macropinocytosis
macropinocytosis
Large sheets of membrane shoot out form cell surface and wrap around the virus taking it into the cell
Active dissemination: movement within a cell via microtubules: axonal spread of HSV
Many viruses spread from primary site of infection by entering local nerve endings eg HSV1, 2, rabies, polio
Retrograde spread: movement of virus towards cell body
Anterograde spread: movement of virus away from cell body
Viral proteins can mediate movement along microtubules
HSV1 and 2 move along microtubules to travel with axons, viral regiment proteins interact with dynein after entry - retrograde toward cell body
and newly made viruses use kinesiology to move th eother way - anterograde
Herpes Zoster causes chicken pox and shingles
Herpes establishes a latent infection in sensory ganglia by moving in a retrograde fashion from the periphery to the nerve bodies in the ganglia
Upon reactivation, (due to stress), new particles are made that move in anterograde fashion along axons, delivering virus to periphery–> painful rash
Herpes Zoster mainly affects a single dermatome of the skin when latent virus reactivates in a sensory ganglion and tracks down sensory nerve to appropriate segment (anterograde transport)
Characteristic eruption of vesicles in the involved dermatome
How do viruses move efficiency from cell to cell?
Filopods from infected cell makes contact with target cell
Long lived interaction established: viral envelope protein binds to receptor on target cell
Virus surfing to the site of contact
Endocytosis of the protrusion by the target cell
Surfing in reverse move from surface of infected cell to unaffected cell
HIV buds at sites of cell to cell contact–> specific protein transport, only buds at sites of contact with uninfected T cells–> super efficient virus spread! —> large number of visions are transferred from the synapse to the target cell
Actin rockets
Some viruses move between cells using these
Eg shigella, listeria, rickettsia
Viruses can be super efficiency
Actin polymerizes at the nod of the virus and virus then shoots around inside the cell, propelled by actin polymerization
Can also be pushed out of the cell, pushing the membrane with it and projection may impale adjoining cells nearby–> virus has a new host–> virus can spread from cell to cell without entering extracellular space so this movement is immune to antibodies
Virus shedding and transmission
Shedding: release of infectious virus from infected host, required for transmission!, can occur locally at primary site of infection or via many routes for viruses disseminated in the host widely
- respiratory secretions (flu, RSV)
- Saliva (CMV, mumps)
- feces (enteric and hepatic viruses, Norwalk, hepA)
- blood (HIV, filoviridae, hep B)
- urine, semen, milk
- skin lesions (HSV, papillomavirus, smallpox)
Other
- germline
- cannabalism (prions
What are the major ways in which viruses cause disease?
Direct cytopathic effects (death of the host cell by apoptosis) - eg cell rounding and death by Ebola virus--> loss of function due to death of parenchyma cells - Virus induced immunopathology - cell mediated - ab mediated - autoimmunity - immunosuppressive
Viral oncogenesis
- cellular transformation by a virus
Disease caused by direct cytopathic effects (cell killing via lysing the cell or apoptosis)
eg west Nile infects neurons and induces apoptosis via caspases 3–> encephalitis and paralysis
- eg Ebola–> hemorrhagic fever–> loss of vascular integrity, spike of the protein is the culprit! (Spike causes cells to lose contact with neighbors ‘round up’–> vascular integrity breached–> bleeding occurs)
Disease caused by Ab mediated immunity
Dense hemorrhagic fever
- dengue exists as 4 distinct serotypes
- Ab to one serotype dont neutralize other serotypes
- causes acute self limited febrile illness
- infection with second dengue serotype greatly increases risk for dengue hemorrhagic fever and shock syndrome
Mechanism: Ab dependent enhancement
- AB binds to virus, FC region binds to macrophage; virus now infects macrophage
- Ab produced against first serotype bind to but do not neutralize the second serotype so the virus is partially coated with Ab so it binds to cells with FC receptors–> massive release of cytokines and vascular leakage and hemorrhage
- incidence of DHF has increased greatly in the world because dengue serotypes have spread
CANT MAKE VACCINE FOR SINGLE SEROTYPES need to cover all four
Disease caused by virus initiated autoimmunity
Virus infection elicits B and T cell responses to virus
- some virus epitopes are similar to those on one or more host proteins
- virus induced Ab or CD8 cells react with cognate epitopes on host proteins leading to autoimmune disease
- eg Guillane-Barre syndrome: ascending paralysis due to immune mediated destruction of myelin (think campylobacter), due to immune targeting of myelin basic protein and the disease usually follows a viral infection - molecular mimicry–> immunosuppressive diseases
Disease caused by virus induced immunosuppresion
HIV- infects and destroys CD4+ T helper cells–> immunosuppresion
Can get transient immune superior and then bacterial infection due to this immune suppression
Measles virus
- infects DC and monocytes
- reduces Ag processing and presentation
- places pt at risk for other infections
- eg HIV + child gets infected with measles, HIV virus load increases dramatically
- kills ppl because it suppresse the immune system by suppresssing secretion of certain cytokines so then you are susceptible to infection from other agents
HIV infection impairs CD4 function leading to reactivation of what? TB!
