Biology subjects

Grasberger, H.

Publications and source records attributed to Grasberger, H..

3 recordsLinked to original sources

bioRxiv2024

Inflammation induced Th17 cells synergize with the inflammation-trained microbiota to mediate host-resiliency against intestinal injury

Background and AimsInflammation can generate pathogenic Th17 cells and cause a inflammatory dysbiosis. In the context of Inflammatory Bowel Disease (IBD) these inflammatory Th17 cells and dysbiotic microbiota may perpetuate injury to intestinal epithelial cells (IECs). However, many models of IBD like T-cell transfer colitis and IL-10-/- mice rely on the absence of regulatory pathways, so it is difficult to tell if inflammationcan also induce protective Th17 cells. MethodsWe subjected C57BL6, RAG1-/- or JH-/- mice to systemic or gastrointestinal (GI) Citrobacter rodentium (Cr). Mice were then subject to 2.5% dextran sodium sulfate to cause epithelial injury. Fecal microbiota transfer was performed by bedding transfer and co-housing. Flow cytometry, qPCR, 16s sequencing and histology were used to assess parameters. ResultsTransient inflammation with GI but not systemic Cr was protective from subsequent intestinal injury. This was replicated with sequential DSS collectively indicating that transient inflammation provides tissue-specific protection. Inflammatory Th17 cells that have a tissue resident memory signature expanded in the intestine. Experiments with reconstituted RAG1-/-, JH-/- mice and cell trafficking inhibitors showed that inflammation induced Th17 cells were required for protection. Fecal microbiota transfer showed that the inflammation-trained microbiota was necessary for protection, likely by maintaining protective Th17 cells in situ. ConclusionInflammation can generate protective Th17 cells which synergize with the inflammation-trained microbiota to provide host resiliency against subsequent injury, indicating that inflammation induced Th17 tissue resident memory T cells are heterogenous and contain protective subsets.

immunology↗

bioRxiv2023

IL-15 promotes inflammatory Th17 cells in the intestine

Ulcerative Colitis (UC) is a chronic gastrointestinal condition with high morbidity. While modern medical therapies have revolutionized the care of UC, 10-25% of patients fail medications and still progress to surgery. Thus, developing new treatments is a core problem in UC. T-cells, especially Th17 cells, are strongly linked with UC and are major targets of medications in UC. Tissue-resident memory T-cells (TRM) are a distinct class of T-cells that are highly enriched in the intestine, closely aligned with the microbiota, and are implicated in the pathogenesis of UC. Unlike circulating T-cells, TRM are difficult to target because they do not recirculate. Thus, we focused on cytokines like IL-15 which act as a tissue danger signal and regulate T-cells in situ. We found that the IL15 axis is upregulated in UC and predicts treatment response. IL-15 was redundant for Th17 differentiation but could activate terminally differentiated Th17 cells to promote intestinal inflammation. Finally, in CD4+ TRM from patients with UC, IL-15 upregulated RORC, the master transcription factor for Th17 cells, via a Janus Kinase (JAK)1 pathway. Thus, IL-15 promotes terminally differentiated inflammatory Th17 cells in the intestine raising the possibility that IL-15 may be a target for UC treatments.

immunology↗

bioRxiv2017

Chemotaxis allows bacteria to overcome host-generated reactive oxygen species that constrain gland colonization

The epithelial layer of the gastrointestinal tract contains invaginations, called glands or crypts, which are colonized by symbiotic and pathogenic microorganisms and may function as designated niches for certain species. Factors that control gland colonization are poorly understood, but bacterial chemotaxis aids occupation of these sites. We report here that a Helicobacter pylori cytoplasmic chemoreceptor, TlpD, is required for gland colonization in the stomach. tlpD mutants demonstrate gland colonization defects characterized by a reduction in the percent of glands colonized, but not in number of bacteria per gland. Consistent with TlpDs reported role in reactive oxygen species (ROS) avoidance, tlpD mutants showed hallmarks of exposure to large amounts of ROS. To assess the role of host-generated ROS in TlpD-dependent gland colonization, we utilized mice that lack either the ability to generate epithelial hydrogen peroxide or immune cell superoxide. tlpD gland colonization defects were rescued to wild-type H. pylori levels in both of these mutants. These results suggest that multiple types of innate immune generated ROS production limit gland colonization and that bacteria have evolved specific mechanisms to migrate through this gauntlet to establish in the glands.\n\nClassification: Biological sciences; microbiology\n\nSignificance statementMicrobial colonization of the gastrointestinal tract occurs at distinct sites within the tissue including glandular structures found in the stomach and intestine. Multiple lines of evidence suggest that glands supply niches that promote chronic microbial colonization, a process that is critical for symbiotic and pathogenic bacteria to maintain themselves. In this report, we show that host-produced reactive oxygen species (ROS) constrain gland colonization by the gastric pathogen Helicobacter pylori. A bacterial cytoplasmic chemoreceptor, TlpD, allows H. pylori to avoid ROS and enhances H. pyloris ability to colonize a broad swath of glands. We propose that hosts limit gland access and spread by producing ROS, and bacteria counter with chemotactic responses that allow navigation through this gauntlet.

microbiology↗