Clinical Research and Public Health
Abstract
BACKGROUND. Malaria caused by Plasmodium malariae is geographically widespread and sometimes associated with prolonged infection, yet little is known about its genomic epidemiology. METHODS. We performed hybrid capture and whole genome sequencing of 77 isolates collected from Cameroon (n=7), the Democratic Republic of the Congo (n=16), Nigeria (n=4), and Tanzania (n=50) between 2015 and 2021, and analyzing parasite genetic population structure and demography. RESULTS. There is no evidence of geographic population structure. Nucleotide diversity was significantly lower than in co-localized P. falciparum isolates, while linkage disequilibrium was significantly higher. Genome-wide selection scans identified no erythrocyte invasion ligands or antimalarial resistance orthologs as top hits; however, targeted analyses of these loci revealed evidence of selective sweeps around four erythrocyte invasion ligands and six antimalarial resistance orthologs. Demographic inference modeling suggests that African P. malariae is recovering from a bottleneck. CONCLUSION.P. malariae is genomically atypical among human Plasmodium spp. and lacks strong population structure in Africa. The low diversity has potential impacts on understanding persistent versus new infection through genomic epidemiology.
Authors
Zachary R. Popkin-Hall, Kelly Carey-Ewend, Farhang Aghakhanian, Eniyou C. Oriero, Misago D. Seth, Melchior M. Kashamuka, Billy Ngasala, Innocent M. Ali, Eric Mukomena SOMPWE, Celine I. Mandara, Oksana Kharabora, Rachel Sendor, Alfred Simkin, Alfred Amambua-Ngwa, Antoinette Tshefu, Abebe A. Fola, Deus S. Ishengoma, Jeffrey A. Bailey, Jonathan B. Parr, Jessica T. Lin, Jonathan J. Juliano
Abstract
BACKGROUND. Chimeric antigen receptor T-cell (CAR-T) therapies have revolutionized treatment for relapsed/refractory multiple myeloma (RRMM). However, cytokine release syndrome (CRS), a common and potentially severe complication, requires inpatient monitoring, limiting access and increasing costs. Wearable devices could support outpatient CAR-T delivery, but feasibility for CRS detection versus standard care remains unproven. METHOD. We conducted a prospective, single-center observational pilot study to assess the feasibility of using wearable devices for monitoring vital signs and detecting CRS. Thirty patients receiving idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel) were enrolled; 25 with sufficient monitoring data were evaluable. Sensors collected skin and axillary temperature, oxygen saturation, respiratory and heart rate, and motion. Peripheral blood cytokines were analyzed pre- and post-infusion using a multiplex proteomic platform. The primary outcome was feasibility, assessed by CRS detection sensitivity and specificity; secondary outcomes included adherence, lead time, and performance of models integrating wearable and cytokine data. RESULTS. CRS occurred in 20 of 25 patients. The best-performing wearable model detected 18 or 20 CRS episodes with a sensitivity of 0.72 (mean 0.75; 95% CI 0.60–0.91) and a specificity of 0.80 (mean 0.76; 95% CI 0.68–0.84), and a median lead time of 7:00 hours before nursing recognition. Median adherence during high-risk periods was 71%. Cytokine changes paralleled temperature elevations, and IFN-γ emerged as a consistent biomarker. CONCLUSION. Wearable devices are feasible for early CRS detection and may support outpatient CAR-T care. Larger outpatient studies are warranted. TRIAL REGISTRATION. This study did not meet the criteria for ClinicalTrials.gov registration.
