Jacques Deguine

Dysregulated immune responses are at the core of sepsis pathology and can drive both acute organ dysfunction and long-term morbidity and mortality. To better understand the association between specific immune histories, perturbations and sepsis outcomes, we combined immune phenotyping, functional cytokine production assays and antibody repertoire profiling. While sepsis immune profiles were highly heterogeneous, we identified a strong association between the frequency of CXCR3-expressing CD4 memory T cells at time of enrollment and six-month survival in sepsis without shock. Surprisingly, the same population was linked to improved organ function trajectories in septic shock patients but did not influence six-month survival, highlighting the importance of considering physiological states to define immune predictors. Finally, phage display profiling revealed that these Th1 cells were generally expanded in CMV-seropositive individuals, suggesting that previous and latent infections may modulate sepsis outcomes.

Background: Host response and biomarker research to advance sepsis therapeutics requires well-characterized cohorts with longitudinal biospecimens across a range of hosts and infections. Automated screening based on SIRS criteria is sensitive but nonspecific and identifies more candidates than research teams can approach, sample, and follow longitudinally. We evaluated a structured enrichment review by non-physician study staff, done after automated screening in a hospital-wide prospective sepsis cohort. Methods: The CISID cohort is a prospective observational study of hospitalized patients with suspected sepsis, enrolling adults from the ED, inpatient wards, and ICUs at a tertiary academic medical center. Patients were identified through: (1) automated electronic health record screening for two or more SIRS criteria with a 24-hour lookback, documentation of microbiologic culture or PCR, and receipt of a new antibiotic; (2) a sepsis enrichment step of structured chart review by trained non-physician study staff; and (3) discussion with the primary clinical team. Enrolled patients underwent physician adjudication into four diagnostic categories. To evaluate the enrichment step, we analyzed all patients screened during a 9-week period, assigned a composite “sepsis-likely” variable (CDC Adult Sepsis Event criteria or ICD-10 code R65.20/R65.21 within 48 hours before or after screening), and assessed mortality across each stage of screening. We also assessed concordance of the composite with physician adjudication among enrolled patients. Results: From November 2023 through February 2026, 4,318 patients screened in through EHR-based automated screening; 1,220 (28%) were flagged for enrollment, and 288 were enrolled. Physician adjudication classified 209 (73%) as sepsis, 46 (16%) as infection without sepsis, 14 (5%) were classified as undifferentiated critical illness, and 19 (6.6%) as non-infectious sepsis mimics. Patients with sepsis were severely ill (median SOFA score, 9; ICU admission, 80%; shock, 48%), and 51% were immunocompromised; mortality was 14% in hospital and 27% at 90 days. In a 9-week sample of 907 screened encounters, 21% of those deferred and 70% of those flagged for enrollment met the sepsis-likely composite, a 3.3-fold increase in prevalence after structured study team review. Conclusions: A brief structured enrichment review after automated screening tripled the prevalence of EHR-based sepsis indicators among patients selected for enrollment, while concentrating enrollment efforts on roughly one-quarter of screened-in patients in this hospital-wide, all-source suspected-sepsis cohort. This approach may help prospective cohorts direct limited biospecimen resources toward patients most informative for host-response and biomarker research.

Background: Mortality in sepsis is often considered a direct consequence of infection and organ dysfunction, although many deaths occur after withdrawal of life sustaining treatment. The clinical factors leading to these decisions and their implications for interpreting sepsis mortality are not well characterized. Methods: We performed a secondary analysis of a prospective observational cohort of adults with physician adjudicated sepsis at a tertiary academic medical center. Patients who transitioned to comfort measures only (CMO) during the index hospitalization underwent structured chart review to characterize baseline health and functional status, clinical severity, care preferences, anticipated outcomes following survival, and the primary reason for CMO transition. Results: Among 239 patients with adjudicated sepsis, 42 (17.6%) transitioned to CMO. These patients had substantial underlying disease, including malignancy in 76% and immunocompromised status in 62%. However, 88% lived at home before hospitalization, 52% were independent in activities of daily living, an additional 26% were partially independent, and 90% were full code on admission. Progressive multi organ failure (19%), refractory septic shock (19%), and irreversible respiratory failure (12%) accounted for half of CMO transitions, while advanced frailty (5%) and poor baseline functional status (2%) were infrequent primary reasons. Median time from admission to CMO was 16 days (IQR 7 to 33), and median time from admission to death was 18 days (IQR 11 to 35). Anticipated ventilator dependence (62%), dialysis dependence (36%), and cognitive impairment frequently influenced goals of care discussions. Overall, 38 patients died during the index hospitalization, and 35 (92%) of these deaths followed transition to CMO. Conclusions: Most CMO transitions in this cohort occurred after an evolving course of severe sepsis and were driven primarily by progressive organ dysfunction and failure to recover rather than advanced frailty or poor baseline function. These findings identify failure to recover after the acute septic insult as an important clinical trajectory and highlight the need to account for treatment limitation when interpreting sepsis mortality. Understanding why some patients recover from sepsis associated organ dysfunction while others progress to irreversible organ failure may help identify patients and mechanisms for future therapeutic intervention.

