1/ In this first @SciImmunology paper (immunology.sciencemag.org/content/6/62/e…), we show that at least 1% of men younger than 60 years with life-threatening COVID-19 are sick because of X-linked recessive (XR) TLR7 deficiency.
2/ In an unbiased burden test, we found TLR7 as the most significant hit on the X chromosome; with very rare (MAF<10e-4) nonsynonymous variants found in patients with critical COVID-19, but not in patients with asymptomatic/mild infection. 
3/ By testing all known TLR7 variants, we found that only 4 of the 8 previously reported TLR7 variants in COVID-19 patients are LOF, and that the cumulative MAF of LOF variants in men in the general population is < 6.5x10e-4.
4/ Among relatives of index cases, XR TLR7 deficiency shows high but not complete penetrance for severe and critical COVID-19 pneumonia; young age seems to confer some protection.
5/ The immunological mechanism involves the disruption of TLR7-dependent virus sensing by plasmacytoid dendritic cells (pDCs), which are the most potent type I IFN-producing cells of the human body.
6/ An unbiased genetic approach therefore brings us back to type I IFN, in line with our previous candidate gene approach that had focused on TLR3-dependent type I IFN influenza susceptibility genes (science.sciencemag.org/content/370/65…).
7/ While TLR3 governs type I IFN tonic levels in pulmonary epithelial cells (PECs) but not pDCs, TLR7 controls the induction of type I IFNs in pDCs but not PECs. Both type I IFN pathways and both cells are thus required to control SARS-CoV-2.
8/ This study reports the long-awaited evidence that any TLR7 is essential in natural conditions of infection.
9/ The human TLR7 locus was known to be under negative selection since 2009 (journals.plos.org/plosgenetics/a… ) but no viral diseases had been documented in patients with IRAK4 or MYD88 deficiency. (annualreviews.org/doi/abs/10.114…).
10/ It also suggests that pDCs are essential for protective immunity. XR TLR7 deficiency is therefore an experiment of nature that clarifies the ecologically relevant and evolutionarily selected function of both TLR7 and pDCs.
11/ Huge thanks to @takaki0908, @Boisson_Bebo, @tutu_ZQ and @AurelieCobat who led this new CHGE effort (covidhge.com), with the fantastic collaboration of
@panomics, @alexbolze, @ALNeehus, @amara_lab, @anne_puel, @BeziatV, @BigioBenedetta, @BoissonDupuis...
@panomics, @alexbolze, @ALNeehus, @amara_lab, @anne_puel, @BeziatV, @BigioBenedetta, @BoissonDupuis...
12/ @BrodinPetter, @BustamanteJaci1, @danipleguezuelo, @felipereye, @IladAlavi, @JouanguyE, @JRosain, @JulianRojasSilv, @LabCflores, @LaurentAbel4, @ldnotar, @Marce_MoncadaV, @ocabreramarante, @panhammarstrom, @pelham_simon, @PhilippotQ, @PujolLab, @SanRaffaeleMI...
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