Host response to viral infection Flashcards
Explain how host responds to infection with virus?
How is virus-infection detected (cells? Receptors?) in peripheral tissues?
Detection by pattern recognition receptors (PRRs):
1: within the cytosol…
a) cytoplasmic sensors; cytosolic DNA sensors signals through STING; cGAS (cyclic GMP-AMP synthase) detects cytosolic DNA and synthesis cGMP, which then activates the adaptor proteins STING (stimulator of interferon genes). The STING signaling leads to the production of type I IFNs and other cytokines.
b) Nod-like receptors (NLRs) recognise various PAMPs and DAMPs. Some NLRs can form inflammasomes (= multiprotein complexes that activate caspase-1, which then processes pro-inflammatory cytokines like IL-1beta and IL-18 into their active forms, and contributing to the inflammatory response against the virus).
c) Rig-like receptors (RLRs) recognise RNA. RIG-I detects short dsRNA, and MDA5 recognise long dsRNA.
2: in the membrane of the endosomes/phagosomes are the Toll-like receptors (TLRs) type 3 (recognise dsRNA), type 7 and 8 (recognise ssRNA), and type 9 (recognise unmethylated CpG motifs - viral DNA)
3: on the surface are the TLRs type 2, 4, and 6.
Which cells secrete type I interferons?
Infected epithelial cells and tissue-resident macrophages.
Describe two different effects of type I interferon important for containment of virus-infection.
1: induction of an antiviral state in cells by inhibit the viral replication or the viral entry and release, and then activate the immune cells.
2: modulation of the immune response by activate the NK cells thus increased killing of virus-infected cells.
Which PRRs trigger production of type I interferon, and which trigger production of inflammatory cytokines in immune responses against SARS-CoV-2 infection? Explain the overall role of these two cytokines for stimulating efficient immunity against SARS-CoV-2.
Receptors: TLR2 (triggered by enveloped proteins, important to stimulating the inflammatory cytokines), RIG-1 signaling and NLRs.
PRRs: type I interferons and inflammatory cytokines (TNF-alpha, IL-1beta) can signal both ways.
Ebola’s VP35 protein is a virulence factor. What does it do? What cellular pathway does it target? What is the outcome of a mutation in VP35 in a mouse infection model?
Ebola’s VP35 virulence factor block/inhibits the interferon I signaling pathway. The cellular pathway target is the RLR signaling pathway. And the outcome gives a reduction of the viral replication (the virus has no effect on the mice by this mutation).
Describe an important role for plasmacytoid dendritic cells (pDC) in immunity against virus infection.
Plasmacytoid DCs produces huge amount of type I interferons.
Which two TLRs are especially important for activation of pDC? What are their ligands?
TLR7 recognising ssRNA, and TLR9 recognising CpG motifs.
Describe two mechanisms by which NK cells can recognize virus-infected cells.
1: express the receptor (NK-G2D) that bind molecules that are expressed on infected cells. One of such molecules is myc. It induces killing by granular exocytosis, which is a common killing mechanism of both NK and active T cells, resulting in apoptosis.
2: “missing cell hypothesis”: downregulation of MHC-I molecules by virus to avoid detection by cytotoxic T cells. However, the NK cells can detect the absence of the MHC-I molecule on the cell and thus kill it. The NK cells has receptor containing both I-TIM (inhibitory motif) and I-TAM (activating motif).
How do antibodies against viruses provide efficient immunity?
They provide efficient immunity by neutralizing the virions. The antibodies bind to the virus extracellularly, either by neutralizing it immediately (by binding it to the virus coat proteins which alters the viral receptor of the target cell) or blocking its interaction with host cells. The antibody binding to the virus can block the infection of a cell in various ways: attachment of virus to the cell surface, penetration of virus into the cell, or uncoating of virus inside the cell.
Describe effector functions of adaptive immunity other than antibodies that may be important for overcoming infection by viruses.
Physical barriers - ex: cell membrane. And cell-mediated immunity involving T cells, ADCC, macrophages, and NK cells.
