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Virology > Viral pathogenesis > Flashcards

Viral pathogenesis Flashcards

1
Q

Pathogenicity

A

Ability to cause disease

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2
Q

Pathogenesis

A

means by which organism produces disease in host

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3
Q

Virulence

A

Capacity to produce disease

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4
Q

Environment - hostile place

A
  1. Heat, drying, UV - viruses produce large numbers of virions
  2. Stable at low pH or proteases- survive in gut, faecal-oral transmission
  3. Many virions never experience environment - life cycles involve insect vectors e.g. arbovirus
  4. Many spread by physical contact - transfer by body fluids, virions not outside for long
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5
Q

To be maintainted in nature viruses must:

A
  1. Shed into environment OR
  2. taken up by an arthropod vector or needle OR
  3. passed congenitally (mother-child)
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6
Q

Most common route of entry

A

Respiratory tract

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7
Q

Skin entry

A
  • Penetrated by mechanical trauma - HPV, HIV, HSV, HBV
  • Injection - HBV, HIV, HCV (more education now)
  • Bite of infected mosquito - arboviruses
  • Bite of infected animal - rabies
  • Most do not multiply locally and are carried away from site of infection by bloodstream (HBV, arbovirus) or migration along nerves (Rabies)
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8
Q

Respiratroy entry

A
  • Aerosol inhalation or mechanical transmission of infected nasal secretions
  • Droplet size determines initial site of virus deposion
    • >10micros - nose
    • 5-10 microns - airways
    • <5 microns - alveoli
  • Barriers to infection: mucus, cilia, alveolar macrophages, temperature gradient, IgA
  • Localised or spread further
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9
Q

Respiratory tract anatomy

A
  • Goblet cells produce mucous
  • Different temp between URT and LRT
  • Lower temps: rhinovirus, corona, influenza
  • Higher temps (37C): influenza, adeno - rely on alveolar macrophages
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10
Q

Genitourinary entry

A
  • Tears/abrasions allow for entry
  • e.g. HIV, HSV II mostly, papilloma, Hep B
  • cervical mucous, pH of vaginal secretions and composition of urine - host defence
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11
Q

Alimentary tract

A
  • Local - rotavirus, corona, adeno
  • Systemic: eneterovirus, hep A from invasion of tissues underlying mucosal layer

Viral survival depends on:

  • acid stability
  • Resistance to bile salts - non enveloped viruses survive, coronavirus can associate with milk products and prevent inactivation
  • Prevent inactivation by proteolytic enzymes - some use it as a REQUIREMENT
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12
Q

Anatomy - alimentary tract

A
  • M cells - sample proteins/particles that come through, take to underlying layers where t cells, macrophages are BUT unique opportunity to microbes to gain entry
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13
Q

Viral spread within the body

A
  • Cell-cell transmission
  • Dissemination –> systemic
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14
Q

Systemic spread

A
  • Polarized infection - can be targeted to basal surfaces –> gain entry into underlying tissues
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15
Q

Viremia

A
  • Presence of infectious virus particles in the blood - free in blood or contained within infected cells e.g. lymphocytes
  • Active: produced by replication - newly synthesized virions
  • Passive: Viral particles are introduced into blood without viral replication at site of entry e.g. needle, bite of animal or mosquito
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16
Q

Viremia graph

A
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17
Q

Haematogenous spread

A
  • Barrier to entering tissues - capillary endothelial cells
  • Some viruses replicate in endothelial cells (lytic e.g. ebola)
  • Viruses transported by transcytosis - lumen into underlying tissue, NOT INFECTION, pass straight through e.g. M cells
  • Some tissues are not joined by tight junctions and virus can pass between them e.g. mumps in choroid plexus
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18
Q

Neural spread

A
  • Peripheral nerves - HSV, rabies, varicella
  • Uncoated nucleocapsid carried along axons/dendrites
  • Viruses protected from attack by CTL - nerve cells do not have class I molecules, not destroyed by natural killer cells
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19
Q

Rabies neural spread

A
  • Rabies replicates at site of infection until enough come in contact with sensory/motor nerve cells
  • Enter unmyelinated axons and move towards nueron’s nucleus by retrograde axoplasmic flow
  • Virus entry -> striated muscle –> peripheral nerves –> CNS –> peripheral nerves –> salivary glands –> environment
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20
Q

Herpes neural spread

A
  1. Infection of conjunctiva/mucosa of URT
  2. Viral replication in lymph nodes
  3. Primary viraemia
  4. REplication in liver/spleen
  5. Secondary viraemia
  6. Infection of skin (can also bind to nerve cells and become latent) and vesicular rash
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21
Q

Infectious rashes?

