Biology subjects

Tomalka, J. A.

Publications and source records attributed to Tomalka, J. A..

5 recordsLinked to original sources

bioRxiv2026

Preexisting chronic infection skews the epigenetic landscape of subsequent memory CD8 T cell responses

Previous studies suggest that preexisting chronic disease impairs immune responses to subsequent infection and vaccination. However, the underlying epigenetic mechanisms are understudied. Here, we show that preexisting chronic infection with LCMV clone 13 (CL13) compromised the formation of central memory CD8 T cells (TCM) to subsequent Listeria monocytogenes infection, despite not profoundly impacting effector responses. This correlated with a skewed cytokine milieu. Our chromatin-accessibility profiling of Listeria-specific CD8 T cells showed significant epigenetic skewing of both TCM and effector memory (TEM) in mice with preexisting LCMV-CL13, a skewing that started in memory-precursor effector cells (MPECs) during the effector phase. Transcription-factor binding sites (TFBS) analyses highlighted the interferon regulatory factor (IRF) family as major TFs implicated in this skewing. Thus, our results suggest that preexisting persistent inflammation skews the phenotypic and epigenetic landscape of subsequent memory responses, arguing for interventions to optimize vaccine-induced memory in hosts with preexisting chronic disease.

immunology↗

bioRxiv2026

Interleukin-6 restricts pre-thymic T cell lineage commitment of progenitors driving loss of SIV control

Effective T cell reconstitution in people living with HIV is central to durable immune control and cure strategies. Sustained thymic output underpins T cell recovery and requires continuous seeding by T cell-committed progenitors originating in the bone marrow (BM). Using the SIV/rhesus macaque model, we identified a thymus-seeding progenitor (TSP; CD4-CD8-CD34CD38-CD7) in BM declining rapidly following SIV infection. This loss closely associated with reduction in T cell lineage committed differentiation of BM-derived hematopoietic stem and progenitor cells (HSPCs). Importantly, both the decline in TSPs and the impairment of pre-thymic T cell potential were strongly associated with early loss of viral control, independent of peripheral T cell dynamics. Plasma interleukin-6 (IL-6) levels robustly predicted the magnitude of TSP loss and the restriction of T cell-biased HSPC differentiation. Integrated transcriptomic and proteomic analyses revealed inflammatory imprinting of HSPCs characterized by activation of the IL-6-JAK-STAT axis, inflammasome engagement, and coordinated suppression of key T cell specification factors, including RUNX1, FYN, and ZAP70. In a nonanimal model of thymopoiesis, IL-6 exposure of rhesus macaque and human HSPCs inhibited their transition from DN1 (CD38-) to DN2 (CD38) TSP states, indicating an early block in T cell lineage commitment. Conversely, ex vivo IL-6 receptor blockade restored thymocyte differentiation to levels comparable to untreated controls. Collectively, these findings demonstrate that pathogenic inflammation restricts pre-thymic T cell development early after infection, directly contributing to loss of viral control. These findings have important implications for understanding the mediators of anti-viral T cell immunity and HIV cure.

immunology↗

bioRxiv2026

Clinical and Cross-Domain Validation of an LLM-Guided, Literature-Based Gene Prioritization Framework

