M14: Virology II: Viral Pathogenesis Flashcards
Stages in Viral Pathogenesis:
1) _
(2) Primary _
(3) Primary _ (spread through bloodstream
(4) Secondary _
(5) Spread to _
(6) Further _, _, and _
(1) Entry
(2) Primary replication
(3) Primary viremia (spread through bloodstream)
(4) Secondary replication
(5) Spread to target organs
(6) Further replication, cell injury, and clinical disease
Pathogenesis of Viruses:
Routes of acquisition (6)
Alimentary tract; Fecal-Oral spread.
Respiratory tract.
Urogenital tract; Sexual contact.
Eyes.
Parenteral inoculation
Insect vector or animal bite
Pathogenesis of Viruses:
Routes of acquisition:
a. Alimentary tract; Fecal-Oral spread.
i) Localized: (1)
ii) Systemic: (3)
b. Respiratory tract.
i) Upper localized: (8)
ii) Lower localized: (4)
iii) Systemic: (7)
c. Urogenital tract; Sexual contact.
i) Localized: (1)
ii) Systemic: (3)
d. Eyes.
i) Systemic: (3)
e. Parenteral inoculation – directly into the _: (2)
f. Insect vector or animal bite: (4)
i) Coronavirus (SARs).
ii) Enteroviruses, Reovirus, Adenovirus.
i) Rhinovirus, Hantavirus, RSV, Coronavirus, Coxsackievirus, Arenavirus, Parainfluenza and Influenza viruses.
ii) RSV, Adenovirus, Parainfluenza and Influenza viruses.
iii) Rubella, Mumps, Measles, Hantavirus, Foot & mouth disease virus, VZV, Pox virus.
c. Urogenital tract; Sexual contact.
i) Localized: HPV.
ii) Systemic: HIV, HSV, hepatitis B virus (HBV).
d. Eyes.
i) Enterovirus, HSV, Adenovirus.
e. bloodstream: HIV, hepatitis B virus.
f. Rabies, Bunyavirus, Togavirus, Flavivirus.
Pathogenesis of Viruses:
Dissemination: _
Routes of dissemination (3)
Spread throughout the host:
Hematogenous spread (viremia)
Localized spread
Neural spread
Pathogenesis of Viruses:
Routes of dissemination:
i) Hematogenous spread (viremia) – important route of spread for (many / few) viruses
ii) Localized spread – some viruses _ (e.g. rhinoviruses: common cold; papillomaviruses: warts, cervical cancer)
iii) Neural spread – a few viruses can infect and _ (e.g. rabies, HSV, VZV, arboviruses).
many
remain in close proximity to their site of entry
spread through the nervous system
Pathogenesis of Viruses:
Factors affecting dissemination (3)
i) Portal of entry.
ii) Host immunity.
iii) Cell-specific virus receptors.
Factors affecting viral tropism.
a. The proteins on the _ (presence of a viral receptor).
b. The proteins on the _ that interact with the cell surface receptor.
cell surface
virus surface
Outcomes of viral infection (from the point of view of the cell).
a. _ of the infected cell (_).
b. No _ or _.
c. Cell dysfunction or morphologic changes without _.
i) _ of cells (Example: warts caused by human papilloma viruses).
ii) Excessive _ secretion by cells (Example: common colds caused by rhino- and coronaviruses).
iii) _ formation – fusion of two or more cells together to form _ cells (Examples: respiratory syncytial virus, HSV).
iv) _ formation (nuclear vs cytoplasmic).
d. Transformation of the cell into an _ phenotype (cancer). [Examples: HTLV-I; EBV; HPV-16 /18]
i) _ – cancer causing genes.
ii) Inhibition of cellular _.
a. Lysis (cell death)
b. morphological or deleterious change
c. cell death
i) Hyperplasia
ii) mucous
iii) Syncytia, multinucleated giant
iv) Inclusion body
d. immortalized
i) Viral oncogenes
ii) tumor suppressor genes
Diagnosis of Viral Infections:
Tissue culture:
a. Growth of viruses on _ or _ cells.
