Biology subjects

Murzin, E.

Publications and source records attributed to Murzin, E..

4 recordsLinked to original sources

bioRxiv2025

A Multigenerational ''Dirty'' Mouse Model for Studying Trauma-Induced Immune Dysregulation and Infection Susceptibility

Trauma induces immune dysregulation in both humans and mice, increasing infection susceptibility. Mouse models are critical in research but have been criticized for lacking translational relevance. This study tested whether multigenerational "natural immune" (NI) mice - generated by co-housing C57BL/6 mice with "dirty" pet shop mice and breeding through multiple generations - would develop a more human-like immune response to trauma and infection than "clean" specific pathogen-free (SPF) C57BL/6 mice whose immune systems developed without normal flora. To address this gap, SPF and NI mice underwent burn trauma followed by Pseudomonas aeruginosa lung infection. Peripheral blood and bone marrow immune cells were characterized by flow cytometry and mass cytometry (CyTOF). Blood samples from trauma patients were analyzed for comparison. At baseline, NI mice exhibited more neutrophils compared to SPF mice, closer resembling human peripheral immune composition. Following injury, SPF mice demonstrated increased blood neutrophils and monocytes with reduced B and T cells, whereas NI mice exhibited a muted blood immune cell response. In contrast, NI mice showed a robust emergency granulopoiesis response and preserved hematopoietic stem cells (HSCs) following secondary infection, whereas HSCs decreased in SPF mice. Time-matched blood samples from human trauma patients revealed alterations more closely resembling those observed in NI mice. These findings support the hypothesis that NI mice develop a more human-like immune response to trauma and infection than SPF mice. This suggests that NI mice may provide a more translationally relevant platform for studying trauma-induced immune dysfunction and infection susceptibility mechanisms. Summary SentenceMultigenerational natural immune mice exhibit more human-like immune responses to trauma and infection that offer a model with significant translatable advantages for studying post-injury immune dysfunction in patients.

immunology↗

bioRxiv2025

Sub-phenotypes of pneumonia defined by pulmonary histopathological features

Establishing sub-phenotypes of pneumonia based on distinct host processes will be a step towards using host-directed therapies (to complement microbe-directed therapies) more rationally and precisely. Although pneumonia is a pulmonary pathophysiology, histological changes within the lungs have not been leveraged for sub-phenotyping. We addressed this by scoring 18 histopathology features (e.g., type 2 cell hyperplasia or necrosis) across rapid autopsy lung samples from 276 elderly subjects with pneumonia. Machine learning algorithms segregated subjects into seven different sub-phenotypes of pneumonia with distinct histopathology signatures. Quantitative immunofluorescence demonstrated associations of macrophages, neutrophils, T cells, and B cells with select histology features and pulmonary pathology sub-phenotypes. Mouse models revealed corollary sub-phenotypes, although some histology features observed in human lungs were never observed in mice. By illuminating this spectrum of histopathologies and discriminating discrete sub-phenotypes of pneumonia, a foundational framework emerges for developing and using host-directed therapies for subsets of pneumonia patients.

immunology↗

bioRxiv2024

Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis

Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying non-invasive, blood-based pathologic immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation in patients with LN and to identify correlates of renal parameters and treatment response. Unbiased analysis identified 3 immunologically distinct groups of patients with LN that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at one year. Patients with enriched circulating granzyme B+ T cells at baseline showed more severe disease and increased numbers of activated CD8 T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized primarily by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive by immunophenotyping at enrollment but with chronic renal injuries. Main immune profiles could be distilled down to 5 simple cytometric parameters that recapitulate several of the associations, highlighting the potential for blood immune profiling to translate to clinically useful non-invasive metrics to assess immune-mediated disease in LN.

immunology↗

bioRxiv2023

Deep immunophenotyping reveals circulating activated lymphocytes in individuals at risk for rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease with currently no universally highly effective prevention strategies. Identifying pathogenic immune phenotypes in At-Risk populations prior to clinical disease onset is crucial to establishing effective prevention strategies. Here, we applied mass cytometry to deeply characterize the immunophenotypes in blood from At-Risk individuals identified through the presence of serum antibodies to citrullinated protein antigens (ACPA) and/or first-degree relative (FDR) status (n=52), as compared to established RA (n=67), and healthy controls (n=48). We identified significant cell expansions in At-Risk individuals compared with controls, including CCR2+CD4+ T cells, T peripheral helper (Tph) cells, type 1 T helper cells, and CXCR5+CD8+ T cells. We also found that CD15+ classical monocytes were specifically expanded in ACPA-negative FDRs, and an activated PAX5low naive B cell population was expanded in ACPA-positive FDRs. Further, we developed an "RA immunophenotype score" classification method based on the degree of enrichment of cell states relevant to established RA patients. This score significantly distinguished At-Risk individuals from controls. In all, we systematically identified activated lymphocyte phenotypes in At-Risk individuals, along with immunophenotypic differences among both ACPA+ and ACPA-FDR At-Risk subpopulations. Our classification model provides a promising approach for understanding RA pathogenesis with the goal to further improve prevention strategies and identify novel therapeutic targets.

genomics↗