Biology subjects

Kitoko, J. Z.

Publications and source records attributed to Kitoko, J. Z..

3 recordsLinked to original sources

bioRxiv2026

Age-dependent disease tolerance to SARS-CoV-2 infection

Disease tolerance limits infectious disease severity through tissue damage control mechanisms that do not target pathogens directly. Here we demonstrate that age-dependent decline in adipose tissue lipolysis compromises disease tolerance to SARS-CoV-2 infection. Young adult mice exhibited robust adipocyte lipolysis and 80% survival, whereas old mice showed impaired adipocyte lipolysis and only 20% survival. Genetic repression of adipocyte lipolysis eliminated this age-dependent survival advantage without affecting viral titers, revealing that adipocyte lipolysis is essential for disease tolerance to SARS-CoV-2 in young adults. Impaired adipocyte lipolysis in aged mice was associated with a plasma lipidomic signature that predicts COVID-19 severity and mortality in three independent human cohorts. Mechanistically, adipocyte lipolysis provides free fatty acids (FFA) to support bone marrow emergency myelopoiesis, through CD36- and CPT1-dependent FFA cellular uptake and mitochondrial import, respectively. Bone marrow derived monocytes migrate to the lung via CCL2/CCR2-dependent mechanism where they enforce an immune-metabolic communication network with parenchymal cells to sustain lung structure and function. This circuit is not required to confer protection against influenza infection, revealing pathogen-specific disease tolerance mechanisms. These findings reveal adipose tissue catabolism as a central age-dependent factor responsible for exacerbated COVID-19 mortality in aged populations. One-Sentence SummarySARS-CoV-2 infection induces adipose tissue lipolysis to release fatty acids that drive myelopoiesis and monocyte production for lung protection and COVID-19 disease tolerance, but this protective circuit declines with age, increasing disease severity in the elderly.

immunology↗

bioRxiv2025

Disease tolerant mice shelter a pathogenic intestinal microbiota able to trigger lethal disease in low tolerant hosts

Disease tolerance is a defensive strategy that limits tissue damage during infection. Macrophage migration inhibitory factor (MIF)-deficient mice (Mif-/-) are protected in different models of infection and intestinal inflammation due to unclear disease tolerance mechanisms, whereas low disease-tolerant Il10-/-mice develop microbiota-dependent spontaneous gut inflammation. Here, we examined whether IL-10 is required for the phenotype seen in Mif-/-mice and, conversely, the contribution of MIF during IL-10 deficiency. While breeding for double-deficient Mif-/-Il10-/- mice, we unexpectedly observed that Il10-/- individuals died within days after co-housing with Mif-/- mice. We found that healthy Mif-/-hosts endure a highly diverse, unique and dysbiotic-like microbiota composition, including antibiotic-resistant Enterobacteriaceae species, which were sufficient to cause acute and lethal Th1-driven colitis in Il10-/- recipients. The disease was characterized by increased frequencies of IFN{gamma}+ cells and neutrophils within colonic lamina propria. Mif-/-Il10-/-mice died prematurely, and survivors developed communicable disease, - indicating that lack of IL-10 is a dominant trait. These findings suggest that tolerant individuals harbor a gut microbiota enriched in pathogens/pathobionts, which can trigger disease in susceptible hosts.

immunology↗

bioRxiv2021

c-MAF dependent perivascular macrophages regulate diet induced metabolic syndrome

Macrophages are an essential part of tissue development and physiology. Perivascular macrophages have been described in tissues and appear to play a role in development and disease processes, although it remains unclear what are the key features of these cells. Here, we identify a subpopulation of perivascular macrophages in several organs, characterized by their dependence on the transcription factor c-MAF, displaying non-conventional macrophage markers including LYVE1, Folate receptor 2 and CD38. Conditional deletion of c-MAF in macrophage lineages caused ablation of perivascular macrophages in the brain and altered muscularis macrophages program in the intestine. In the white adipose tissue (WAT), c-MAF deficient perivascular macrophages displayed an altered gene expression profile, which was linked to an increased vascular branching into the tissue. Upon feeding on high fat diet (HFD), mice with c-MAF deficient macrophages showed improved metabolic parameters compared to wild-type mice, including less weight gain, greater glucose tolerance and reduced inflammatory cell profile in WAT. These results define c-MAF as a central regulator of perivascular macrophages cell identity and transcriptional program in vivo and reveal a novel role for this tissue resident macrophage population in the regulation of metabolic syndrome.

immunology↗