Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10^-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.

Background. Mortality rates for disseminated coccidioidomycosis remain high despite modern antifungal therapies, resulting in substantial costs to society. We propose that immunomodulation as an adjunctive therapy with antifungals can improve clinical outcomes. Previous work suggested that treatment with interferon gamma or by blocking the IL-4/IL-13 receptor with dupilumab could improve clinical outcomes. Methods. We present a case series of 18 patients at UCLA with severe or persistent coccidioidomycosis receiving maximal antifungal treatment who received immunomodulatory therapy. Treatment selection based on the clinical context and intracellular cytokine staining that measured T helper cells producing interferon gamma or IL-4. Patients with severe disease received recombinant interferon gamma, while those showing Type-2 immune dysregulation were treated with dupilumab. Results. Patients receiving dupilumab showed a reduction in Type-2 T-cell responses. Importantly, 16 of the 18 patients survived (88%), with clinical outcomes improving relative to baseline in the majority. Conclusions. This case series provides evidence that patients with severe and/or disseminated coccidioidomycosis may benefit from immunomodulation. These positive outcomes support the consideration of off-label use of these medications. Clinical trials are warranted for interferon gamma in severe disease and dupilumab for disseminated disease when Type-2 immune dysregulation is present. Further research is needed to identify the specific patient populations that may benefit most from the addition of immunomodulatory medications.

BACKGROUND: Disseminated coccidioidomycosis (DCM) is an often fatal and otherwise intractable condition requiring lifelong antifungal treatment. We have previously shown that a deranged polarization of CD4 ⁺ T cells toward a Th2 phenotype can exist in the context of DCM. Here, we studied a large population to determine the frequency of abnormal Th2 skewing of CD4 ⁺ T cells in patients with coccidioidomycosis and to identify underlying genetic mechanisms supporting this phenotype. METHODS: We collected PBMCs from 204 patients with coccidioidomycosis, including 96 patients with disseminated disease. We measured immune phenotypes and cytokine production by CD4 ⁺ T cells from patients and healthy controls, and comparisons between groups were made based on disease severity and demographics. Whole-genome sequencing was conducted on 180 individuals who also had cytokine profiling. RESULTS: We found that approximately 25% of patients with DCM had a CD4 ⁺ T cell compartment that was abnormally skewed toward a Th2 phenotype, and Th2 skewing was highly correlated with male sex. Coculture of T cells with the IL-4R/IL-13R–blocking antibody dupilumab reduced Th2 skewing. Sequencing revealed rare variants in genes involved in the IL-12/IFN-γ axis in several Th2-skewed patients, and we validated one such variant in IFNGR1 as hypomorphic. CONCLUSION: Patients with DCM, especially males, should be screened for Th2 skewing of CD4 ⁺ T cells. Patients with Th2 skewing should be additionally screened for genetic defects in the IL-12/IFN-γ axis. Our findings give a mechanistic rationale for blockade of IL-4R in Th2-skewed patients with refractory coccidioidomycosis. FUNDING: National Institute of Allergy and Infectious Diseases/NIH grants R21 AI149654 and U19 AI166059 and University of California Office of the President grant VFR-19-633386.

Mitochondria, which have critical roles in energy metabolism and oxidative regulation, also have a role in immune regulation including T cell activation, NET formation, inflammation, and apoptosis. More than 50% of those with systemic lupus erythematosus (SLE) have lupus nephritis due to kidney damage from immune complex deposition. Disease severity is reported to be greater in certain lineages. Mitochondrial DNA (mtDNA) haplogroups, which reflect maternal lineages, may modulate immune balance and disease outcomes in SLE. Methods: DNA was extracted from 25 consecutive, consenting pediatric patients that fulfilled the 1997 criteria for SLE and their maternal mitochondrial DNA (mtDNA) haplogroups were determined through next-generation sequencing (NGS). Results: This study evaluated the associations between mtDNA haplogroups, lupus nephritis, and organ damage in four mtDNA haplogroups: African (n = 5), Amerindian (n = 12), Asian (n = 4), and Caucasian (n = 4). Clinical data, SLE Disease Activity Index (SLEDAI-2K), SLICC Damage Index (SDI), and renal biopsy findings were analyzed. Median SLEDAI-2K scores were higher in Amerindian (10) and African (8) patients than in the Caucasian (5.5) and Asian (3) groups, with significant differences between Amerindian vs. Caucasian (p = 0.045) and Amerindian vs. Asian (p = 0.008). Irreversible organ damage (SDI > 1) was more frequent in Amerindian (54%) and African (40%) patients. Lupus nephritis occurred most often and most severely (Class III–IV, CKD) in the Amerindian (85%) and African (80%) groups, while Caucasian and Asian patients more often showed milder, membranous disease without CKD. Conclusion: Although limited by the small sample size, pediatric SLE severity and renal involvement were found to be greater in Amerindian and African mtDNA haplogroups, suggesting that mitochondrial lineage may contribute to ethnic disparities in SLE.

