Disseminated coccidioidomycosis (DCM) is caused by Coccidioides , pathogenic fungi endemic to the southwestern United States and Mexico. Illness occurs in approximately 30% of those infected, less than 1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled patients with DCM and performed whole-exome sequencing. In an exploratory set of 67 patients with DCM, 2 had haploinsufficient STAT3 mutations, and defects in β-glucan sensing and response were seen in 34 of 67 cases. Damaging CLEC7A and PLCG2 variants were associated with impaired production of β-glucan–stimulated TNF-α from PBMCs compared with healthy controls. Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were overrepresented in DCM, including CLEC7A Y238* and PLCG2 R268W. A validation cohort of 111 patients with DCM confirmed the PLCG2 R268W, CLEC7A I223S, and CLEC7A Y238* variants. Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1–derived hydrogen peroxide [H ₂ O ₂ ] in transfected cells. Heterozygous DUOX1 or DUOXA1 variants that impaired H ₂ O ₂ production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired β-glucan sensing or response affecting TNF-α and H ₂ O ₂ production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2 , which encodes G _αi2 , a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase–mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G _αi2 mutations had clinical presentations that included impaired immunity. Mutant G _αi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G _αi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)–activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal–regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)–AKT S6 signaling to drive cellular growth and proliferation.

The TB Portals program provides a publicly accessible repository of TB case data containing multi-modal information such as case clinical characteristics, pathogen genomics, and radiomics. The real-world resource contains over 3400 TB cases, primarily drug resistant cases, and CT images with radiologist annotations are available for many of these cases. The breadth of data collected offers a patient-centric view into the etiology of the disease including the temporal context of the available imaging information. Here, we analyze a cohort of new TB cases with available radiologist observations of CTs taken around the time of initial registration of the case into the database and with available follow up to treatment outcome of cured or died. Follow up ranged from 5 weeks to a little over 2 years consistent with the longest treatment regimens for drug resistant TB and cases were registered within the years 2008 to 2019. The radiologist observations were incorporated into machine learning pipelines to test various class balancing strategies on the performance of predictive models. The modeling results support that the radiologist observations are predictive of treatment outcome. Moreover, inferential statistical analysis identifies markers of TB disease spread as having an association with poor treatment outcome including presence of radiologist observations in both lungs, swollen lymph nodes, multiple cavities, and large cavities. While the initial results are promising, further data collection is needed to incorporate methods to mitigate potential confounding such as including additional model covariates or matching cohorts on covariates of interest (e.g. demographics, BMI, comorbidity, TB subtype, etc.). Nonetheless, the preliminary results highlight the utility of the resource for hypothesis generation and exploration of potential biomarkers of TB disease severity and support these additional data collection efforts.

Functional antibody responses to malaria transmission-blocking vaccines (TBVs) are assessed using the standard membrane feeding assay (SMFA). This assay quantifies the percentage reduction of oocyst levels in mosquitoes fed gametocytes mixed with antisera/antibodies, referred to as transmission-reducing activity (TRA). As TBVs advance to large clinical trials, new scalable assays are needed to characterize vaccine responses. Here, we developed an epitope-specific competitive ELISA platform (P230Compete) for TBV candidate Pfs230D1, based on single-chain variable fragments against epitopes recognized by human monoclonal antibodies with high TRA. We quantified functional epitope-specific antibody responses (F) in phase I Pfs230D1-EPA/AS01 vaccine trial participants, using 171 serum samples collected at 2 postvaccination time points. Five antibody features were examined by P230Compete, including total IgG (reported as ELISA units, EU _F ), IgG subclasses (IgG1 _F , IgG3 _F , IgG4 _F ), and bound complement factor C1q (C1q _F ). EU _F and IgG1 _F demonstrated strong correlation and excellent prediction of TRA (≥80%) in logistic regression analysis (AUC of 0.81 for both assays after dose 3, and 0.80 and 0.76 after dose 4). Furthermore, combining EU _F and IgG1 _F showed even better predictive performance at each time point. P230Compete offers a promising proxy assay to replace SMFA in late-stage Pfs230D1 trials.

The evolving legal landscape has increased marijuana accessibility across the United States, including for medical use to manage clinical symptoms among people with HIV. The effects of marijuana use remain understudied in youth with HIV (YWH), who face lifelong antiretroviral therapy (ART) and an elevated risk of developing comorbidities. This study applied a multi-modal approach, including plasma biomarker analysis, peripheral blood cell phenotyping, and transcriptome profiling, to examine the effects of recreational marijuana alone, tobacco alone, or marijuana combined with tobacco in virally suppressed YWH (≤50 RNA copies/mL) on ART compared to youth without HIV and YWH who used no substance. Marijuana use alone was associated with elevated IL-10 levels and normalization of pro-inflammatory genes and pathways, suggesting an immunomodulatory effect. Conversely, tobacco use alone or combined with marijuana was linked to increased IL-1β levels and heightened pro-inflammatory responses, including upregulation of genes involved in inflammasome activation. This study is the first to demonstrate GPR15 upregulation and potential marijuana-associated epigenetic modulation in HIV-suppressed youth. The findings identify potential markers for early detection of inflammation-related comorbidities in YWH, particularly among those exposed to tobacco and underscore the need for targeted profiling to guide personalized monitoring and early substance use intervention strategies for YWH.