Biology subjects

Furtado, G. C.

Publications and source records attributed to Furtado, G. C..

5 recordsLinked to original sources

bioRxiv2024

Heterozygosity for Crohn's Disease Risk Allele of ATG16L1 Protects against Bacterial Infection

The T300A substitution in ATG16L1 associated with Crohns Disease impairs autophagy, yet up to 50% of humans are heterozygous for this allele. Here we demonstrate that heterozygosity for the analogous substitution in mice (Atg16L1T316A), but not homozygosity, protects against lethal Salmonella enterica Typhimurium infection. One copy of Atg16L1T316A was sufficient to enhance cytokine production through inflammasome activation, which was necessary for protection. In contrast, two copies of Atg16L1T316A inhibited the autophagy-related process of LC3-associated phagocytosis (LAP) and increased susceptibility. Macrophages from human donors heterozygous for ATG16L1T300Adisplayed elevated inflammasome activation while homozygosity impaired LAP, similar to mice. These results clarify how the T300A substitution impacts ATG16L1 function and suggest it can be beneficial to heterozygous carriers, providing an explanation for its prevalence. One-Sentence SummaryHeterozygosity of Crohns diseases risk variant ATG16L1 T300A confers protection against bacterial infections.

immunology↗

bioRxiv2021

Enteric pathogens induce tissue tolerance and prevent neuronal loss from subsequent infections

The enteric nervous system (ENS) controls several intestinal functions including motility and nutrient handling, which can be disrupted by infection-induced neuropathies or neuronal cell death. We investigated possible tolerance mechanisms preventing neuronal loss and disruption in gut motility after pathogen exposure. We found that following enteric infections, muscularis macrophages (MMs) acquire a tissue-protective phenotype that prevents neuronal loss and dysmotility during subsequent challenge with unrelated pathogens. Bacteria-induced neuroprotection relied on activation of gut-projecting sympathetic neurons and signaling via {beta}2-adrenergic receptors ({beta}2AR) on MMs. In contrast, helminth-mediated neuroprotection was dependent on T cells and systemic production of interleukin (IL)-4 and -13 by eosinophils, which induced arginase-expressing MMs that prevented neuronal loss from an unrelated infection located in a different intestinal region. Collectively, these data suggest that distinct enteric pathogens trigger a state of disease- or tissue tolerance that preserves ENS number and functionality.

immunology↗

bioRxiv2018

Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1 infected individuals

Herein, we present the first human study of anti-4{beta}7 therapy in a cohort of HIV-1 infected subjects with mild inflammatory bowel disease. 4{beta}7+ gut homing CD4+ T cells are early viral targets and contribute to HIV-1 pathogenesis, likely by seeding the gastrointestinal (GI) tract with HIV. Although, simianized anti-4{beta}7 monoclonal antibodies (Mab) have shown promise in preventing or attenuating the disease course of SIV in Non-Human Primate studies, the mechanisms of drug action remain elusive and the impact on HIV-1 persistence remains unanswered. By sampling the immune inductive and effector sites of the GI tract, we have discovered that anti-4{beta}7 therapy led to a significant and unexpected attenuation of lymphoid aggregates, most notably in the terminal ileum. Given that lymphoid aggregates serve as important sanctuary sites for establishing and maintaining viral reservoirs, their attrition by anti-4{beta}7 therapy has important implications for HIV-1 therapeutics and eradication efforts, and defines a rational basis for the continued evaluation of anti-4{beta}7 therapy in HIV-1 infection.\n\nOne Sentence SummaryAnti-4{beta}7 integrin therapy results in attrition of lymphoid aggregates within the gastrointestinal tract of HIV-1 infected individuals

immunology↗

bioRxiv2018

Interleukin 22 mediates interleukin 23-induced pathology in newborn mice by disrupting the function of intestinal and pancreatic cells

Mice expressing IL-23 constitutively in the intestine or skin fail to grow and die prematurely. These phenotypes are associated with marked changes in the levels of circulating cytokines and with changes in the transcriptome of the pancreas and intestine. Marked changes are observed in the expression of molecules involved in digestion and absorption of carbohydrates, proteins, and lipids, resulting in a malabsorptive condition. Genetic ablation of IL-22, or one of the subunits of the IL-22R in mice expressing IL-23, restores normal growth and increases the life span of the animals. Mechanistically, IL-22 acts directly at the level of pancreatic acinar cells to decrease expression of the pancreas associated transcription factor 1a (Ptfla), an important transcription factor controlling expression of genes encoding pancreatic enzymes, and acinar cell identity. The results indicate that dysregulated expression of IL-23 and IL-22 has severe consequences in newborns and reveal an unsuspected role for IL-22 in controlling pancreatic enzyme secretion and food absorption.

immunology↗

bioRxiv2018

Diet Modifies Colonic Microbiota and CD4+ T cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23

A wealth of experimental data points to immunological and environmental factors in the pathogenesis of inflammatory bowel disease (IBD). Here we study the role of IL-23, the microbiome, and the diet in the development of colitis. To promote IL-23 expression in vivo, we generated a mouse model in which IL-23 was conditionally expressed by CX3CR1+ myeloid cells, upon cyclic administration of tamoxifen in a specific diet (diet 2019). IL-23 expression induced an intestinal inflammatory disease that resembled ulcerative colitis in humans with cycles of acute disease and remission. The relapses were caused by the diet switch from the conventional diet used in our facility (diet 5053) to the diet 2019, and were not dependent on tamoxifen after the first cycle. The switch in the diet modified the microbiota, but did not alter the levels of IL-23. Colitis induction depended on the microbiota and required CD4 T lymphocytes. Colitis-inducing CD4+ T cells were found in the mesenteric lymph node and large intestine during remission and were able to trigger disease when transferred to lymphopenic mice, but only upon diet modification. The CD4 TCR repertoire in the diseased recipient Rag-/- mice had reduced diversity associated with the expansion of dominant T cell clones. These findings reveal a critical role for IL-23 in generation of a CD4+ T cell population in mice that is sensitive to a modification of intestinal bacterial flora subsequent to a dietary manipulation. Dietary changes occurring in the context of altered IL-23 expression may contribute to the onset and progression of IBD.

immunology↗