Authors
Sridevi Rajeeve, Matt Wilkes, Nicole Zahradka, Lewis Tomalin, Mujahid Quidwai, Darren Pan, Nicholas J. Calafat, Martin Cusack, Adolfo Aleman, Kseniya Serebryakova, Katerina Kappes, Hayley Jackson, Sarita Agte, Santiago Thibaud, Larysa Sanchez, Shambavi Richard, Joshua Richter, Cesar Rodriguez, Hearn Jay Cho, Ajai Chari, Sundar Jagannath, Alessandro Laganà, Adriana C. Rossi, Samir Parekh
Abstract
BACKGROUND. Asparaginase is essential for curing acute lymphoblastic leukemia (ALL), but its use is limited by asparaginase-associated pancreatitis (AAP), a severe and unpredictable toxicity lacking validated prospective biomarkers. We sought to define early systemic molecular features of susceptibility to AAP. METHODS. We performed longitudinal lipidomic and proteomic profiling in two independent pediatric ALL cohorts (n = 161; 79 AAP cases, 82 controls) using paired blood samples collected before asparaginase exposure and at the end of induction therapy (including a single dose of asparaginase), thereby capturing pre-injury biology rather than consequences of pancreatitis. We applied differential abundance and network-based analyses, and integrated lipid–cytokine associations using proteomics. RESULTS. Across cohorts, we identified a reproducible lysophosphatidylcholine (LPC)–centered signature characterized by attenuated induction therapy-associated LPC responses and disruption of LPC co-regulation at the network level. Proteomic profiling revealed enrichment of cytokine signaling pathways, and integrative analyses demonstrated altered lipid–cytokine coupling, including a flip in association direction for LPC species and interleukin-18 (IL-18) between cases and controls. Although IL-18/LPC ratios do not differ globally, elevated post-induction IL-18/LPC ratios identify AAP risk within a protocol-defined very high-risk ALL subgroup (AUC = 0.81). CONCLUSION. These findings support a systems-level model in which failure of coordinated lipid–immune responses under therapeutic stress confers vulnerability to AAP, providing a framework for validation and mitigation strategies. TRIAL REGISTRATION. NCT00400946; NCT01574274; NCT03020030 (parent trials). FUNDING. Servier Pharmaceuticals (IIT-95014-027-USA); SDRC (P30DK116074); Stanford SPARK; Fonds de Recherche du Québec – Santé; Fondation Charles-Bruneau; The Leukemia & Lymphoma Society of Canada.
Authors
Cheng-Yu Tsai, Na Bo, Thai Hoa Tran, Maisam Abu-El-Haija, Gayathri Swaminathan, Bomi Lee, Sudhir Ghandikota, Li Wen, Yves Théorêt, Steven D. Mittelman, Elena J. Ladas, Anil G. Jegga, Lewis B. Silverman, Ying Ding, Sohail Z. Husain
Abstract
Enhancing NAD+ levels with nicotinamide riboside (NR) confers anti-inflammatory effects in human disease, although immunoregulatory mechanisms remain poorly characterized. We previously showed that ex vivo NR supplementation of primary CD4+ T cells from psoriatic individuals dampened immune responsiveness. To validate this in vivo, we performed a randomized, placebo-controlled NR supplementation study in individuals with mild-to-moderate psoriasis. Participants received oral NR (500 mg twice daily) or matching placebo for 4 weeks, with blood samples collected at baseline and after supplementation. NR reduced Th17 immune responsiveness. Bulk CD4+ T cell RNA-seq identified induction of the SLIT-ROBO signaling pathway. NR supplementation increased circulating SLIT2 levels and enhanced SLIT2 production in dermal fibroblasts. Pharmacologic and genetic interrogation in CD4+ T cells and fibroblasts demonstrated that SLIT2, acting through the ROBO1 receptor, inhibited Rho GTPase signaling, thereby attenuating canonical Th17 polarization and fibroblast inflammatory activation. These findings indicate that NAD+ augmentation exerts anti-inflammatory effects in psoriasis through SLIT2-ROBO1-mediated crosstalk between dermal fibroblasts and circulating CD4+ T cells, leading to suppression of Th17-driven inflammation.
Authors
Kim Han, Rachael J. Klein, Thomas C. Recupero, Anna Chiara Russo, Rahul Sharma, Anand K. Gupta, Shahin Hassanzadeh, Rebecca D. Huffstutler, Pradeep K. Dagur, Bryan Fisk, Neelam R. Redekar, Michael N. Sack
Abstract
Background Cancer accounts for over 20% of late post-transplant mortality, yet the contribution of genetic susceptibility to post-transplant cancer risk remains unclear. This study investigates germline genetic risk factors for post-transplant cancer in the Finnish population using data from the FinnGen cohort. Methods A pan-cancer polygenic risk score (PRS) was constructed using genetic variants identified in UK and US populations to assess the influence of common germline variants on time to first cancer diagnosis in 1,802 Finnish kidney transplant recipients (KTRs), of whom 317 developed post-transplant cancer. The PRS was first validated in the FinnGen non-transplantation cohort and subsequently applied to KTRs, with replication in lung and liver transplant recipients (n = 476). Functional relevance was explored by assessing associations between the PRS and expression levels of 2,923 plasma proteins in the UK Biobank (n = 53,013). Results Compared to a matched non-transplantation cohort (n = 68,294), KTRs exhibited earlier cancer onset. The PRS was significantly associated with time to first cancer diagnosis in the non-transplantation population (HR 1.04; 95% CI 1.038-1.056; p = 3.75 x 10-25). Among KTRs younger than 40 years, higher PRS was associated with earlier cancer onset (HR, 1.08; 95% CI ,1.01-1.17; p = 0.036), indicating a stronger genetic effect at younger ages. The PRS significantly (Bonferroni < 0.05) altered the regulation of 87 plasma proteins, several of which were known cancer-related markers. Conclusion Inherited genetic predisposition, captured by pan-cancer PRS, may contribute to individual susceptibility to cancer after solid organ transplantation, particularly at younger ages.
