Virus Pathology

Question 1

Viral Pathogenesis

Virulence

Answer 1

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

Question 2

GEneral principles

Answer 2

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

Question 3

Different patterns of virus infection in people

Answer 3

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

Question 4

Patterns of viral infections in vivo: acute infection

Answer 4

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

Question 5

What do viruses that cause acute infections do to host cell protein synthesis?

Answer 5

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

Question 6

Viruses that cause acute infections are cytopathic

Answer 6

Replicate quickly, killing cell and producing new visions

Cytopathic effects observed: inclusions, syncytia, cell stealing, cell death from apoptosis, cytomegalovirus, negribody in rabies neurons

Question 7

Some cytopathic viruses induce cell fusion (syncytia)

Answer 7

Virus infects cell
Viral fusion protein delivered to surface
Infected cell fuses with adjoining cell

Question 8

Viruses that cause acute infections have to deal with innate immunity, especially type 1 interferons

Answer 8

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

Question 9

What does interferon do (IFN)?

Answer 9

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.

Question 10

Viruses also have to deal with the fact that infection triggers apoptosis of the host, what mechanisms are employed to inhibit apoptosis?

Answer 10

Death receptors, FAS ligand, p53 activation–> caspases–> cell death
- many viruses interdict apoptotic pathways

Question 11

Patterns of chronic infections in vivo

Answer 11

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

Question 12

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?

Answer 12

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

Question 13

Chronic infections & MHC Class I? How do viruses modify immune response?

Answer 13

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

Question 14

Latent Infections

Answer 14

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

Question 15

Classic examples of latent infections

Answer 15

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

Question 16

What are the steps of virus infection and dissemination

Answer 16

1. 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)
2. 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

Question 17

How does a virus infect the host?

Answer 17

Infect cells at one or more body surfaces

Be introduced by parenteral inoculation (needle, wound, bite)

Question 18

Routes of Viral Transmission

Answer 18

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

Question 19

Virus dissemination

Answer 19

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

Question 20

Passive dissemination: hematogenous and lymphatic spread

Answer 20

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

Question 21

Active dissemination: hitching a ride on migratory cells

Answer 21

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

Question 22

Viral surfing: active dissemination

Answer 22

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

Question 23

Why evolve the ability to move along the cell surface?

Answer 23

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

Question 24

Active dissemination/ more ways cells can move

Endocytosis

Answer 24

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

Question 25

macropinocytosis

Answer 25

Large sheets of membrane shoot out form cell surface and wrap around the virus taking it into the cell

Question 26

Active dissemination: movement within a cell via microtubules: axonal spread of HSV

Answer 26

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

Question 27

Herpes Zoster causes chicken pox and shingles

Answer 27

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

Question 28

How do viruses move efficiency from cell to cell?

Answer 28

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

Question 29

Actin rockets

Answer 29

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

Question 30

Virus shedding and transmission

Answer 30

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

Question 31

What are the major ways in which viruses cause disease?

Answer 31

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

Question 32

Disease caused by direct cytopathic effects (cell killing via lysing the cell or apoptosis)

Answer 32

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)

Question 33

Disease caused by Ab mediated immunity

Answer 33

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

Question 34

Disease caused by virus initiated autoimmunity

Answer 34

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

Question 35

Disease caused by virus induced immunosuppresion

Answer 35

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!

Question 36

Disease caused by virus induced tumorigenesis

Answer 36

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

Question 37

HPV

Answer 37

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

Question 38

Functions of HPV gene productions
E1
2
3
4
5
6
7
L1
L2

Answer 38

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

Question 39

Transformation mechanism of h IgG risk HPVS

Answer 39

• 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

Question 40

HPV vaccines

Answer 40

• 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