M14: Virology II: Viral Pathogenesis Flashcards Preview

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Flashcards in M14: Virology II: Viral Pathogenesis Deck (33)
1

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

2

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

3

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.

4

Pathogenesis of Viruses:

Dissemination: _

Routes of dissemination (3)

Spread throughout the host:

Hematogenous spread (viremia)
Localized spread
Neural spread

5

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

6

Pathogenesis of Viruses:

Factors affecting dissemination (3)

i) Portal of entry.
ii) Host immunity.
iii) Cell-specific virus receptors.

7

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

8

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

9

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

10

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

11

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

12

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.

13

Patterns of Viral Infection in the Host:

Acute infection followed by death of the host

EXAMPLES: (2)

Ebola, Hantavirus

14

Patterns of Viral Infection in the Host:

Acute infection followed by clearance of virus

EXAMPLES: (3)

Rhinovirus, Rotavirus, Influenza virus

15

Patterns of Viral Infection in the Host:

Persistent chronic infection

EXAMPLES: (3)

Hepatitis B and C viruses, HIV

16

Patterns of Viral Infection in the Host:

Latent infection and reactivation

EXAMPLES: (6)

HIV, HSV, EBV, VZV, CMV, and other human herpesviruses

17

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

18

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

19

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

20

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.

21

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

22

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.

23

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

24

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

25

Human immunodeficiency virus (HIV):

Life cycle.

- Processing of transcripts: regulation of splicing and transport by _.
--> Multiply-spliced RNAs (Early times post infection): REV-(dependent / independent).
--> Un-spliced and singly-spliced RNAs (Late time post infection): REV-(dependent / independent) (RRE)

- Synthesis and processing of virion proteins.
--> Protease (PR) cleaves _ and other products (RT and IN) from GAG-POL (Pr160).
--> Protease (PR) cleaves _ precursor protein (Pr55) into MA, CA and NC during assembly resulting in wedge-shaped nucleocapsid core.
--> Cleavage of _ precursor protein (gp160) into SU (gp120) and TM (gp41).

- Assembly and egress occurs in _ or at _.

• Latency verses Persistence (Chronic): _ specific, macrophages vs DCs vs resting T-cells.

REV
independent
dependent

itself
nucleocapsid
ENV

cytoplasm
cell surface

cell type

26

Mechanisms of Viral Adaptation:
Evolution of viruses due to mutation (3)

Point mutations
Recombination
Reassortment

27

Mechanisms of Viral Adaptation:
Evolution of viruses due to mutation:

a. _ mutations. In general, viral genome replication is (more / less) error-prone than cellular genome replication.

i) RNA viruses – RNA polymerase and reverse transcriptase are intrinsically (more / less) error-prone than DNA polymerases and may (contain / lack) proofreading functions.

ii) DNA viruses – proofreading (post-replication repair) may be (more / less) accurate in virus-infected cells.

iii) Because viruses replicate so (quickly / slowly) and in such (large / small) numbers, the opportunity for mutation is magnified.

b. Recombination of _ between related viral strains.

c. Reassortment of _.

i) Can only occur in viruses with _ RNA genomes, e.g. influenza virus.

ii) Swapping of segments between two different viruses that _.

iii) Antigenic Shift – _

iv) Antigenic Drift – more subtle change in viral antigens due to point mutations.

a. Point, more

i) more, lack

ii) less

iii) quickly, large

b. homologous nucleic acid sequences

c. viral genes

i) segmented

ii) infect the same cell

iii) sudden dramatic shift in viral antigen due to reassortment.

iv) more subtle change in viral antigens due to point mutations.

28

Mechanisms of Viral Adaptation:
Escape Mechanisms:

Latency: _ expression of viral antigens.

Infection of sites not readily accessible to the _

Antigenic variation: virus rapidly _ and _ antigenic sites that are critical for immune recognition

Antigenic variation: _ of viral genes (antigenic shift)

Viral “_” molecules that interfere with _ function, such as antigen processing and presentation

Infection of _ cells with destruction or alteration of _ cell function

Minimal to no

immune system

evolves, mutates

reassortment

defense, immune

immune, immune

29

Mechanisms of Viral Adaptation:
Escape Mechanisms Examples:

Latency: Minimal to no expression of viral antigens.

Infection of sites not readily accessible to the immune system

Antigenic variation: virus rapidly evolves and mutates antigenic sites that are critical for immune recognition

Antigenic variation: reassortment of viral genes (antigenic shift)

Viral “defense” molecules that interfere with immune function, such as antigen processing and presentation

Infection of immune cells with destruction or alteration of immune cell function

HSV and VZV in latently infected neurons, EBV in B cells, HIV in resting T cells

HSV, VZV in neurons of PNS and CNS

HIV, hepatitis C virus

Influenza A

Suppression or inhibition of MHC Class I molecules by Adenoviruses, CMV, HSV, EBV, Vaccinia, Poliovirus RSV, and HIV

HIV (CD4 T cells, macrophages, DCs), EBV (B-cells)

30

Definitions:

Viral Pathogenesis - the entire process or mechanism by which viruses _

Virulence - the capacity of a virus to _

Viremia - _

Tropism – the ability of a virus to _

Incubation period - the period of time between _ and _. Incubation period can vary from days to weeks depending on the virus.

cause disease

produce a disease

the presence of infectious virus in the bloodstream

infect a specific species, tissue-type or cell-type

virus entry (exposure)
development of symptoms

31

Definitions:

Permissive cell – _

Non-permissive cell – _

Acute infection – _ infection.

Persistent infection – _ infection.

Latent infection – form of persistent infection in which virus is _.

allows for virus replication and production of infectious virus.

one which a particular virus cannot productively infect (cannot produce infectious virions)

rapid, self-limiting

long-term

quiescent

32

Definitions:

Asymptomatic infection: _

Abortive infection: infection of cells in which virus replication _

Viral tropism: _

Disseminated infection: spread of an infectious organism _

Systemic infection: spread of an infection _

inapparent acute infection.

is not complete.

what cells or tissues that the virus can infect.

beyond the site of primary infection.

to multiple organ systems.

33

Definitions:

Active viremia: produced by _

Passive virmia: produced by _

Primary viremia: _ spread of virus in the _ ((high / low) particle numbers).

Secondary viremia: _ spread of virus in the _ ((high / low) particle numbers).

Viruria: presence of virus particles in the _.

active virus replication at primary or secondary site.

direct inoculation of virus into bloodstream in absence of replication.

initial, bloodstream, (low)

delayed, bloodstream, (high)

urine