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Flashcards in Virus Pathology Deck (40)
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31

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

32

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)

33

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

34

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

35

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!

36

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

37

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

38

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

39

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

40

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