Biology subjects

Mortha, A.

Publications and source records attributed to Mortha, A..

11 recordsLinked to original sources

bioRxiv2026

Sequential infection reprograms the immune landscape to shape future responses

Mouse models have been instrumental in defining immune mechanisms but often fail to capture the complexity of human immunity, limiting clinical translation. A major limitation is the immunological immaturity of specific pathogen-free (SPF) mice relative to pathogen-experienced adult humans. Here, we use a sequential infection (SI) model that recapitulates cumulative pathogen exposure and define its impact on immune composition and function. Beyond the previously reported expansion of memory T cells, SI induced durable, system-wide remodeling across lymphoid and non-lymphoid tissues, reshaping innate and adaptive immune populations, tissue-resident immunity, and hematopoietic output. Single-cell transcriptomic analyses revealed inflammatory imprinting of naive CD4 and CD8 T cells, whereas memory T cells acquired enhanced effector programs coupled with reduced biosynthetic activity, transcriptional states that more closely resemble those of pathogen-experienced adult humans. Functionally, SI mice recapitulated the human response to anti-CD28 super-agonist and exhibited altered magnitude and differentiation of acute and chronic antiviral T cell responses, demonstrating that cumulative pathogen exposure reshapes both existing immunity and the generation of future immune responses. Thus, cumulative pathogen exposure coordinately remodels hematopoiesis and naive and memory lymphocyte states, establishing a durable inflammation-experienced immune landscape that reshapes both immune memory and future immune responses, with broad implications for the translational fidelity of preclinical mouse models.

immunology↗

bioRxiv2026

GM-CSF regulates ILC states and myeloid cell signaling during ulceration in Crohns disease

Macrophage (M-), granulocyte (G-), and granulocyte-macrophage (GM-) colony-stimulating factors (CSFs) regulate myeloid cell function, yet their relative roles during inflammation remain poorly defined. To uncover how CSFs shape spatial immune niches in Crohns disease, we performed Xenium single-cell spatial transcriptomics on ileal tissues, revealing cell-type-specific expression and source-target interactions for each CSF. GM-CSF, unlike M-CSF or G-CSF, was locally enriched in ulcerated regions where lymphocytes adjacent to macrophage aggregates signaled through STAT5 phosphorylation. To study functional consequences, we developed a csf2rb-/- zebrafish model of intestinal injury. Using this model, we found that loss of GM-CSF signaling exacerbated epithelial damage and inflammation, whereas recombinant human GM-CSF limited injury by restraining ILC1 expansion, sustaining ILC3 maintenance, and promoting IL-22 production. Cross-species single-cell analysis revealed conserved ILC gene modules and GM-CSF-dependent transcriptional networks linking lymphoid and myeloid populations. These findings establish GM-CSF as a critical spatial regulator of myeloid- lymphoid crosstalk and intestinal immune homeostasis in Crohns disease.

immunology↗

bioRxiv2024

Single-cell transcriptomics reveals colonic immune perturbations during amyloid-β driven Alzheimer's disease in mice

The "gut-brain axis" is emerging as an important target in Alzheimers disease (AD). However, immunological mechanisms underlying this axis remain poorly understood. Using single-cell RNA sequencing of the colon immune compartment in the 5XFAD amyloid-{beta} (A{beta}) mouse model, we uncovered AD-associated changes in ribosomal activity, oxidative stress, and BCR/plasma cell activity. Strikingly, levels of colon CXCR4+ antibody secreting cells (ASCs) were significantly reduced. This corresponded with accumulating CXCR4+ B cells and gut-specific IgA+ cells in the brain and dura mater, respectively. Consistently, a chemokine ligand for CXCR4, CXCL12, was expressed at higher levels in 5XFAD glial cells and in in silico analyzed human brain studies, supporting altered neuroimmune trafficking. An inulin prebiotic fiber diet attenuated AD markers including A{beta} plaques and overall frailty. These changes corresponded to an expansion of gut IgA+ cells and rescued peripheral Tregs levels. Our study points to a key glia-gut axis and potential targets against AD. Study HighlightsO_LIAD is associated with altered immune parameters in the gut of 5XFAD mice. C_LIO_LI5XFAD colon has reduced ASCs, including CXCR4+ cells with a migratory gene signature. C_LIO_LI5XFAD brain gliosis includes increased CXCL12 expression. C_LIO_LICXCR4+ B cells and gut-specific IgA+ ASCs accumulate in the 5XFAD brain and/or dura mater. C_LIO_LIInulin diet attenuates AD disease parameters while boosting IgA+ cell and Treg levels. C_LI

immunology↗

bioRxiv2023

Cell therapy with IL-10-producing group 2 innate lymphoid cells suppresses Graft-versus-Host disease

