*M39: Persistence and Latency Flashcards
Persistence vs. Latency:
- Persistence: ability of a pathogen to remain long-term within the host.
- Latency: form of persistent infection in which the pathogen is quiescent (NO overt disease).
- Reactivation: persistent/latent pathogen re-enters PRODUCTIVE replication.
- Carrier state: infected individual that displays no overt disease (serves as a reservoir)
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Pathogens that Establish a Persistent or Latent Infection:
- Bacteria: Mycobacteria, Treponema.
- Protozoa: Plasmodium, Toxoplasma, Trypanosomes.
- Viral: EBV, HSV-1, HSV-2, CMV, VZV, KSHV, HIV, HBV, HCV, HPV.
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How Pathogens Modulate the Host Response to Establish Persistence:
- Infection and destruction of host immune cells.
a. Human immunodeficiency Virus (HIV): T-cells.
b. Mycobacteria: macrophages.
c. Epstein-Barr Virus (EBV): B-cells.
d. Trypanosomes: macrophages.
e. Human cytomegalovirus (CMV): T-cells and macrophages. - Establish latency.
a. EBV: B-cells.
b. Herpes simplex virus type-1 (HSV-1): trigeminal ganglion neurons.
c. Herpes simplex virus type-2 (HSV-2): dorsal root ganglion neurons.
d. Varicella zoster virus (VZV): neurons and glia.
e. CMV: monocytes.
f. Human papilloma virus (HPV): keratinocytes.
g. HIV: resting T-cells.
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How Pathogens Modulate the Host Response to Establish Persistence:
- Induction of autoimmune disease.
a. Streptococci: M-protein. - Antigenic variation of major surface antigens.
a. Trypanosomes: switch in major surface antigen.
b. Influenza virus: antigenic shift/drift in HA and NA envelope glycoproteins.
c. HIV: antigenic variation in gp120/gp41 envelope glycoproteins.
d. Neisseria: pillin switching. - Molecular mimicry of host molecules.
a. Treponema: outer sheath antigens block ADCC.
b. Neisseria: group B capsular polysaccharide.
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A Case History: A 60 year-old patient is admitted for abdominal pain and fever. A CT scan shows acute cholecystitis and he undergoes an emergent cholecystectomy. Post-operatively he develops multi-organ failure and requires mechanical ventilation. Two weeks into his illness, the ICU physicians note hemorrhagic lesions on his lips and in the mouth-around the intubation tube. A culture swab is used to collect fluid from the lesions in the mouth, and sent for a Tzanck smear and viral culture. The Tzanck smear shows multi-nucleated giant cells, suggestive of an infection/reactivation with one of the human herpesviruses. Empirically, the patient is started on IV acyclovir. _ grows on tissue culture, confirming the diagnosis of orolabial herpes infection. Acyclovir was continued and the lesions healed. The patient was eventually discharged to a nursing home.
Cause: _
HSV-1
Herpes simplex virus (HSV)
Herpes simplex virus (HSV):
a. Member of herpesvirus family.
i) 8 known human viruses (HSV-1, HSV-2, VZV, CMV, EBV, HHV6, HHV7, KSHV).
b. Serotypes.
i) HSV-1: 60% orofacial lesions/40% genital lesions.
ii) HSV-2: 40% orofacial lesions/60% genital lesions.
c. Infects a variety of cell types; dependent on presence of virus receptors.
d. Not species-specific as virus can infect cells from various species in culture, BUT humans are the sole reservoir for virus transmission.
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Herpes simplex virus (HSV):
e. Virus particle.
i) Envelope: acquired from host, contains 13 viral glycoproteins.
ii) Tegument: surrounds capsid, 23 viral + 49 cell proteins.
iii) Capsid: icosahedral-shape, 162-capsomeres, 4 major proteins.
iv) DNA genome: double-stranded linear DNA genome of 152 kb.
g. Latent infection of neurons.
i) Spread: retrograde axonal transport to PNS.
ii) DNA persists as an extrachromosomal circular episome.
iii) Absence of lytic gene proteins.
iv) Expression of Latency-Associated Transcript (LAT).
v) No overt disease.
