Thread by @BryanHeit

Excited to present my labs latest pre-print, in which we uncover one of the mechanisms used by #SARS-CoV-2 to evade the #ImmuneSystem. A short tweet-torial on what we found 1/10
biorxiv.org/content/10.110…

Innate immune cells respond first to infection, often by "eating" pathogens. This slows infection, but full clearance often requires adaptive immunity - as in the antibodies and T cells that respectively neutralize pathogens and kill pathogen-infected cells. 2/10

Activating adaptive immunity requires antigen presentation, where an innate immune cell shows fragments (antigens) of a pathogen to cells of the adaptive immune system. If the adaptive cell recognizes the antigen, it becomes activated and begins fighting the infection. 3/10

The key molecule in this process is #MHCII, which is the protein on the innate immune cell that holds and presents the antigen. Turns out, SARS-CoV-2 can turn off expression of MHC II. The way it does this is somewhat nefarious. 4/10

MHC II is made when another protein – CIITA – binds to the MHC II gene. SARS-CoV-2 hijacks 2 of our cells own proteins to inactivate CIITA, and in doing so, turns off antigen presentation. The first protein is HDAC2, which “compacts” DNA so that it is no longer “readable”. 5/10

SARS-CoV-2 uses HDAC2 to compact the DNA that codes for CIITA, making it impossible for the innate immune cell to produce CIITA. But hijacking HDAC2 is not enough – SARS-CoV-2 needs to send it to the right gene. It needs a map. 6/10

So what is that map? Its another host protein called IRF3. IRF3 is activated when an innate immune cell detects a pathogen, and then binds to the CIITA gene, allowing CIITA to be expressed (made) by the cell. 7/10

By hijacking IRF3, SARS-CoV-2 can send HDAC2 to the CIITA gene, turning off CIITA while leaving most of the host cells genes running normally. This turns off antigen presentation, while leaving cellular functions used by the virus to replicate itself running normally 8/10

This is rather nefarious approach, as innate immune cells activate IRF3 and send it to the CIITA promoter when they detect pathogens – meaning the virus uses the innate immune cell’s intrinsic anti-viral response against itself! 9/10

Amazingly, SARS-CoV-2 only needs one protein – NSP5 – to hijack antigen presentation. NSP5 binds to HDAC2, and then delivers it to IRF3-bound sites in our genome. This allows HDAC2’s activity to be directed against a select set of genes. Pretty cool (if scary) stuff! /fin