Disease caused by virus induced tumorigenesis
20 - 25% of human cancers have viral origin, cause tumors directly or indirectly causing cellular transformation
Targeting tumor suppressor: pRB inactivated by phosphorylation, virus induces degradation of p53 gene
Inappropriate expression of growth factors
Induction of chronic injury (hepB)
Retroviruses can encode oncogenes
- oncogene - gene whose protein product functions as a major effector in conversion of a normal cell to a cancerous cell
Cellular onc cellular gene activated in tumor cells or a normal gene altered to become an active oncogene
Viral onc - viral homologous of a normal cellular gene or viral gene with no homology to cellular genes which when activated function as a tumor inducers
Viruses can also lead to tumors more indirectly by causing immunosuppresion for prolonged periods
Eg cervical and liver cancer, HPV, hepB and C
HPV
Small non enveloped DNA virus that infect skin and mucosal epithelia = chronic infection
> 140 HPV types have been identified
HPV types associated with cancer = high risk, low risk types (6, 11) cause benign growths like warts
Infection with high risk HPVS (16, 18, 31, 33) is primary risk for cervical cancer
Different types of HPV are structurally the same but infect different types of cells eg cutaneous vs mucosal, HPV infects basal cell layer through breaks in the skin or mucosa, early genes stem growth and viral replication
As basal layer differentiates, specific nuclear factors expressed in different layers and types of skin and mucosa impact viral gene expression
HPV induced disesease
Skin warts (common warts, plantar, subungual or periungual, flat warts) Genital or anal warts
Respiratory papillomatosis
Cancer: cervical, anal, vulvar, penile, head and neck
HPV is most commonly occurring STD in the US atleast 50% of sexually active men and women will get it at some point in their lives but new vaccine is good
Functions of HPV gene productions E1 2 3 4 5 6 7 L1 L2
E1 - initiation o viral DNA replication
E2 - transcriptional red protein, enhancement of viral DNA replication, viral episode maintenance
E4 (late protein) disruption of cytoskeleton network
E5- interaction with growth factor receptors
E6 - degradation of p53 *
E7 - binding and inactivation of pRB*
L1 - major capsid protein
L2 - minor capsid protein
E2 suppresses expression of E6 and 7
E6 and 7 are viral oncogenes–> retain differentiating host keratinocytes in a state amiable to amplification of viral genome replication and late gene expression
Transformation mechanism of h IgG risk HPVS
- HPV DNA integrated into host DNA genome in carcinoma in situ
- integration of circular HPV DNA genome specifically disrupts or deletes E2 gene which normally inhibits the production of E6 and 7 proteins
- disruption of E2 after integration results in a high level of e6 and 7 proteins
- E6 and 7 function as oncogenes that promote tumor growth and malignant transformation by inhibiting tumor suppression genes p53 and RB
HPV vaccines
- recombinant subunit vaccine: virus like particles derived from expresssion of structural genes from four high risk HPV subtypes
Gardasil - protects against intiial infection with HPV types 16, 18 which together cause 70% of cervical cancers
- also targets HPV 6, 11 which cause 90% genital warts
- also recommended for 11-12 yo males
Cervarix
- block infx with HPV 16, 18
- hollow virus like particles VLPs assembled from recombinant HPV coat proteins
- elicit virus neutralizing Ab responses that prevent initial infx with HPV types represented in vaccine
- dont pretect women against all HPV types that cause cervical cancer
- vaccine is preventative, no antivirals for ppl with HPV
HPV vaccine works, prevalence decreased by 50%, vaccine effectiveness of atleast one dose was 82%
Disease is in the vaccine types only 16, 6, 18, 11