A

Varicella -YES

Measles - NO

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22
Q

Determinism of tropism - availability of receptors

A
  • Key factor for susceptibility
  • Ubiquitous receptors? but can still have restricted tropism
    • influenza - sialic acid, tropism for respiratory tract
    • rhinovirus - ICAM-1, tropism for URT
    • HSV: glycosaminoglycan receptor, tropism for epithelial cells
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23
Q

Permissivity

A

May be able to enter but ALSO needs to have right intracellular gene products to replicate viral genome

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24
Q

Accessibility

A

Can virus get to susceptible cells - are cells deep?

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25
Q

Local factors for tropism

A
  • Optimal temperature e.g. rhinovirus restricted to URT
  • Stability in extremes of pH: low pH of stomach, high pH of intestines
  • Survive destruction of lipids and proteases from pancreas
    • Some viruses become activated by host factors
    • Polio activated by activated by low pH, rhinovirus destroyed but BOTH belong to PICORNA
26
Q

Ability of cleavage-activating proteases -tropism

A
  • Influenza HA cleaved next to fusion peptide for virus to be infectious
  • Cleavage mediated by tryptase Clara - host enzyme secreted respiratory tract
  • Highly virulent avian influenza contain insertion of multiple basic amino acids at HA cleavage site which permits cleavage by ubiquitously expressed intracellular proteases furins –> infect more cells, many organs
  • H5N1 - contained amino acid susbstitutions
27
Q

Genome transcription requirements - tropism

e.g. papillomavirus

A
  • Virus commences replication in germinal cells in basal layer but cells produce proteins taht block transcription of late structural genes
  • Codon usage:
    • Different tissues use different tRNA
    • Papilloma genome only uses certain tRNAs in basal layers –> genome transcription, more differerentiated skin layer where it wants virus produced, uses different tRNA
    • Stops immune system recognising it because its not making structural proteins
28
Q

Virus induced changes in cells

A
  • Cell transformation –> tumour formation e.g. polyomaviruses, adenoviruses, oncogenic retroviruses
  • Multiplication –> lytic infection e.g. entero, reovirus
  • Slow virus without cell death –> chronic infection e.g. HCV, HBV, HPV
  • No damage to cell but virus can later emerge as lytic –> latent e.g. herpes simplex and zoster, EBV
29
Q

Viral-induced damage to tissues and organs

A
  • Cytocidal virus
  • e.g. tissue specific killing in rotavirus diarrhoea - enterocytes
  • e.g. paralytic poliovirus infection - neurones in spinal cord
  • Non-enveloped virus rely on cell lysing, some evnelope viruses also leads to death
30
Q

Mechanisms of cell damage: cytocidal virus

A
  1. Cell lysis - direct destruction of membrane integrity
  2. Shutdown of cellular protein synthesis
    • Adenovirus protein inhibits transport of cellular mRNA from nucleus to cytoplasm
    • Polio: protease 2A cleaves elongation factor 46, cellular mRNA cannot be translated
    • OR competition of viral and cellular mRNA for ribosomes
  3. Shutdown of cellular nucleic acid synthesis - consequence of host protein shut down or e.g. poxvirus encodes DNase
  • Usually cytocidal for viruses that have fast replication cycles
31
Q

Cytopathic effects of viral proteins

A
  1. Accumulated viral proteins can be cytotoxic
    * e.g. adeno - nuclear inclusions, reovirus - cytoplasmic inclusions, expression of Ebola envelope protein in endothelial cells –> acute haemorrhagic shock in infection
  2. Remodelling membrane structure
  3. Formation of synctia - viral proteins inserted into membrane may cause cell fusion (measles) or lead to changes in membrane permeability and cell lysis
  4. Apoptosis: Caspases –> induction of cytokines, infected cells release proteins that are subsequently presented by MHCII, activation of CTLs
32
Q

