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MMI 415 > Virus tropism & entry > Flashcards

Virus tropism & entry Flashcards

1
Q

Name 4 cellular barriers to virus entry

A
  1. glycocalyx (proteogylcans + protein layer)
  2. plasma membrane
  3. late endosomal pH
  4. can only use one high affinity receptors OR a few low affinity receptors
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2
Q

What are the 7 major stages of virus entry?

A
  1. binding to cell surface
  2. lateral movement/diffusion
  3. activation of signaling
  4. virus endocytosis/membrane fusion
  5. penetration
  6. intracellular transport
  7. genome uncoating
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3
Q

Name a few ways viruses enter cells – state if this pathway is done by enveloped or naked or both viruses

A
  1. env – fusion at the pm
  2. naked – pore-mediated penetration
  3. both – endocytosis: RME (clathrin, caveloin, lipid rafts)
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4
Q

name 3 properties that makes a good viral entry receptor?

A
  1. ubiquitous expression
  2. evolutionarly conserved across species
  3. essential for cell/host survival
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5
Q

what are some common cellular receptors used by viruses?

A
  • sialic acid residues
  • cell adhesion molecules, IgSF or integrins (e.g. CD4 and JAM-A)
  • PtdSer receptors
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6
Q

when does a measles rash appear post exposure?

A

14 days

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7
Q

how does measles lead to death among young children?

A

infects and kills immune cells (including memory cells) – can wipe out preexisitng immunity

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8
Q

what are two reasons why some kids are not vaccinated against measles?

A
  1. poor accessibility in developing countries
  2. vaccine hesistancy (claims that measles vaccine causes autism)
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9
Q

Describe the general features of the measles virus

A
  • (-)ssRNA genome
  • enveloped
  • replication occurs in the cytoplasm
  • MeV P, C, and V proteins block innate antiviral repsonses within HCs
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10
Q

what are the 3 known measles virus entry receptors?

A
  1. SLAM/CD150
  2. MCP/CD46
  3. PVRL4/Nectin 4
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11
Q

CD46/MCP: what is its normal cellular function, expression, what other pathogens use it as an entry receptor, what MeV strains use it, why is a target of gene therapy/oncolytic virus applications?

A
  • regulator of complement activation
  • expressed on all nucleated cells
  • pathogens: human herpesvirus 6, adenoviruses, strep pyogenes, neisseria
  • strains: vaccine only
  • target: in cancer cells CD46 is highly upregulated –> selective and this R is ubiquitous
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12
Q

CD150/SLAM: what does SLAM stand for, which cells is this expressed on, what domains does this R contain, what MeV strains use it?

A
  • SLAM = signaling lymphocyte activating molecule
  • expressed on a subset of immune cells: DCs, macrophages, activated T and B cells –> can cause immunosuppression by decreasing circulating T and B cells
  • contains Ig-like domains (variable or constant)
  • strains: vaccine and wt
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13
Q

Nectin4/PVRL4: which cells express this, what is this a marker of, what do mutations in this receptor cause, what MeV strains use this?

A
  • expression normally restricted to placenta in humans (epithelial cells)
  • tumor associated marker for breast, lung and ovarian cancer
  • mutations –> ectodermal dysplasia/syndactyly syndrom (webbed hands and feet)
  • strains: vaccine and wt – use to get out not in!
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14
Q

describe how MeV receptors dictate disease progression following infection

A

when using SLAM in immune cells (wt): infects upper respiratory LNs –> trojan horses to LNs
when using Nectin4: MeV dissemination and viremina –> MeV exit via respiratory epitherlium (aersolized)

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15
Q

when MeV enters the respiratory tract how does it enter ICs?

A
  • uses DC-SIGN (measles coR) and SLAM to enter ICs –> specifically DCs and macrophages
  • virus attatchement causes increases SMase activity and increased SLAM R clustering
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16
Q

how does MeV enter lymphocytes?

A

DCs present it to T cells in the LNs

17
Q

how does MeV exit the body/is coughed out?

A

infected T cells and DCs are present on the basolateral side of airway epithelial cells and squeeze into the tight junctions where MeV enters the epithelial cells via Nectin 4 and then the virus is apically releases into the lumen and coughed out

18
Q

what is the major protein decorating SARS-Cov2?

A

spike (S) a glycoprotein

19
Q

Briefly describe SARS-CoV-2 entry into cells: endosomal entry and cell surface entry

A

endosomal entry

  1. virus binding to ACE2
  2. internatlization
  3. endosomal acidification
  4. cleavage of S2 by cathepsin L
  5. membrane fusion
  6. uncoating of viral RNA

cell surface entry

  1. virus binding to ACE2
  2. cleavage of S2 by TMPRSS2
  3. membrane fusion
  4. unocating of viral RNA
20
Q

what makes SARS CoV 2 spike different from other beta-coronaviruses?

A

before release, spike is cleaved into S1 and S2 domains at the furin cleavage site

21
Q

describe how a SARS CoV2 pseudovirus is made and what this assay would look for? whats the advanatages what are the disadvantages?

A
  • trasnfect HEK293T cells with lentriviral vector-GFP plasmis and spike plasmid –> spike-pseudotypes lentiviral partciles are packaged and releases –> newly infected cells will express GFP –> cannot replicate because no replication machinery in pseudovirus
  • looks for cells that can sufficiently intake the virus
  • advantages: safety and quanity one round of infection
  • disadvantages: only one round of infection, role of other viral proteins
22
Q

do SARS and COVID enter different or similar cell types?

A

similar cell types

22
Q

Describe sars-cov-2 membrane fusion

A

RBD samples “one-up”/”three-down” conformation –> RBD in “up” conformation binds ACE2 which exposes the S2’ cleavage sight (secondary cleavage via Cathepsin L or TMPRSS2) –> cleavage at the S2’ site releases structural constraints on the fusion peptide (major conformational changes in S2) –> post fusion structure of S2 forms, which brings the cell and viral membranes together, facillitating formation of the fusion pore and virus entry

23
Q

what does the sars cov 2 virion architecture look like, what is a consequence of this? what consideration does this make for vaccination?

A

have s1/s2 trimers and just s2 proteins –> body created non-neutralizing Abs to s2 –> should make vaccine to stimulate S1 Abs

24
Q

what are the two S cleavage sites for TMPRSS2?

A

S1/S2 and S2’ sites

25
Q

which cells highly express TMPRSS2?

A

upper airway respiratory cells

26
Q

what is the function of hydroxychloroquine?

A

prevents acidification of the late endosome

27
Q

what is the function of camostat?

A

blocks TMPRSS2 protease cleavage

28
Q

describe a couple of proposed therapeutic treatments for COVID19

A
  1. target ACE2 receptors: souble RBC mimic or scFV against ACE2 –> virus cannot bind to ACE2
  2. target RBD of spike protein: mAb therapy (bamlanivimab)
29
Q

what is the ancestral lineage of Sars Cov 2? what did this mutate to? what is the advantage of this mutation?

A

ancestral: D614 –> G614

G614 –> less premature s1 shedding on spike –> –> more spike in one up conformation –> productive viral entry –> March Lockdown

MMI 415 (13 decks)

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