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Flashcards in Virus Pathology Deck (40)
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1

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

2

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

3

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

4

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

5

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

6

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

7

Some cytopathic viruses induce cell fusion (syncytia)

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

8

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

9

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.

10

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

11

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

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?

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

13

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

14

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

15

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

16

What are the steps of virus infection and dissemination

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

17

How does a virus infect the host?

Infect cells at one or more body surfaces

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

18

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

19

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

20

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

21

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


22

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

23

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

24

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

25

macropinocytosis

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

26

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

27

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

28

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

29

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

30

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