Noncytocidal virus

A

Loss of function

e.g. LCMV causes non-lytic persistent infection of growth hormone producing cells in pituitary gland and transcription of growth hormone mRNA is reduced

33
Q

Transformation

A

Viruses can encode ocogenes –> tumour production

  • Uncontrolled cell proliferation
  • Reduced contact inhibition
34
Q

Immunopathology

A

Lymphocytes, macrophages, cytokines –> inflammation

Symptoms: fever and fatigue - IL1, 6, TNF acting on hypothalamus, muscle pain, nausea

35
Q

Antibody-mediated pathology

A
  • Antibody-dependent enhancement of infection by FcR-mediated uptake of virus Ab complexes into macrophages and monocytes e.g. dengue - Ab bind to virus but not neutralize
  • Antigen-antibody complexes deposited in kidney –> glomerulonephritis , vasculitis in blood vessel e.g. Hep B in chronic carriers
36
Q

Immune complexes

A

Deposition of immune complexes in blood vessels, kidney, brain

e.g. HCV-mediated effects on lymphocytes –> antibody + formation/deposition of immune complexes containing rheumatoid factor –> damage

37
Q

CD4 T cell-mediated responses

A
  1. CD4 T cells mediate an immune response to virus involving inflammation in endothelial cells of small blood vessels e.g. measles Koplick spots
  2. CD4 T cells induce cytokines that recruits eosinophils e.g. bronchiolitis with RSV in infants
38
Q

CD8 mediated responses

A
  1. Liver damage in Hep B infeciton - lysis of hepatocytes, recruitment of monocytes, neutrophils –>jaundice
    • Old RBCs destroyed by macrophages in spleen
    • Heme from haemoglobin converted to bilirubin
    • –> bloodstream –> liver for secretion in bile –> faeces
39
Q

Autoimmunity

A
  • Molecular mimicy: myelin basic protein and proteins of influenza - Guillain-Barre syndrome
  • Coxsackie B4 virus with heart muscle - myocarditis
  • Triggers for autoimmune diseases
40
Q

Immunosuppression

A
  • e.g. HIV - replicates in CD4 T cells and monocytes - kills/inhibits
  • Norovirus - replicates in macrophages/DCs, stops them producing cytokines and interferons - stops communication
  • Measles temporary immunosuppression from nonproductive replication in T cells and macrophages; suppression of proliferation of non-infected T cells by engagement of measles surface glycoproteins with cell surface receptors (CD46) that result in suppression of IL12
  • –> susceptibility to secondary infections
41
Q

Genetic factors

A
  • Inherited defects - absence of Ig class
  • Polymorphisms in genes controlling immune responses e.g. MHC
  • Interferon-inducible genes (MxA, MxB: resistance to -ve strand RNA viruses (HIV))
  • Receptor genes e.g. CCR5 - receptor for Black Death –> confers resistance to HIV
  • STAT 1 disabled - Mouse infected with norovirus died
42
Q

Outcomes of virus infection

A
  • Fatal - viral diseases where man is not natural host e.g. Ebola
  • Full recovery - e.g. influenza
  • Recovery but permanent damage - virus cleared, left with symptoms e.g. poliomyelitis, cancer
  • Persistent - virus not cleared and can resurface to cause disease e.g. herpesviridae - stress
43
Q

Virulence quantitated by:

A
  • Mean time to death
  • Mean time to appearance of symptoms
  • Measurement of fever, weight loss
  • Measurement of pathological lesions (polio); reduction in blood CD4+ lymphotyes (HIV1)
44
Q

Viral is relative

A
  • Influenced by dose, route of infection, species, age, gender, susceptibility
  • CANNOT compare virulence of different viruses - different routes, pathologies
  • For similar viruses - assays must be the same
45
Q

Genetic determinants of virulence

A
  1. Gene products that alter the ability of the virus to replicate.
  2. Gene products that modify the host’s defense mechanisms.
  3. Genes that enable the virus to spread in the host.
  4. Toxic viral proteins
46
Q

Gene products that alter ability of the virus to replicate

A
  1. Viral mutants that exhibit reduced or no replication in animal host/cultured cell types - reduced virulence from failure to produce sufficient numbers of virus particles to cause disease
  2. Mutants that exhibit impaired virulence in animals but NO replication defects in cells in culture - identify genes specifically required for disease
47
Q

