Thanks! We think the TBK1 (likely IFN-dependent) restriction therefore happens at assembly (post RNA replication anyway) but we never followed that up…it’d be cool to define that though and find out what happens to all that viral RNA 😀

Thanks Natalia! The most important starter pack of all 😉

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Thanks Jesse! Please add me :)

Huge thanks to all of the people who contributed to this project including my fantastic lab, brilliant collaborators and the imaging and microscopy experts at IMB, UQ because seeing is believing.

Our study sheds light on how our favourite innate immune sentinel cells trigger inflammation and control virus infections.

We think all of those ACE2-neg macrophages will instead respond to neighbouring infected cells cell.com/cell-host-mi...,

These ACE2-pos macs CAN make new infectious virions, BUT, all those anti-viral cytokines the macs make stop new virion release. If we block cytokine induction with a TBK1 inhibitor (BX795) then we rescue ACE2-pos mac virus production.

But SARS-CoV-2 can enter ACE2-pos macs (maybe even fuse at the plasma membrane) AND trigger macrophage cytokine release.

Macrophages are of course big eaters, and we saw some virus in ACE2-neg HMDM, but we speculate it doesn’t make it into the cytosol to trigger macrophage sensors. Accordingly, ACE2-neg macs don’t make any cytokines.

Huge scRNA seq efforts from many groups found macrophages with lots of viral RNA in COVID-19 patients, but not many macrophages expressing ACE2.
So, we modelled some ACE2-neg (incl. HMDM) and ACE2-pos macs and saw that SARS-COV-2 only replicates in ACE2-pos Macs (THP-1 ACE2).

Macrophages are key players in COVID-19, so we asked the crucial questions 1) does SARS-CoV-2 need ACE2 to replicate in macrophages 2) does ACE2 enable macrophage cytokine responses?