Authors
Jarmo Ritari, Kati Hyvärinen, Kirsi Jahnukainen, Jukka Partanen, Ilkka Helanterä, Timo Jahnukainen
Abstract
BACKGROUND. IL-7 is a critical cytokine in T cell development, survival, and homeostasis. Previous preclinical and clinical studies reported that IL-7 treatment increased T cell counts, but its effect on peripheral blood T cells in cancer patients and molecular mechanisms have not been explored. METHODS. We investigated effects of long-acting recombinant human interleukin-7 (rhIL-7-hyFc) on peripheral T cells in patients with advanced solid tumors. Peripheral blood samples were collected before and after treatment, followed by analysis through single-cell transcriptomics and flow cytometry. RESULTS. We found that rhIL-7-hyFc induced marked expansion of proliferating T cells, and promoted transcriptional changes associated with immune activation, cell cycle progression, and anti-apoptosis. Trajectory analysis revealed that post-treatment T cells had distinct transcriptional states enriched for cytokine- and TCR-mediated signaling pathways. Notably, a second dose administered after three weeks yielded diminished proliferation and minimal transcriptional changes, which were independent of antidrug antibody or CD127 downmodulation. Examination of elements of the IL-7 signaling pathway revealed intact proximal signaling (e.g., STAT5 phosphorylation) but downregulation of distal elements, including PIM-1 kinase and c-Myc. CONCLUSIONS. Our results demonstrate that rhIL-7-hyFc induces robust peripheral T-cell expansion and activation in patients with solid tumors, supporting its potential use for lymphopenic patients treated with cancer immunotherapy. TRIAL REGISTRATION. NCT03478995, NCT03619239. FUNDING. NRF-2022R1A2C3007292, RS-2024-00439160, RS-2025-02213409, RS-2025-25460003
Authors
Ho Cheol Jang, Jeong Yeon Kim, Sojeong Kim, Heewon Kim, Mi-Sun Byun, Myung Ah Lee, Jong Hee Chang, Do-Hyun Nam, Tae Won Kim, Sin-Soo Jeun, Joohyuk Sohn, Su-Hyung Park, Eui-Cheol Shin
Abstract
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 of subjects 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 peripheral blood mononuclear cells 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 ~25% of DCM patients had a CD4+ T-cell compartment that was abnormally skewed toward a Th2 phenotype, and Th2 skewing was highly correlated with male sex. Co-culture of T cells with the IL4R/IL13R-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 IL4R in Th2-skewed patients with refractory coccidioidomycosis.
Authors
Timothy J. Thauland, Smriti S. Nagarajan, Alexis V. Stephens, Samantha L. Jensen, Anviksha Srivastava, Miguel A. Moreno Lastre, Terrie S. Ahn, Chantana Bun, Michael T. Trump, Royce H. Johnson, George R. Thompson III, Maria I. Garcia-Lloret, Valerie A. Arboleda, Manish J. Butte
Abstract
Background. Coccidioidomycosis 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, though 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. Methods. From a cohort of over 300 subjects 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. Results. Male sex was significantly associated with disseminated disease (odds ratio 2.5; 95% CI: 1.5 – 4.0). 52% of subjects showed Coccidioides-specific T cell responses in our AIM assay. We noted a significant difference in subjects sampled in the first year of diagnosis, where only 8% of DCM subjects had T cell responses during this time, as compared to 44% of UVF subjects (p = 0.04). Among DCM patients with detectable AIM responses, CD4+ T cells demonstrated an exhausted phenotype with elevated PD-1 expression compared to UVF subjects. In vitro PD-1 blockade augmented IFNγ production in most tested DCM subjects. Conclusion. These 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.