i) _ assay to measure virus titer or infectious units (Herpesviruses, Adenovirus).
ii) _ or _ assay (Retroviruses).
b. Viruses cannot be _ like bacteria or fungi since they cannot survive outside cells.
c. Detection of viral _ (e.g. rounding of cells, lysis, syncytia formation = fused cells).
a. human or animal
i) Plaque
ii) Transformation or focus forming
b. cultured
c. (CPE) cytopathic effect
Diagnosis of Viral Infections:
Detection of virus particles or virion components:
a. _ examination for typical cell morphology associated with viral infections.
b. _ with antibodies specific for viral antigens.
c. _ for identification of viral particles.
d. _ assay for erythrocyte lattice formation, e.g. influenza RBC agglutination.
e. _ detection of circulating viral antigens, e.g. p24 (gag) antigen detection of HIV.
f. Other specific _, e.g. Tzanck smear for multi-nucleated giant cells and inclusion bodies (ground glass).
a. Light microscopic
b. Immunofluorescence (IF)
c. Electron microscopy (EM)
d. Hemagglutination
e. ELISA
f. stain
Diagnosis of Viral Infections:
(Direct / Indirect) detection of the viral genome by _ techniques.
a. PCR (polymerase chain reaction).
Detection of _ made against viruses that circulate in the _ (Serology).
a. ELISA for antibodies against viral antigens.
b. Virus neutralization.
Direct
molecular
antibodies
serum
Diagnosis of Viral Infections:
(IgG / IgM) – early, or acute infection
(IgG / IgM) – prior infection
- A rise in virus-specific _ between the _ phase (symptomatic phase) and the _ phase (2 to 4 weeks later) is diagnostic of a recent viral infection.
- The window period is the period of time before _.
IgM
IgG
- IgG, acute phase, convalescent
- circulating antibodies appear.
Patterns of Viral Infection in the Host:
Acute infection followed by death of the host
EXAMPLES: (2)
Ebola, Hantavirus
Patterns of Viral Infection in the Host:
Acute infection followed by clearance of virus
EXAMPLES: (3)
Rhinovirus, Rotavirus, Influenza virus
Patterns of Viral Infection in the Host:
Persistent chronic infection
EXAMPLES: (3)
Hepatitis B and C viruses, HIV
Patterns of Viral Infection in the Host:
Latent infection and reactivation
EXAMPLES: (6)
HIV, HSV, EBV, VZV, CMV, and other human herpesviruses
Poliovirus:
Biologic Characteristics:
i) Member of the _ genus of the _ family: 3 strains (WPV-1, WPV-2, WPV-3).
ii) Small, (enveloped / unenveloped), (positive / negative) sense RNA virus.
iii) Life cycle.
1. attachment: binds the _, an Ig-like family receptor.
2. entry: _ with conformational changes in VP1 and VP4 resulting in _.
3. _
4. _ in the cytoplasm.
5. _ within the cytoplasm.
6. _: plasma membrane vs. endosomal (10,000 particles/cell).
i) Enterovirus, Picornavirus
ii) unenveloped, positive
1. Poliovirus receptor (Pvr)
2. endocytosis, fusion
3. uncoating
4. replication
5. assembly
6. egress
Poliovirus:
Reservoir/Transmission.
i) _ are the sole reservoir: spread by _ in contaminated food and water.
ii) (Seasonal / No seasonal) incidence.
Diagnosis.
i) Culture in tissue culture cells from _ samples or _.
i) Humans, oral-fecal route
ii) No seasonal
i) stool, cerebrospinal fluid
Poliovirus:
Virulence factors.
i) Ability to infect and spread through the _.
ii) Ability to survive the acid environment of the _ (un-enveloped virus).
iii) 2A protein: inhibits eIF4G and _.
iv) 2BC/3A proteins: inhibit _ dismantling cell secretory pathway (IL-6,IL-8,ß-IFN).
v) 3C protease: cleaves _ subunit of TFIId, unable to bind to TATA box inhibiting _
i) central nervous system
ii) GI tract
iii) host protein translation
iv) cell vesicle transport
v) Tbp, cell transcription
Poliovirus:
Pathogenesis.
i) Entry via _: must withstand acid environment of the stomach.
ii) Primary replication and multiplication in _ in small intestine.