BACKGROUNDCoccidioidomycosis ranges from self-limiting uncomplicated Valley fever (UVF) in most cases to life-threatening disseminated coccidioidomycosis (DCM) in rare individuals. A few patterns of immunologic deficits allowing for dissemination have been identified, although the specific defects in most individuals with DCM remain undefined. We hypothesized that chronic antigen exposure in DCM engenders a state of T cell exhaustion.METHODSFrom a cohort of over 300 individuals with confirmed diagnoses of coccidioidomycosis, circulating T cell phenotypes were characterized via flow cytometry and Coccidioides-specific T cell responses were measured by activation-induced marker (AIM) assay.RESULTSMale sex was significantly associated with disseminated disease (OR 2.5, 95% CI 1.5-4.0). A majority (52%) of individuals showed Coccidioides-specific T cell responses in our AIM assay. We noted a significant difference in patients sampled in the first year of diagnosis, where only 8% of patients with DCM had T cell responses during this time, as compared with 44% of individuals with UVF (P = 0.04). Among DCM patients with detectable AIM responses, CD4+ T cells demonstrated an exhausted phenotype with elevated PD-1 expression compared with UVF individuals. In vitro PD-1 blockade augmented IFN-γ production in most tested individuals with DCM.CONCLUSIONThese findings suggest that dissemination may occur in some individuals during a period of impaired antigen-specific T cell activity. Importantly, these responses can be augmented in vitro by PD-1-blocking antibodies, supporting further study of immune checkpoint therapy as an adjunct to antifungal treatment in disseminated coccidioidomycosis.FUNDINGNational Institute of Allergy and Infectious Diseases grants U19 AI166059 and R21 AI149654 and University of California Office of the President grant VFR-19-633386.

Coccidioidomycosis, also known as Valley Fever, is a fungal disease endemic to the Americas that kills hundreds annually, yet the host factors that lead to increased risk of life-threatening dissemination of coccidioidomycosis remain poorly understood. We assembled the largest comprehensively sequenced coccidioidomycosis cohort to date, comprising 795 individuals with laboratory confirmed coccidioidomycosis and clinical disease severity phenotyping, many with paired whole blood genomic and transcriptomic data. Individuals with greater than 50% African genetic ancestry have increased risk for disseminated coccidioidomycosis (DCM) cases (OR=13.37, p=1.08×10⁻¹⁸), reflecting ancestry-associated differences in allele frequencies at immune loci. Transcriptomic profiling (n=267) revealed upregulation of interferon-inducible genes IFI44 and IFI44L , the fungal recognition receptor CLEC4D , and pro-inflammatory protein S100A12 , with sex-specific expression differences in immune cell composition. Gene-burden testing identified NOD-like receptor NLRX1 as the only gene carrying significantly more damaging rare variants than expected by chance (p=5.85×10⁻⁴). We identified a rare missense variant, NLRX1 p.Arg252Trp (rs145644388), in five patients with DCM that represents a founder variant: all carriers share African local genetic ancestry and carry 0.6–1.1 centimorgans of identical-by-descent sequence, indicating origin from a common ancestor. In gnomAD, NLRX1 p.Arg252Trp shows has higher allele frequency in African (AF=0.00615) compared to European (AF= 2.25x10 ^-5 ) populations, directly linking this rare variant to population-level African genetic ancestry enrichment in DCM. NLRX1 disruption impairs LC3-associated phagocytosis, an antifungal mechanism in macrophages. Together, these findings reveal both immune gene expression dysregulation and rare-variant architectures associated with African genetic ancestry underlying severe coccidioidomycosis and identify new targets for risk stratification and treatment. Highlights: Patients with disseminated coccidioidomycosis are significantly more likely to have African genetic ancestry. Whole-blood transcriptomics identifies upregulation of interferon-inducible genes IFI44 , IFI44L , and fungal pattern-recognition receptor CLEC4D in disseminated disease. Rare missense variants in NLRX1 , a mitochondrial NOD-like receptor involved in LC3-associated phagocytosis, are significantly enriched in disseminated cases by gene-burden testing. Context and Significance: Valley fever (coccidioidomycosis) is a fungal infection endemic to the southwestern United States that causes life-threatening disseminated disease in a small fraction of those infected. The biological determinants underlying why some develop severe, disseminated infection remains poorly understood. Epidemiological studies have noted that individuals of African American or Filipino background face disproportionately higher risk for severe disease, but these studies relied on self-reported race, a social construct that is not biologically based. By assembling the largest genomically characterized Valley Fever cohort to date and using genome sequencing to directly quantify genetic ancestry, we show that genetic variation that is more common in populations with African ancestry is associated with risk for dissemination. We further identify disruption of interferon signaling and LC3-associated phagocytosis — a cellular mechanism by which macrophages contain fungal infections — as likely contributors to severe disease. These findings open new avenues for risk stratification and potential therapeutic targeting in this neglected fungal infection.