Effect of noncoding sequences on virulence

A
  • Attenuated Sabin vaccine strains of poliovirus contain mutation in 5’ noncoding region that reduces neurovirulence - deletions within long poly C tract in 5’ NCR of mengovirus reduce virulence in mice
  • U base change MUCH higher lethal dose needed than wild type C base
48
Q

Gene products modify host defence mechanisms

A
  • Virokines - faulty cytokines
  • Viroreceptors - homologs of host receptors (faulty or secreted)
  • Mostly in large DNA viruses
49
Q

Genes that enable virus to spread in the host

A
  • Mutation of viral genes disrupts spread from peripheral sites of inoculation to organ where disease occurs
  • e.g. reovirus 1 - spreads to CNS through blood, type 3 spreads neural routes
  • Gene encoding viral outer capsid protein sigma1 (recognises cell receptor) determines route of spread
50
Q

Toxic viral proteins

A
  • Rotavirus protein NSP4 glycoprotein –> formation of transient rotaviurs envelope as particles bud into ER
    • acts as viral enterotoxin –> triggers signal transduction pathway in intestinal mucosa –> intracellular accumulation of ER –> mitochondria induced apopotosis
51
Q

RNA viruses - genetic determinants of virulence

A
  • RNAP error-prone replication –> quasispecies
    • Most are deleterious, others can be benefical –> slightly affect conformation, but not function of structural protein = antigenic drift
  • RdRP can switch templates if 2 different viral strains infect same cell –> chimeric viral genome
    • occurs when sub-genomic RNAs produced e.g. calici -norovirus
    • full length copy but also subgenomic RNA - NOT REASSORTMENT
    • SYDNEY 2212 - Composite of New orleans and Lordsdale at subgenomic break point between ORF 1 and 2
52
Q

Poliovirus replication

A
  • 3A - aids in genome replication but is cleaved to release 3B (VpG) and 3A
  • 2B and 2C are essential for viral RNA synthesis; 2C is an NTPase
  • Induces vesicular clusters
  • Viral RNA replication occurs on outside of rosettes
  • Loss of cellular organelle e.g. golgi
53
Q

Intracellular traffic

A
  • Transport vesicles with coatomer proteins (COP)
  • COPII - anterograde
  • COPI - retrograde
  • Polio 2BC protein recruits COPII to facilitate replication complex formation
  • 3A protein impairs function of GTPases that regulate COP transfer
54
Q

Why does Polio disrupt secretory pathway via disassembly of golgi?

A
  • Requires membrane biogenesis
  • Prevents surface expression of MHC1 - prevents CTL-mediated killing
  • Prevents secretion of cytokines and interferon
  • Doesn’t encode glycosylated proteins
  • Non-enveloped
  • Not dependent on secretory pathway for virion production
  • Requires COP II for replication, but also immune evasion
55
Q

EBOLA hemorrhagic fever

A

Shock associated with release of cytokines by macrophage/monocytes - not completely virus driven pathology

56
Q

Ebola symptoms

A

IP:2-21 days

Red eyes, fever, headache, flu-like symptoms, fatigue, bleeding, massive hemorrhage

57
Q

Ebola transmission

A
  • Transmitted through bodily fluids and/or direct contact with infected individuals
  • Spread to human populations through contact with infected primates
  • Natural sources - bats?
58
Q

Ebola virus - cures/treatment

A
  • No cure
  • Put diseased in straw hut –> burn down when dead
59
Q

Ebola pathogenesis

A
  • Ebola glycoprotein - major structural component & antibody target
  • Additional ebola GP generated by transcriptional editing - 75% decoys, sequesters circulating antibody to avoid neutralization
  • Virion-associated GP requires furin cleavage for activation
  • VP35 protein - polymerase co-factor
    • prevents activation of IRF3 and restrict IFN production
  • VP24 - virus assembly and budding
    • Prevents nuclear translocation of STAT1 to imped transcription and production of interferon stimulated genes of which most are antiviral
60
Q

Ebolavirus - filovirus (pathogenesis)

A

TNF-a: induce necrosis and is potent proinflammatory cytokine

  • Destruction and vascular instability result from TNF-a overproduction

Virology (9 decks)

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