BackgroundWe previously published a literature-based pipeline for sepsis gene prioritization (PS3 and candidate genes) using an LLM-enabled retrieval and judging framework. Here, we extend that work to ask whether these prioritized genes show independent clinical validity and whether the same strategy generalizes to a drug-obesity- infection setting. MethodsUsing the original LLM-guided workflow, we evaluated PS3 and the Candidate set in two new settings. First, we tested 28-day mortality prediction in the independent VANISH sepsis trial, benchmarking PS3 and Candidate against two established immune signatures--the Severe-or-Mild (SoM) signature and Immune Health Metric (IHM)--under a uniform logistic-regression framework with clinical covariates. Second, we applied the same genome-wide screening and tiered judging pipeline to GLP-1/obesity/infection biology centered on semaglutide, comparing Tier-1 and Tier-2 gene sets to STEP trial serum proteomics at gene and Hallmark pathway levels. In parallel, we fine-tuned an open-weight GPT-OSS-20B model on curated sepsis justifications to obtain a domain-aware "LLM-as-judge," and compared its scoring behavior with the base model on semaglutide Tier-2 genes. ResultsIn the full VANISH cohort, PS3 and the Candidate set showed moderate discrimination, whereas SoM remained the strongest single predictor of 28-day mortality. In the Critical/High APACHE II subgroup, PS3 achieved ROC and precision-recall performance comparable to, or slightly better than, SoM despite its smaller, knowledge-derived composition, indicating that literature-prioritized genes capture mortality-relevant immune dysregulation under severe illness. In the semaglutide case study, gene-level overlap between LLM-prioritized genes and differentially abundant serum proteins was modest, but Tier-1 genes recapitulated the main semaglutide-responsive metabolic programs from STEP and highlighted additional immune-metabolic pathways relevant to infection, with discordances largely explained by serum proteome coverage. The fine-tuned judge remained moderately concordant with the base GPT-OSS across mechanistic themes, preserving overall ranking while inducing systematic, biologically interpretable shifts in immune and infection-related scores. ConclusionsAn LLM-guided, literature-based gene prioritization framework yields compact gene sets that show independent sepsis mortality signal and pathway-level concordance in a semaglutide/obesity/infection setting, while a sepsis-aware LLM-as-judge provides domain-specific refinements without overturning core rankings. Together, these findings support knowledge-grounded, LLM-derived gene sets and judges as interpretable components for probing immune dysregulation across diseases and therapies. Short abstractWe previously published a literature-based pipeline for sepsis gene prioritization (Priority Set 3, PS3, and a Candidate set) using an LLM-enabled retrieval and judging framework; here, we test whether these prioritized genes show independent clinical validity and whether the same strategy generalizes to a drug-obesity-infection setting. Using the original workflow, we first evaluated 28-day mortality prediction in the independent VANISH sepsis trial, benchmarking PS3 and the Candidate set against two established immune signatures--the Severe-or-Mild (SoM) signature and Immune Health Metric (IHM)--within a uniform logistic-regression framework adjusted for clinical covariates. In the full cohort, PS3 and Candidate showed moderate discrimination, while SoM remained the strongest single predictor; however, in the Critical/High APACHE II subgroup, PS3 achieved ROC and precision-recall performance comparable to, or slightly better than, SoM despite its smaller, knowledge-driven composition, indicating that literature-prioritized genes capture mortality-relevant immune dysregulation under severe illness. We then applied the same genome-wide screening and tiered judging pipeline to GLP-1/obesity/infection biology centered on semaglutide, comparing Tier-1 and Tier-2 genes with STEP trial serum proteomics; although gene-level overlap with differentially abundant proteins was modest, Tier-1 genes recapitulated key semaglutide-responsive metabolic programs and highlighted additional immune-metabolic pathways relevant to infection, with discordances largely attributable to serum proteome coverage. Finally, supervised fine-tuning of an open-weight GPT-OSS model on curated sepsis justifications yielded a domain-aware "LLM-as-judge" that remained broadly concordant with the base model while inducing systematic, interpretable shifts in immune and infection-related scores. Together, these results support LLM-guided, literature-based gene sets and judges as compact, mechanistically interpretable components for probing immune dysregulation across diseases and therapies.

bioinformatics↗

bioRxiv2025

A combination TLR7/8 and RIG-I agonist adjuvant reverts asthmatic allergic sensitization and prevents aggravated influenza infection in OVA-sensitized mice.

Allergen-specific immunotherapy (AIT) is the only disease-modifying treatment currently available to treat allergy. However, it has limitations, as most allergens are poorly immunogenic, resulting in an AIT process that can take years. Therefore, adjuvant selection becomes critical to achieve a more efficacious therapy. Our group has developed and tested an amphiphilic TLR7/8 agonist (IMDQ) and a RIG-I agonist (SDI) that used alone, or in combination, have demonstrated strong adjuvant activity for influenza and SARS-CoV-2 vaccines in preclinical models. Here we describe the effect of these adjuvants in the sensitization of preclinical models with the ovalbumin (OVA) asthmatic allergic model via an in-depth humoral and cellular immune profiling. We assess their immune skewing and tolerance inducing capacities in previously sensitized preclinical models with different genetic backgrounds (C57BL/6 vs. BALB/c mice). Moreover, we evaluate their effect in an unrelated antigenic challenge with influenza. Finally, we investigate the role of IgG subclasses and T-cell subpopulations in the protection against OVA challenge conferred by the combination of IMDQ and SDI. We demonstrate that OVA-immunization in combination with IMDQ+SDI prevents allergic sensitization via the induction of a balanced Type 1/Type 2 response. Furthermore, it can revert the allergic phenotype in mice previously sensitized with OVA-Alum, through reducing lung eosinophilia, as well as IL-4 and IL-5 production. However, this was dependent on genetic background. IMDQ+SDI sensitization also led to reduced morbidity of a secondary influenza challenge in OVA-sensitized mice. Finally, we demonstrated that IgG2c, by itself, cannot protect from allergic sensitization and that both CD4+ and CD8+ T-cells are needed for IMDQ+SDI prevention of eosinophil recruitment and activation upon intranasal OVA-challenge.

immunology↗

bioRxiv2021

IL-10 driven memory T cell survival and Tfh differentiation promote HIV persistence

Mechanisms regulating HIV persistence are complex and not well understood. Increased IL-10 levels were positively associated with HIV reservoir in blood and lymph nodes (LN) of treated HIV aviremic individuals. In LNs, B cells, regulatory T cells, follicular T helper cells (Tfh), monocytes and macrophages contributed to the frequencies of IL10+ cells. Cells with HIV DNA in LNs were in close proximity to IL-10+ cells and/or had the active form of STAT3, the transcription downstream of IL-10. Gene signatures and proteins associated to cell survival, Co-inhibitory receptors expression, maintenance of memory T cells, immune metabolism and Tfh frequencies were all modulated by IL-10 and associated with HIV reservoir persistence. In vitro, STAT3 knockout or neutralization of IL-10, reverted all the aforementioned pathways and resulted in 10-fold decay in HIV reservoir. Collectively, these results provide strong evidence for a pivotal role of IL-10 in HIV persistence, and a potential therapeutic strategy for HIV cure.

immunology↗