IL-10 producing group 2 innate lymphoid cells (ILC210) have immunoregulatory functions, and limit harmful immune responses across various tissues. Despite their crucial roles in maintaining immune homeostasis, the cell therapy potential of human ILC210 has not been demonstrated, due to both limited numbers in human peripheral blood and lack of definitive markers for identification. Here, we isolate and expand circulating human ILC210, and assess their cell therapy potential in a humanized model of Graft-versus-Host Disease (GVHD). Cell therapy with human ILC210 decreased GVHD severity and prolonged survival of NOD-scid IL2R{gamma}null (NSG) mice. Adoptive transfer of ILC210 inhibited pathogenic T cell proliferation and intestinal infiltration, and suppressed CD4+ Th1 and CD8+ Tc1 cells in an IL-4 and IL-10 dependent manner. Critically, increased proportions of ILC2s did not correlate with higher rates of cancer relapse in HSCT recipients, and adoptive transfer of ILC210 did not compromise graft-versus-leukemic (GVL) effects in a humanized model. Finally, we identify CD49d and CD86 as novel markers that discriminate ILC210 from conventional ILC2s. Collectively, these findings demonstrate the potential of harnessing ILC210 in cell therapies for GVHD and other immune-driven pathologies.

immunology↗

bioRxiv2023

The commensal protist Tritrichomonas musculus exhibits a dynamic life cycle that induces B cell-modulated remodeling of the gut microbiota

Commensal protists and gut bacterial communities exhibit complex relationships, mediated at least in part through host immunity. To improve our understanding of this tripartite interplay, we investigated community and functional dynamics between the murine protist Tritrichomonas musculus (T. mu) and intestinal bacteria in healthy and B cell-deficient mice. We identified dramatic, protist-driven remodeling of resident microbiome growth and activities, in parallel with T. mu functional changes, accelerated in the absence of B cells. Metatranscriptomic data revealed nutrient-based competition between bacteria and the protist. Single cell transcriptomics identified distinct T. mu life stages, providing new evidence for trichomonad sexual replication and the formation of pseudocysts. Unique cell states were validated in situ through microscopy and flow cytometry. Our results reveal complex microbial dynamics during the establishment of a commensal protist in the gut, and provide valuable datasets to drive future mechanistic studies.

microbiology↗

bioRxiv2022

The protozoan commensal Tritrichomonas musculis is a natural adjuvant for mucosal IgA.

Immunoglobulin(Ig) A antibodies are the most abundant antibodies supporting mucosal immune homeostasis and host-microbiota interactions. Driven by gut commensal microbes, IgA-secreting plasma cells (PC) differentiate through T cell-dependent (Td) or T cell independent (Ti) mechanisms. While commensal bacteria within the microbiota are known for their ability to promote IgA, the role of non-bacterial commensal microbes on the induction of IgA remains elusive. Here, we demonstrate that permanent colonization with the protozoan commensal Tritrichomonas musculis (T.mu) promotes T-cell dependent, IgA class-switch recombination and intestinal accumulation of IgA-secreting PC. T.mu colonization specifically drives the expansion of T follicular helper cells and a unique ICOS+ non-Tfh cell population, accompanied by an increase in germinal center B cells. Blockade of ICOS:ICOSL co-stimulation or MHCII-expression on B cells are central for the induction of IgA following colonization by T.mu, implicating a previously underappreciated mode of IgA induction following protozoan commensal colonization. Finally, the commensal T.mu further improves the induction of IgA-secreting plasma cells and their peripheral dissemination, even against non-protozoan, orally ingested antigens, identifying T.mu as natural adjuvant for IgA. Collectively, these findings propose a previously unknown, protozoa-driven mode of IgA induction that supports intestinal immune homeostasis even against non-microbial antigens.

immunology↗

bioRxiv2022

A gut commensal protozoa remotely shapes a lung niche for asthma-promoting eosinophils.

The gut microbiome influences chronic inflammation of the airways via the gut-lung axis. However, causal connections between microbes and their host, including the underlying mechanisms for this phenomenon remain largely unknown. Here, we show that colonization with the gut commensal protozoa, Tritrichomonas musculis (T.mu), remotely shapes the lung immune landscape and exacerbates allergic airway inflammation. We demonstrate that colonization with T.mu mediates the T and B cell-dependent accumulation and activation of inflammatory group 2 innate lymphoid cells in the lungs to constitute a tripartite immune network that serves as a niche for lung eosinophils. Animals colonized with T.mu show severely exacerbated allergic inflammation in the airways and reveal a new protozoan-driven gut-lung axis that remotely shapes the lung immune network to potentiate chronic pulmonary inflammation. One-Sentence SummaryA gut microbe exacerbates asthma severity by promoting lung eosinophilia through a tripartite lymphocyte immune network.

immunology↗

bioRxiv2022

Microbial Energy Metabolism Fuels a CSF2-dependent Intestinal Macrophage Niche within Tertiary Lymphoid Organs