1. _, _ symptoms in 10% (vomiting, diarrhea).
2. 90% of people infected are _ (but still infectious).
3. infectious virus is excreted in _.
iii) Spread through _ and secondary replication in _ and _.
iv) Spread to _: 99% of spread is prevented by antibody response.
v) Multiplication in _ and _ spread.
vi) Infection of brain: (2)
1. symptoms: (2), usually self-limiting, lasts a few days to two weeks.
vii) Infection of spinal cord and brainstem.
1. _: acute flaccid paralysis due to motor neuron and muscle damage.
a. occurs in ~1/200 people with CNS infection.
2. _ (rare): paralysis and muscle wasting can occur decades after infection due to aging of damaged neuromuscular anterior horn and muscle cells (FDR).
i) GI tract (fecal-oral transmission)
ii) mesenteric lymph nodes
1. fever, gastrointestinal
2. asymptomatic
3. stool
iii) bloodstream, liver and spleen
iv) central nervous system
v) CNS, intraneural
vi) Meningitis, encephalitis
1. headache, fever
1. Paralytic poliomyelitis
2.
Poliovirus:
Treatment/Prevention.
i) _ had eradicated polio in America (1916-28,000 cases; 2013-0 cases), Europe, and Australia: outbreaks in groups refusing vaccination and 3 endemic (Afghanistan, Pakistan, Nigeria) (Global: 2013-362 [2012-214, 2009-1604]; WPV-1 183 Somalia, 77 Pakistan, 50 Nigeria, 17 Syria).
ii) Salk (inactivated _, 1954) vs. Sabin (oral attenuated , 1963, good intestinal tract immunity).
1. OPV can revert to wild-type (): 5 cases Haiti (2001), (2012-68 VDPV2; 2013-58 VDPV2).
2. IPV used in (3)
a. blocks _, not _ infections: Combined with Diptheria, Pertussis, Tetanus, Hib (Pentacel)
iii) _: an antiviral drug which has activity against enteroviruses and other picornaviruses.
Polio vaccine
ii) IPV, OPV
1. VDPV
2. (i) US, (ii) immunosuppressed, (iii) where live vaccine can not be employed.
a. CNS, gut
iii) Pleconaril
Paradigm of latent/chronic infections.
a. _ is part of the virus life cycle and strategy for survival of certain viruses
b. During latency, there is _ (no replication of the viral genome, no production of viral capsid structural proteins).
c. A latent virus has the potential to undergo _.
d. During reactivation from latency the virus enters the _ cycle and produces infectious virus.
e. Reactivation of a latent virus is typically in response to certain stimuli (3)
a. Latency
b. no production of infectious virus
c. reactivation
d. replicative
e. stress, cellular injury, or the availability of a cell-type permissive for replication.
Human immunodeficiency virus (HIV):
Biologic Characteristics.
Member of _ subfamily of _.
Virion particle of 100 nm.
- _-shaped dense nucleocapsid core.
- 5 to 10 copies of RT and IN found in _ (RT activated (before / after) attachment/entry).
Genome.
- Linear (ss / ds, DNA / RNA) present as (homo / hetero / either) dimer: genetic diversity of HIV sub-species
- Complex _ structure: many accessory genes compared to other retroviruses
lentivirus
retroviruses
Wedge
nucleocapsid
after
ssRNA
either
genome
Human immunodeficiency virus (HIV):
Life cycle.
- Attachment: SU envelope _ interacts with CD4 and chemokine co-receptors (CXCR4: lymphocytes vs. CCR5: macrophages) [Priming of Cell].
- Entry: conformational change in _ (_).
- _ converts linear ssRNA genome into circular dsDNA.
- Transit of dsDNA to the nucleus with IN protein that allows HIV DNA to _.
- Transcription by _: stimulated by _ interaction with HIV LTR (promoter).
glycoprotein
TM (membrane fusion)
Virion-associated RT
integrate
RNAPII
TAT
