Herpesviruses & Prions

Herpesviruses

Baltimore Type I, enveloped, ubiquitous viruses.

8 types can infect humans and different vertebrates have their own associated viruses

Alphaherpesvirinae

Herpesviruses with neurotropic site of latency and express Thymidine kinase.

Includes HSV1, HSV2, and VZ

Gammaherpesvirinae

Herpesviruses which are lymphotropic and immortalize cells.

Includes Epstein Barr virus

Cellular receptors of HSV

nectin-1, HVEM, and O-sulfated heparin sulfate

HSV1

Herpes simplex virus type 1

HSV2

Herpes simplex virus type 2

VZ

Varicella zoster virus

HSV viral transcription is divided into

Immediate early, early, and late products

HSV clinical presentation

Initial outbreak of clusters of opalescent, blister-like lesion on background of Reddened skin with itching burning sensation (eventually drain and heal with no scarring).

Clusters can be at slightly different locations

Heroes Whitlow

Uncommon presentation of herpes virus with lesions on fingers and thumbs.

Caused by HSV1 or HSV2

Herpes Gladiatorum

“Scrumpox,” Wrestler’s pox, Matpox, etc.

Transmitted via contact sports (virus is rubbed into skin abrasions)

Neonatal herpes

Herpes in newborns from birth, utero, or post-Nataly

Is either external, disseminated, or CNS

Acyclovir

Drug taken by pregnant women with history of HSV to prevent neonatal herpes.

Phosphorylated by virally-encoded Thymidine kinase (TK) and cellular kinases to be mistaken for guanine by DNA machinery and acts as a chain terminator.

Works against alphaherpesvirinae

Antibodies (and thus vaccines) are only effective against

Varicella Zoster virus (VZ)

Chicken pox

Caused by Varicella Zoster virus

Evasion of immune response by HSV1 and HSV2

Passive strategies include viral latency and cell-to-cell transmission.

Active strategies are the expressions of IPC47 and ICP34.5

IPC47

Prevents recognition and killing by cytotoxic T cells by stopping MHC-peptide complexes from reaching the infected cell surface

ICP34.5

Prevents eIF2alpha phosphorylation so viral replication is not stopped by Type I interferons

Triggers of HSV Recurrences

• UV-b radiation

• Fever

• Emotional and physical stress

• Acidic and spicy foods or allergens

• Immunosuppression

VZ is different from HSV 1&2 via its ability to

Be transmitted through aerosol secretions, spread from lungs to skin, are susceptible to antibodies, and has live vaccines and VZ immune globulin (VZIG)

Shingles

Reactivation of VZ restricted to one area of the body along a dermatome.

Pain or tingling in the area 2-4 days prior to outbreak.

Possible post-herpetic neuralgia

Post-herpetic neuralgia

Persistent nerve pain months or years later after a herpes outbreak

EBV infection Sx

Sore throat, swollen glands, fever and splenomegaly

EBV’s ability to immortalize B lymphocytes can cause

Cancer (Burkitt’s lymphoma, Nasopharyngeal Carcinoma, Lymphoproliferative disease, Hodgkin’s and Non-Hodgkin’s Lymphoma)

Infectious mononucleosis

Disease caused by EBV

“Kissing disease” or glandular fever.

T cells and infected B cells fight one another causing a triad of bone-weariness, sore throat with very swollen tonsils/cervical lymph nodes, and persistent fever

Hairy oral leukoplakia

Disease caused by EBV seen normally only in AIDS pateints

T cell hyperplasia (downy cells)

CD8+CTL

Hunt down and kills EBV infected B cells

Side effects: swelling of glands, liver, and spleen

EBV transmission

through saliva

Scrapie

Fatal, degenerative disease of sheep and goats

Behavioral changes: increased chewing, ataxia, inability to keep up with flock, compulsive desire to scratch themselves against objects

Sx: progressive wasting followed by tremors and convulsive collapse

Scrapie Transmission

Passed via mother’s milk and directly between sheep through the alimentary canal.

Persists in soil for years

Bovine spongiform encephalopathy Mad Cow Disease

Cow version of scrapie’s including abnormal posture, aggressiveness, lack of coordination and ataxia, difficulty standing, and general wasting

Creutzfeldt-Jakob disease

Human form of scrapie’s with a spongiform encephalopathy

Characterized y dementia, loss, behavior changes, hallucinations, obsessive compulsive ataxia, rigid posture, and seizures.

Death occurs d/t pneumonia from impaired swallowing reflexes

Kuru

Neurological disorder that is endemic to the tribal regions of Papua New Guinea.

General weakness, inability to stand, and inability to take nourishment d/t violent shaking.

Caused by direct contact with human tissues (funerary cannibalism)

Prion (PrP^C)

Protein involved in neuron myelination, maintenance of long-term memory, and stem cell self-renewal

PrP^Sc

misfolded prion which causes disease by forcing PrP^C’s to become misfolded

Amyloids

Deposits/plaques in the CNS caused by fibrils of polymerized PrP^Sc

Can lead to holes in tissue and astrogliosis

Astrogliosis

Excess of astrocytes (neurological equivalent of scar formation)

Prion disease etiologies in humans

1. Spontaneous

2. Inherited

3. Acquired

Spontaneous Prion Disease

Arises due to an unlucky misfolding of PrP^C that starts a chain reaction leading to disease or form a somatic mutation that misfolds.

Classical CJD; majority of cases

Inherited Prion Disease

CJD running in families via an autosomal dominant fashion

Acquired Prion Disease

Comes from an external source such as consumption or medical procedures (Human BSE or Variant CJD, Iatrogenic CVD)

Human BSE or Variant CJD

Getting prion disease from consumption of animal products contaminated with PrP^Sc

Iatrogenic CVD (iCVD)

acquired CJD through a medical procedure.

Ex. Growth hormone and gonadotropin injections from undiagnosed CJD human cadavers, dural grafts, corneal grafts, or infected surgical instruments

Prions can only be inactivated by

Extended contact with bleach, NaOH, or acidic detergents