Authors
Gregory D. Whitehill, Alexis V. Stephens, Timothy J. Thauland, Miguel A. Moreno Lastre, Matthew M. Tate, Sinem Beyhan, Royce H. Johnson, George R. Thompson III, Maria Garcia-Lloret, Manish J. Butte
Abstract
BACKGROUND In chronic alcohol consumers, immune cells may drive the progression from mild liver injury to more severe alcohol-associated liver diseases (ALD), including alcohol-associated hepatitis (AAH) and cancer. Liver macrophages, both resident and infiltrating, express Allograft Inflammatory Factor 1 (AIF1), which is upregulated during inflammation and enhances immune activation. METHODS Using serum and urine samples from 868 individuals classified as having alcohol use disorder or not based on DSM-IV/V criteria, along with serum and liver biopsy tissue from a second cohort of 27 patients diagnosed with AAH, we evaluated the impact of the AIF1 promoter single nucleotide polymorphism (SNP) (rs3132451; C/C, C/G, G/G) on liver function markers and immune cell profiles. RESULTS AIF1 transcript levels were genotype-dependent: C/C homozygotes expressed 5.2% of the levels observed in G/G individuals, while C/G heterozygotes expressed 46%. Unlike most SNPs associated with harmful effects, the G/G genotype is highly prevalent, present in ~70% of patients. Among chronic alcohol users, G/G individuals exhibited elevated markers of liver injury and a more than threefold increase in hepatic immune cells, including infiltrating AIF1⁺ macrophages and neutrophils. Despite similar durations of alcohol misuse, G/G individuals had higher Model for End-Stage Liver Disease scores compared to C/G individuals, indicating a significantly greater 90-day mortality risk. Notably, some immune abnormalities, such as elevated neutrophils, persisted in G/G males even after alcohol abstinence. CONCLUSION These findings suggest that functional genetic variation in AIF1 may contribute to the severity and persistence of ALD. TRIAL REGISTRATION ClinicalTrials.gov NCT02231840. FUNDING Research support was provided from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) of the National Institutes of Health (NIH) under grant 1ZIAAA000440-02 and R24AA025017.
Authors
Priscila C. Antonello, Colin A. Hodgkinson, Dechun Feng, Cheryl Marietta, Baskar Mohana Krishnan, Maria A. Parra, Zhaoli Sun, Bin Gao, David Goldman, Michelle W. Antoine
Abstract
Introduction: BK polyomavirus (BKV) infection is associated with injury and subsequent graft loss due to the extent of injury or rejection. However, the molecular mechanisms driving injury and subsequent adverse outcomes remain poorly understood. Methods: In a cross-sectional study, single-cell RNA sequencing from kidney allograft biopsies was used to assess cell type-specific responses between uninfected controls and two distinct phases of BKV infection: peaking (increasing viral blood titers) and resolving (decreasing viral titers following immunosuppression reduction). Results: Genes upregulated in BK viral nephropathy (BKVN) were enriched for polyomavirus infection hallmarks, including ribosome biogenesis, translation, and energy restructuring. Additionally enriched pathways included wound healing, cellular stress, antigen presentation and immune signaling. Even without BKVN (peaking BK viremia alone), epithelial cells expressed signatures for wound healing, cellular stress, and extracellular matrix remodeling. In vivo tubular cell responses at single-cell resolution were validated against single cell transcriptomic data of BKV infected cells in a cell culture model. Despite similarities, in vivo tubular cells underwent metabolic adaptation favoring fatty acid oxidation and proinflammatory responses not observed in culture models likely due to an absent innate and adaptive immune system. Despite lymphopenia and immunosuppressive therapies, the proportion of recipient derived intrarenal adaptive immune cells was increased in biopsies associated with peaking viremia alongside activation of innate immune responses. Adaptive immune cells exhibited persistent inflammatory signaling and remodeling of energy metabolism during the resolving phase of infection. Conclusion: These not previously reported insights into BKV-associated injury may have implications for clinical management and improved allograft outcomes.
Authors
Tess Marvin, Rachel Sealfon, Phillip J. McCown, Fadhl AlAkwaa, Evan A. Farkash, Edgar A. Otto, Felix Eichinger, Ping An, Rajasree Menon, Celine C. Berthier, Tavis J. Reed, Paula Arrowsmith, Lalita Subramanian, Kelly J. Shaffer, Silas P. Norman, Ramnika Gumber, Michael J. Imperiale, James M. Pipas, Olga G. Troyanskaya, Matthias Kretzler, Chandra L. Theesfeld, Abhijit S. Naik
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