Barriers To Viral Infection Flashcards by Claire Delargy

Generalised virus replication cycle

Attachment/uncoating
Transcription
Translation
Replication
Assembly
Release

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Barriers to viral infection (4)

Immunological
Biochemical
Physical
Genetic

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Geographical barriers

Location

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Biological barriers (6)

Skin
Mucous membranes
Mucous
Tears
Stomach acid
Intestinal secretions

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Dengue virus

An example of a geographical barrier
Transmitted by mosquitos, transmission limited by mosquito distribution

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Coxackie/adenovirus receptor (CAR)

CAR not found on apical surface, so virus has to find the receptor deep in the cell

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Viral precursor protein cleavage

Paramyxovirus F protein
Influence virus HA

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HIV receptors

CD4
CCR5 or CXCR4
Found on human T cells

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Avian sarcoma and leukosis virus receptors

TVA
TVB

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Paramyxovirus fusion protein cleavage is…

Required for function

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RSV paramyxovirus F protein cleavage

Furin enzyme
Trans golgi
Systemic

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SeV paramyxovirus F protein cleavage

Tryptase clara
Extracellular
Respiratory tract

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RSV F fusogenic activity is measured by

Fusion assay w/o acetylated trypsin
LLC-MK2 cells
Incubate SeV WT = weak fusogenic activity
Incubate SeV/RSV F = strong fusogenic activity

Incubation is 5-6 days at 33oC

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_____ cleavage is essential for virus infectivity.

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Genetic barriers to infection (2)

Retroviruses - > APOBEC3G
SARS-CoV-2 - > ACE2

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Retrovirus Vif

Blocks APOBEC3G activity

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APOBEC3G

Packaged into virions
Hypermutation of minus strand cDNA (dC to dU)
Defective non-infectious progeny

HIV Vif blocks ________ APOBEC3G

Human and green African monkey

SIV Vif blocks __________ APOBEC3G

Simian

Immunological barriers

Type 1 interferon
Antigen presentation

IFN induction 2nd wave

Newly synthesized IFN-β, from the first wave, binds to the type I IFN receptor and activates the expression of numerous ISGs via the JAK/STAT pathway.

IRF-7 amplifies the IFN response by inducing the expression of several IFN-β subtypes. SOCS and PIAS are negative regulators of the JAK-STAT pathway. Mx, ISG20, OAS and PKR are examples of proteins with antiviral activity.

dsRNA, a characteristic by-product of virus replication, leads to activation of…

the transcription factors NF-κB, IRF-3 and AP-1

How is IFN-Beta promoter activated?

Cooperative action of NF-κB, IRF-3 and AP-1

What is the second signalling pathway for formation of TBK-1/IKKe?

A second signaling pathway involves endosomal TLR-3 and TRIF.

Interferon signalling pathways

Type I IFNs bind type I IFN receptor, composed of two subunits, IFNAR1 and IFNAR2, which are associated with TYK2 and JAK1 Type II IFN, IFN-γ, binds type II IFN receptor, composed of two subunits, IFNGR1 and IFNGR2, which are associated with JAK1 and JAK2, respectively. Activation of JAKs associated with type I IFN receptor => tyrosine phosphorylation of STAT2 and STAT1=> ISGF3 complexes=> bind IFN-stimulated response elements in DNA => gene transcription. Both type I and type II IFNs also induce the formation of STAT1–STAT1 homodimers that translocate to the nucleus and bind GAS (IFN-γ-activated site) elements that are present in the promoter of certain ISGs, thereby initiating the transcription of these genes.

Rubulavirus V proteins (C-ter) inhibition of interferon signalling

STATs to proteasome

Respirovirus C proteins (C-ter) inhibition of interferon signalling

Inhibit STAT1, STAT2 or TYK2 tyrosine phosphorylation

Morbillivirus V proteins (C-ter) inhibition of interferon signalling

Inhibit STAT1, STAT2 tyrosine phosphorylation STAT1/IFNr complex retained

Henipavirus P,V, W (N-ter) inhibition of interferon signalling

STATs sequestered in high molecular weight complexes

Pneumovirus NS1 and NS2

STAT2 to proteasome

Sendai Virus C protein inhibiting interferon role in pathogenicity

WT => blocks STAT1 signalling = anti-IFN activity Cm* mutant (3 amino acid substitutions) = > no anti-IFN activity

Type 1 IFN system in virus induction and suppression

Major player in antiviral defence Secreted in response to viral infection Induce expression of potent antiviral mechanisms Virus ability to block type I IFN system determines … Virulence Interspecies transmission

HIV nef protein

Down regulates MHC expression on infected cells Redistributes CD80 and CD86 away from cell surface in antigen presenting cells - functionally significant - compromises activation of naive T cells

Mucosal epithelium

Mucus layer Cilia Goblet Cells Glycocalyx -> thick layer over endothelial cells

MeV paramyxovirus F protein cleavage

Furin Trans-Golgi Systemic

HA cleaved by __________

Host protease Eg furin

What reverses the species specificity in APOBEC3G?

Single amino acid change

Type I IFN system?

Virus binds to first cell and releases ds RNA Signalling cascade - TNF beta TNF beta released from cell and binds to interferon receptor of neighbouring cell

Berlin patient

HIV 1 + leukaemia Bone marrow transplant to treat leukaemia Transplant with new donor marrow which happened to have CCR5 mutation only in 10% of population mainly Europeans -> cured of HIV

Biochemical barriers

Viral receptors Viral precursor protein cleavage