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Herpes simplex virus (HSV):
f. Lytic [cell death] life cycle (Production of virus particles).
i) Attachment: two receptors
1. Heparan Sulfate (HS): present on most cells, involves gC, gB.
2. HveA (HVEM/TNFR14) and HveC (nectin-1/CD115), involves gD.
ii) Entry: fusion usually occurs at the cell surface, may be receptor-dependent, involves gD, gB and gH.
iii) Transcriptional cascade: Over 84 gene products (very complex).
iv) DNA replication: Nuclear, see intra-nuclear inclusions.
v) Assembly: Nuclear.
vi) Egress: usually eventually results in cell death
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Herpes simplex virus (HSV):
h. Recurrent Infection / Reactivation.
i) Stimuli: UV, surgery, stress, trauma, hormones, immune suppression.
ii) Virus re-enters lytic cycle.
iii) Anterograde axonal spread from PNS to site of primary infection.
iv) Frequency: high -> occasional recurrences -> never.
v) Asymptomatic virus shedding (60-90%) affects spread.
vi) No apparent lysis of virus-infected neurons [WHY??].
vii) Role of host immune system.
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Herpes simplex virus (HSV):
Reservoir/Transmission:
a. One of the most widespread infectious diseases (776,000 cases/yr USA)
i) 65% adults HSV-1 sropositive; 25% adults HSV-2 seropositive.
ii) 16% of individuals age 14-19 have genital HSV-2 infections.
b. Humans are the sole reservoir.
c. Not seasonal.
d. Spread by intimate (STD) or direct contact.
i) Spread in secretions and respiratory droplets.
ii) Spread to mucosal surfaces or via skin abrasions.
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Herpes simplex virus (HSV):
Virulence Factors:
a. Viral DNA synthesis: maintain nucleotide pools in quiescent cells (neurons).
i) thymidine kinase (tk) and ribonucleotide reductase (RR).
b. Control host cell function: shut-off protein synthesis and block apoptosis.
i) UL41 (vhs) and g34.5.
c. Control host cell function: toxicity/apoptosis.
i) ICP0 protein processing and stability altered in neurons.
d. Immune regulation: block complement, antibody and Ag recognition.
i) gE/gI, gC and ICP47.
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Herpes simplex virus (HSV):
Pathogenesis:
a. Vesicular lesion formation.
i) Cytopathic effects (CPE).
ii) Inflammation: host recognition of virus-infected cells.
b. Virus shedding occurs in presence of high levels of neutralizing antibody.
c. CMI response is important in resolving lesions (usually takes 1-2 weeks).
d. Severity of primary infection.
i) Correlates with increased frequency of reactivation.
ii) Correlates with increased duration of reactivation.
iii) Correlates with increased viral load.
iv) Usually lesions are more severe with longer duration (10-14d).
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Herpes simplex virus (HSV):
Pathogenesis:
e. Severity of recurrent infection (reactivation).
i) Varies with serotype (HSV-1 vs. HSV-2).
ii) Varies with between herpesviruses (HSV vs. VZV).
iii) Spread to CNS: encephalitis.
iv) Usually lesions are less severe with decreased duration.
EXCEPTION: HERPETIC STROMAL KERATITIS (HSK) WHERE CORNEAL OPACITY
RESULTS FROM CMI RESPONSE TO VIRUS-INFECTED CORNEAL STROMAL CELLS
DUE TO FREQUENT RECURRENCES
f. Complications Detected in Immunocompromised Patients.
i) Neonates: 1/10,000 live births -> Cesarean births (720,000/yr).
1. Disseminated.
2. CNS.
3. SEM: Skin, Eye, Mouth
ii) AIDS.
1. Increase in HSV-2/HIV-1 seropositive individuals
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Herpes simplex virus (HSV):
Diagnosis:
a. Important for pregnant women: asymptomatic shedding (5-28%).
i) Infants with disseminated disease born to women shedding virus.
b. Clinical examination: problem of asymptomatic shedding.
c. Serologic tests: sensitive, type specific.
d. Tzanck smear stain: multi-nucleated giant cells with inclusion bodies.
i) Rapid and inexpensive.
e. Direct virus isolation from infected tissues.
f. Fluorescent In Situ Hybridization (FISH).
g. PCR.
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Herpes simplex virus (HSV):
Prevention/Treatment:
a. Incurable disease that persists for life.
b. Prevention by barrier method: STD.
c. Nucleoside antiviral therapy: decreases severity and duration.
i) Acyclovir (ACV): oral, i.v., topical, also valcyclovir.
ii) Penciclovir: topical cream.
d. Drugs to block viral entry: Abreva (n-docosonal).
e. Cesarean delivery: prior exposure to HSV.
f. Vaccines: target HSV glycoproteins, not yet effective.
g. Use as gene delivery vehicle in gene therapy applications (T-Vec and MM).
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