Maintaining intestinal macrophage (MP) heterogeneity is critical to ensure tissue homeostasis and host defense. The gut microbiota and host factors are thought to synergistically shape colonic MP development, although there remains a fundamental gap in our understanding of the details of such collaboration. Here, we report tertiary lymphoid organs (TLOs), enriched in group 3 innate lymphoid cells (ILC3s), as a microbiota-operated intestinal niche for the development of monocyte-derived MPs. ILC3-derived colony stimulating factor 2 (CSF2) serves as a developmental and functional determinant for MPs and required microbe-derived extracellular adenosine 5-triphosphate (ATP) as a trigger. Microbial communities rich in extracellular ATP promoted MP turnover via ILC3 activity in an NLRP3-dependent fashion. Single cell RNA-sequencing of MPs revealed unique TLO-associated, CSF2-dependent MP populations critical for anti-microbial defense against enteric infection. Collectively, these findings describe a fundamental framework that constitutes an intestinal MP niche fueled by microbial energy metabolism.

immunology↗

bioRxiv2021

NLRP1B and NLRP3 control the host response following colonization by the commensal protist Tritrichomonas musculis.

Commensal intestinal protozoa, unlike their pathogenic relatives, are neglected members of the mammalian microbiome. These microbes have a significant impact on the hosts intestinal immune homeostasis, typically by elevating anti-microbial host defense. Tritrichomonas musculis (T. mu), a protozoan gut commensal, strengthens the intestinal host defense against enteric Salmonella infections through Asc- and Il1r1-dependent Th1 and Th17 cell activation. However, the underlying inflammasomes mediating this effect remain unknown. Here, we report that colonization with T. mu results in an increase in luminal extracellular ATP, elevated levels of IL-1{beta}, and increased numbers of IL-18 receptor-expressing Th1 and Th17 cells in the colon. Mice deficient in either Nlrp1b or Nlrp3 failed to display these protozoan-driven immune changes and lost resistance to enteric Salmonella infections even in the presence of T. mu. These findings demonstrate that T. mu-mediated host protection requires sensors of extra and intracellular ATP to confer resistance to enteric Salmonella infections. KEY POINTSO_LIIntestinal colonization with the commensal Tritrichomonas musculis elevates luminal ATP levels C_LIO_LINLRP1B and NLRP3 activation is required for Tritrichomonas musculis-driven Th cell response. C_LI

immunology↗

bioRxiv2018

Inflammatory bowel disease microbiotas alter gut CD4 T-cell homeostasis and drive colitis in mice

To examine the functional contribution of Inflammatory Bowel Disease (IBD) microbes to immune homeostasis and colitis, we colonized unchallenged and colitis-susceptible germ-free mice with over twenty human intestinal microbiotas from healthy and IBD donors. Compared to healthy microbiotas, IBD microbiotas led to expanded ROR{gamma}t+Th17 cells and reduced ROR{gamma}t+Treg in the gut of unchallenged gnotobiotic mice and increased disease severity in colitis-susceptible mice. The proportions of ROR{gamma}t+Th17 and ROR{gamma}t+Treg induced by each microbiota were highly predictive of the human disease status and strongly correlated with disease severity in colitis-susceptible mice colonized with the same human microbiotas. The transmittable functional potential of IBD microbes suggests a mechanism for a microbial contribution to IBD pathogenesis and a potential route for its treatment and prevention.

immunology↗

bioRxiv2017

Deciphering the combinatorial influence of diet and the microbiota on experimental colitis

Background & AimsThe complex interactions between diet and the microbiota that influence mucosal inflammation and inflammatory bowel disease are poorly understood. Experimental colitis models provide the opportunity to control and systematically perturb diet and the microbiota in parallel to quantify the contributions between multiple dietary ingredients and the microbiota on host physiology and colitis.\n\nMethodsTo examine the interplay of diet and the gut microbiota on host health and colitis, we fed over 40 different diets with varied macronutrient sources and concentrations to specific pathogen free or germ free mice either in the context of healthy, unchallenged animals or colitis models (dextran sodium sulfate (DSS) and T cell transfer).\n\nResultsDiet influenced physiology in both health and colitis across all models, with the concentration of protein and psyllium fiber having the most profound effects. Increasing dietary protein elevated gut microbial density and worsened DSS colitis severity. Depleting gut microbial density by using germ-free animals or antibiotics negated the effect of a high protein diet. Psyllium fiber influenced host physiology and attenuated colitis severity through microbiota-dependent and microbiota-independent mechanisms. Combinatorial perturbations to dietary protein and psyllium fiber in parallel explain most variation in gut microbial density, intestinal permeability, and DSS colitis severity, and changes in one ingredient can be offset by changes in the other.\n\nConclusionsOur results demonstrate the importance of examining complex mixtures of nutrients to understand the role of diet in intestinal inflammation.

microbiology↗