Biology subjects

Martinod, K.

Publications and source records attributed to Martinod, K..

3 recordsLinked to original sources

bioRxiv2025

Bacterial suppression of intestinal fungi via activation of human gut γδ T-cells

Gut symbionts condition mucosal immunity to resist infection by enteropathogens, but the specific microbes and mechanisms involved differ significantly between host species. In higher primates, bacterial metabolite HMB-PP is sensed by a specialized population of V{gamma}9V{delta}2+T-cells, which we now report can potently suppress growth of endogenous fungi in human intestinal organ cultures. In healthy intestine, HMB-PP-stimulated V{delta}2+T-cells restricted outgrowth of keystone fungus Candida albicans via a mechanism that required IL-22. In contrast, Crohns disease (CD) patients with reduced V{delta}2+T-cell numbers displayed outgrowth of C. albicans strains that readily formed toxin-producing filaments, triggered neutrophil extracellular traps, and induced macrophage IL-1{beta} release ex vivo. Genomic and proteomic analysis of the Candida isolates suggested increased tissue adhesion of CD-derived strains, which rapidly invaded the gut barrier in an intestine-on-a-chip model. These data reveal that bacterial activation of V{delta}2+T-cells suppresses fungal pathobionts in human gut via an IL-22-dependent mechanism that is dysregulated in CD.

immunology↗

bioRxiv2025

Neutrophil extracellular traps offer a new therapeutic target for elephant endotheliotropic herpes hemorrhagic disease (EEHV-HD)

Elephant survival is threatened by a devastating hemorrhagic disease called elephant endotheliotropic herpes virus-hemorrhagic disease (EEHV-HD). Once clinical signs are observed in elephants, the disease progresses rapidly and frequently results in death. EEHV-HD negatively impacts elephant conservation because very young, reproductively immature elephants are most at risk for death. Ongoing efforts to understand disease pathogenesis and progression may identify treatment targets and improve clinical outcomes. In some lethal EEHV-HD cases, microthrombosis has been observed in organ tissues similar to other hemorrhagic diseases in humans and animals where sticky webs of protein-coated DNA strands called neutrophil extracellular traps (NETs) exacerbate thrombosis and hemorrhage associated with disseminated intravascular coagulation (DIC). In this study, we sought to identify if NET formation occurs in elephants and could contribute to poor outcomes in EEHV-HD. Our study demonstrated NET release for the first time from elephant heterophils (neutrophils) that occurred in response to various stimuli, including plasma from EEHV-HD affected elephants. EEHV-HD affected tissues contained extensive NETs suggesting that dysregulated NET formation contributes to pathogenesis of this disease. Importantly, elephant neutrophils were blocked from releasing NETs in response to EEHV-HD plasma using known NET inhibitors. The ability to stop NETs in EEHV-HD offers a new therapeutic approach that could be combined with current therapies to improve survival for affected elephants and to positively impact conservation efforts.

immunology↗

bioRxiv2022

Neutrophil Peptidylarginine Deiminase 4 is Essential for Detrimental Age-related Cardiac Remodeling and Dysfunction in Mice

AimsWe aimed to study the long-term effect of neutrophils on cardiac health during the process of natural aging. We hypothesized that neutrophil PAD4, via its role in neutrophil extracellular trap (NET) formation, is involved in myocardial remodeling and cardiac fibrosis development, resulting in turn in impaired cardiac function. Methods and resultsWe generated mice with deletion of Padi4, a NET-essential gene, under the neutrophil-specific promoter S100A8 (PAD4fl/flMRP8Cre+). These mice and their littermate controls were aged for two years (coinciding with approximately 70 years of age in humans; the age at which HF is the number one cause of hospitalization), after which cardiac function and remodeling were evaluated. We performed a comprehensive echocardiography analysis including both structural and functional parameter measurements. Deletion of PAD4 in neutrophils resulted in a protection against both systolic, and diastolic dysfunction. Interestingly, these mice showed protection against age induced fibrosis, detected as through the absence of cardiac collagen deposition. To explore this further, cardiac gene expression and plasma cytokine levels were evaluated. Here we saw a clear impact of PAD4-deficiency on cardiac neutrophil recruitment, with both cardiac genes as well as plasma cytokines involved in neutrophil recruitment being downregulated in aged PAD4fl/flMRP8Cre+ animals in comparison to littermate PAD4fl/fl controls, including decreased plasma levels of C-X-C ligand 1 (CXCL1). ConclusionOur data confirms neutrophil PAD4 involvement in heart failure progression by promoting cardiac remodeling, leading to cardiac dysfunction with old age. We saw that the deletion of PAD4 specifically in neutrophils had an influence on the CXCL1-CXCR2 axis, which is known to be involved in HF development. Translational perspectiveIn the developed world, an estimated 2% of the population lives with heart failure (HF). HF can be viewed as an upcoming pandemic, which is only expected to increase due to the aging of the global population. Therefore, research in HF development and progression are needed to establish new avenues for treatment and improved therapies. In our study, we were able to show the contribution of neutrophil PAD4 to HF pathogenesis, providing new supporting evidence for the involvement of NETs in detrimental cardiac remodeling.

physiology↗