Parkinson’s disease (PD) is a movement disorder characterized by the accumulation of alpha-synuclein aggregates leading to dopaminergic neuron loss in the substantia nigra. While PD has been associated with environmental and microbiome changes, our ability to assess the mechanistic impact of these factors on synuclein aggregation in cells has remained limited. Here, we designed and optimized a high-throughput optical screening system to assess the effect of metabolites and small molecules on synuclein aggregation in cell lines expressing a synuclein-fluorescent protein fusion and treated with pre-formed fibrils (PFFs). Using this assay, we identified several compounds that modulate synuclein aggregate accumulation in cells, including harman, a β-carboline that led to reduced synuclein aggregation. We further investigated the transcriptional effect of harman and PFFs and identified changes in peroxiredoxins as a potential mechanism linking harman to aggregate accumulation. Altogether, this work establishes a pipeline to prioritize small molecules that can impact synuclein aggregate formation.

In atopic dermatitis (AD), skin barrier and immune dysfunction result in chronic tissue inflammation, yet our understanding of the tissue ecosystem remains incomplete. Here, we generate a multi-modal census of 280,518 cells from whole skin tissue samples from 17 adults, including 11 AD patients, integrating it with 430,186 cell profiles from four previous studies into a comprehensive human skin cell atlas. Reconstruction of keratinocyte differentiation revealed disrupted cornification in AD associated with signals from an immune and stromal multicellular community – comprising MMP12⁺ and migratory dendritic cells (DCs), cycling innate lymphoid cells (ILC), natural killer cells, inflammatory CCL19⁺ IL4I1⁺ fibroblasts, and clonally expanded IL13⁺IL22⁺IL26⁺ T cells connected by intercellular feedback loops predicted to impact community assembly. Subsets from this community, along with disrupted cornified keratinocytes, were enriched in GWAS, suggesting that dysfunction in this communication network may initiate AD. Our work highlights disease-associated cell subsets and interactions in chronic skin inflammation.

Enteric neurons are essential regulators of intestinal physiology, yet their responses to varying microbial and immune environments along the intestinal tract and or during challenges remain poorly understood. In this study, we regionally profiled enteric neurons across gnotobiotic, allergic, and parasite-infected mice. Timing and complexity of microbial perturbations and type 2 inflammation result in motor neuron state shifts and alter multiple functionally distinct sensory neurons, including interleukin-13– and leukotriene-responsive Nmu -hi cells and Grp -hi neurons, which expand in germ-free colonic tissue and interact with Grpr ⁺ interstitial cells of Cajal. Leveraging adeno-associated virus–based Perturb-seq, we identified Edf1 and Mitf as controllers of motor neuron state transition and gastrointestinal transit time, directly linking enteric neuron states to physiology.

The alpha-variant wave of the COVID-19 pandemic provided a unique opportunity to study, at single-cell resolution, how near-universal exposure to the same pathogen can lead to either effective or dysfunctional immune responses in humans. Although single-cell RNA-sequencing studies have characterized immune cellular features of COVID-19, they have not shown how tocilizumab treatment changes these features at single-cell resolution, or which features might persist into convalescence. In this study, we analyzed 2.5 million circulating immune cells from 428 patients across time points (840 PBMC samples), encompassing three contemporaneous SARS-CoV-2 cohorts: acutely infected patients across five WHO disease severity levels and three time points, patients from the first randomized control trial to study the efficacy of tocilizumab in the management of COVID-19, and convalescent patients three months after infection. We used linear modeling to integrate multiple data types – including single-cell RNA-seq, CITE-seq, TCR and BCR sequencing, viral load measurements, viral neutralization assays, detection of 75 autoantibodies, HLA genotype data, and serum proteomics covering 1,463 targets – to derive the most comprehensive view to-date of the biological features of COVID-19 disease severity. Our findings show that myeloid-derived suppressor cells (MDSCs) act as a key immunologic pivot point in severe COVID-19. Myeloid dysfunction, which is marked by impaired antigen presentation, drives a non-productive adaptive immune response, as reflected by reduced expression of B and T cell gene programs involved in antigen recognition, immune synapse formation, and cytotoxicity. Severe disease is also linked to autoantibodies targeting type I interferons, influenced by specific HLA-DQB1 allelic variants, and strongly correlated with serum IL-6 levels. Tocilizumab treatment eliminates CLU -expressing MDSCs and ISG-positive myeloid subsets, restores antigen presentation, and reactivates productive adaptive immunity. These changes align with improved clinical outcomes and better clinical laboratory measures, including reduced CRP. While many immunologic abnormalities in acute severe COVID-19 resolve during convalescence 3-months post-infection, we observed persistently high ICOS expression in regulatory T cells, potentially linking acute infection to chronic post-COVID syndromes. Overall, we define distinct innate and adaptive host immune responses associated with acute, IL-6–responsive, and convalescent SARS-CoV-2 infection. Our multimodal and high-dimensional dataset with curated clinical metadata provides a foundational and clinically relevant resource for modeling host immune response biology in health and disease.

Genome-wide association studies (GWAS) have linked the locus encoding ankyrin repeat domain 55 (ANKRD55) with numerous autoimmune diseases; however, its biological function and role in inflammation are unclear. Here, we demonstrate that Ankrd55-deficient mice are protected from T cell–mediated colitis but are more susceptible to Citrobacter rodentium infection. Mechanistically, Ankrd55 deletion impairs CD4+ T cell proliferation and reduces effector cytokine production in T helper 17 (TH17) cells in a cell-intrinsic manner. ANKRD55 is associated with mitochondria, and its loss is associated with impaired mitochondrial respiration and activation of the LKB1 pathway. Consistently, IL-17 production can be rescued by the deletion of LKB1 in Ankrd55-deficient T cells. Altogether, our study implicates the protein ANKRD55 as a functional modulator of T cell metabolism that directly impacts TH17 responses, highlighting it as a potential target across multiple autoimmune diseases.