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pathogenesis. The CXorf21 protein product, known as TASL, binds SLC15a4, another gene with SLE-risk alleles, on the surface of the endolysosome. Methods We used CRIPR-Cas to knock down expression of CXorf21 (TASL) in primary monocytes, B cells and T cells. We studied lysomomal pH using LysoSensor Yellow/Blue DND-160 and pHrodo Red. We measured cytokines by ELISA of cell culture supernats. We used an assay for NADP/NADPH conversion to determine whether TASL is a short chain dehydrogenase. Finally, we typed SLE subjects and controls for the lupus-associated single nucleotide polymorphism within CXorf21.Results Knock out of Slc15a4 abrogates TLR7 signaling. Our data demonstrate that CRISPR-cas knock down of TASL expression renders lysosomal pH more alkalotic, which should impair TLR7 signaling.Furthermore, in immune cells expressing TASL (monocytes and B lymphocytes), lysosomal pH was lower in female cells compared to male cells. In female B lymphocytes or monocytes, CRISPR-cas knock down of TASL expression markedly reduced cytokine secretion in response to TLR7 ligand engagement. The TASL protein has several features suggesting it is a short chain dehydrogenase. Our functional studies indicate that TASL catalyzes conversion of NADP to NADPH. Genetic studies demonstrate synergistic interaction among CXorf21 and Slc15a4 for SLE risk. Conclusions The CXorf21 gene is differentially expressed in female and male immune cells based on escape from X inactivation and is critical for lysosomal pH and TLR7 signaling. Risk of SLE may be enhanced among individuals with risk alleles at both CXorf21 and Slc15a4. Sex bias in SLE is attributable to an X chromosome dose effect, which may be mediated in part by CXorf21 and its protein product TASL.
Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity.BackgroundWe find that a number of IFN pathway lupus risk alleles significantly impact mortality following COVID-19 infection. These data support the idea that type I IFN pathway risk alleles for autoimmune disease may persist in high frequency in modern human populations due to a benefit in our defense against viral infections.Translational SignificanceWe develop multivariate prediction models which combine genetics and known biomarkers of severity to result in greatly improved prediction of mortality in acute COVID-19. The specific associated alleles provide some clues about key points in our defense against COVID-19.
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