Biology subjects

Rabinovich, S.

Publications and source records attributed to Rabinovich, S..

3 recordsLinked to original sources

bioRxiv2026

Short chain fatty acids potentiate azoles by reprogramming fungal acetyl-CoA metabolism

Pathogens colonise metabolically diverse host environments. How metabolites found in host environments regulate antimicrobial drug susceptibility remains to be fully understood. Here we report on the roles of gut metabolites, short chain fatty acids (SCFAs), in antifungal drug susceptibility of the gut commensal and fungal pathogen Candida albicans. A genetic screen revealed that C. albicans mutants in peroxisome biogenesis display increased tolerance to the antifungal drug fluconazole. Peroxisomes are important for the metabolism of SCFAs by {beta}-oxidation, and exposure to the SCFAs butyrate and crotonate increased susceptibility and reduced tolerance to fluconazole. To understand if SCFAs inhibit fluconazole tolerance through their ability to inhibit histone deacetylases (HDACs), we compared them with the HDAC inhibitor trichostatin A. These experiments did not reveal an obvious connection between the degree of HDAC inhibition and the degree of fluconazole tolerance reduction. Exposure of C. albicans to crotonate and butyrate revealed transcriptional reprogramming involving remodelling of acetyl-CoA metabolism by upregulation of genes for {beta}-oxidation, peroxisome biogenesis and intracellular transport of acetyl-CoA, while the expression of ergosterol biosynthesis genes was reduced. Since ergosterol gene expression is required to overcome fluconazole stress, these results explain how SCFAs reduce fluconazole tolerance. Taken together, our results implicate peroxisome biogenesis and metabolism in fluconazole susceptibility. We posit that balanced acetyl-CoA metabolism promotes sufficient ergosterol biosynthesis to overcome fluconazole stress and drive tolerant growth. These pathways are perturbed by metabolic changes induced by SCFAs. These findings add to our understanding of the importance of metabolic regulation in antimicrobial drug responses. SIGNIFICANCEMetabolites produced by microbiota or host cells regulate microbial metabolism, physiology and drug responses. In the gut, the human commensal and pathogen Candida albicans is exposed to short-chain fatty acids made by bacteria. C. albicans metabolises short-chain fatty acids via peroxisomal {beta}-oxidation. Additionally, short-chain fatty acids change gene expression by inhibiting histone deacetylases. We found that short-chain fatty acids increase the susceptibility of C. albicans to the antifungal drug fluconazole and reduce fluconazole tolerance. Our mechanistic studies indicate that metabolic utilisation of short-chain fatty acids by C. albicans reduces fluconazole tolerance by changing acetyl-CoA metabolism and causing lower expression of ergosterol biosynthesis genes. Thus, short-chain fatty acids increase fluconazole susceptibility by changing fungal metabolism, while inhibition of histone deacetylases may play a more minor role. These findings shed light on the roles of metabolism and abundant gut metabolites in tolerance to a front-line antifungal drug.

microbiology↗

bioRxiv2022

RORc expressing immune cells support pro-tumorigenic functions of tertiary lymphoid structures

Tertiary lymphoid structures (TLSs) are formed in many cancer types and have been correlated with better prognosis and response to immunotherapy. In liver cancer, TLSs have been reported to be pro-tumorigenic as they harbor tumor progenitor cells and nurture their growth. The processes involved in TLS development and the acquisition of a pro- or anti-tumorigenic phenotype in cancer are largely unknown. RORc expressing immune cells have been previously implicated in TLS formation, however we find that they are not necessary for TLS neogenesis in the context of inflammation-associated liver cancer. On the contrary, RORc expressing cells negatively regulate TLS formation, since in their absence TLSs form in excess. CD4 cells are essential for liver TLS formation whereas B cells are required for TLS formation specifically in the absence of RORc expressing cells. Importantly, in chronically inflamed livers lacking RORc expressing cells, TLSs become anti-tumorigenic, resulting in reduced tumor load. Comparing liver pro- and anti-tumorigenic TLSs by transcriptional, proteomic and immunohistochemical analyses, revealed enrichment of exhausted CD8 cells that retained effector functions as well as germinal center B cells and plasma cells in anti-tumorigenic TLSs. Cell depletion experiments revealed a role mainly for B cells in limiting tumor development, possibly via tumor directed antibodies. Thus, RORc expressing cells negatively regulate B cell responses, and facilitate the pro-tumorigenic functions of hepatic TLSs. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/498540v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@385067org.highwire.dtl.DTLVardef@126c45corg.highwire.dtl.DTLVardef@25ad06org.highwire.dtl.DTLVardef@1829326_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Sex- and context-dependent effects of acute isolation on vocal and non-vocal social behaviors in mice

Humans are extraordinarily social, and social isolation has profound effects on our behavior, ranging from increased social motivation following short periods of social isolation to increased anti-social behaviors following long-term social isolation. Mice are frequently used as a model to understand how social isolation impacts the brain and behavior. While the effects of chronic social isolation on mouse social behavior have been well studied, much less is known about how acute isolation impacts mouse social behavior and whether these effects vary according to the sex of the mouse and the behavioral context of the social encounter. To address these questions, we characterized the effects of acute (3-day) social isolation on the vocal and non-vocal social behaviors of male and female mice during same-sex and opposite-sex social interactions. Our experiments uncovered pronounced effects of acute isolation on social interactions between female mice, while revealing more subtle effects on the social behaviors of male mice during same-sex and opposite-sex interactions. Our findings advance the study of same-sex interactions between female mice as an attractive paradigm to investigate neural mechanisms through which acute isolation enhances social motivation and promotes social behavior.

animal behavior and cognition↗