Biology subjects

Sorrentino, R.

Publications and source records attributed to Sorrentino, R..

3 recordsLinked to original sources

bioRxiv2025

Mycobacterium tuberculosis diversity and macrophage heterogeneity dictate phagosomal acidification

Therapies counteracting pathogen-induced immune modulation of the host responses represent a promising improvement for tuberculosis treatments. Despite the documented role of host immune heterogeneity and bacterial genotypic background in determining infection outcomes, their interplay remains largely uncharacterized. We investigate the Mycobacterium tuberculosis (MTB)-human macrophage interaction considering both macrophage phenotypic variability and MTB genetic diversity. Using single-cell techniques, we show how diverse MTB lineages fine-tune phagosome acidification differently based on macrophage phenotype (M1, M2), revealing very heterogeneous host-pathogen interactions. Our findings underscore the multiplicity of outcomes due to the combinatorial interplay between MTB lineages and macrophage phenotypes, which may have implications in proper design for host-directed therapies. IMPORTANCEThe intricate interplay among host, pathogen, and environmental factors significantly contributes to susceptibility and clinical presentation of tuberculosis. These multifaceted mechanisms are often overlooked in tuberculosis studies, hindering our comprehensive understanding of infection progression and impeding the development of effective host-directed therapies which offer benefits such as reduced drug resistance emergence and heightened host compatibility. Contrary to the prevailing hypothesis, the results observed in this study demonstrate the nuanced response of different M. tuberculosis lineages within distinct macrophage phenotypes in terms of phagosome acidification. The findings of our investigation delineate a crucial yet under-characterized aspect of tuberculosis pathogenesis, emphasizing how the interactions between different M. tuberculosis lineages and macrophage phenotypes could significantly influence the efficacy of host-directed therapies, particularly those targeting phagolysosomal maturation. More broadly, recognizing the impact of both M. tuberculosis and macrophage heterogeneity is paramount in the development of effective strategies to combat tuberculosis.

microbiology↗

bioRxiv2025

Altered endothelial mitochondrial Opa1-related fusion in mouse amplifies age-associated vascular and kidney damages

BackgroundCardiovascular diseases are the major cause of death worldwide and their frequency increases with age in association with progressive kidney damages. Endothelial cells (ECs) are early affected in cardiovascular diseases. Although energy production in ECs involves glycolysis, endothelial mitochondria play a role in modulating cellular signalling. A reduction in fusion protein Opa1 level in ECs decreases the vascular response to flow and increased oxidative stress in perfused kidneys. Thus, we hypothesized that reduced Opa1 expression contributes to vascular aging. MethodsWe used male and female mice with ECs specific Opa1 knock-out (EC-Opa1), and littermate wild-type (EC-WT) mice aged 6 (young) and 20 months (old). Mesenteric resistance arteries (MRA) and kidneys were collected for vascular reactivity and Western-blot analysis. ResultsIn old EC-Opa1 mice blood urea was greater than in age-matched EC-WT mice and MRA showed hypercontractilty and reduced endothelium-dependent relaxation. In kidneys, the mitochondria fission protein Fis-1 and the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (Pgc-1) were increase in old EC-Opa1 mice. The level of eNOS expression was greater in young EC-Opa1 mice and caveolin-1 expression greater in old EC-Opa1 mice. Moreover, in kidneys from EC-Opa1 old mice, NADPH-oxidase subunits gp91, p47 and p67 expression was greater than in age-matched EC-WT mice. No difference was observed between old and young EC-WT mice. ConclusionReduced mitochondrial fusion in mouse ECs altered mesenteric vascular reactivity and increased oxidative stress in aging kidneys. Thus, Opa1 might protect the vascular tree in target organs such as the kidney during aging.

physiology↗

bioRxiv2022

A short ERAP2 that binds IRAP is expressed in macrophages independently from gene variation

The M1 zinc metalloproteases ERAP1, ERAP2 and IRAP play a role in HLA-I antigen presentation by refining the peptidome either in the ER (ERAP1 and ERAP2) or in the endosomes (IRAP). They have been also entrusted with other, although less defined, functions such as the regulation of the angiotensin system and blood pressure. In humans, ERAP1 and IRAP are commonly expressed. ERAP2 instead has evolved under balancing selection that maintains two haplotypes one of which undergoing RNA splicing leading to nonsense-mediated decay and loss of protein. Hence, likewise in rodents in which the ERAP2 gene is missing, about a quarter of the human population does not express ERAP2. We report here that macrophages, but not monocytes or other mononuclear blood cells, express and secrete an ERAP2 shorter form independently from the haplotype. The generation of this "short" ERAP2 is due to an autocatalytic cleavage within a distinctive structural motif and requires an acidic microenvironment. Remarkably, ERAP2 "short" binds IRAP and the two molecules are co-expressed in the endosomes as well as in the cell membrane. Of note, the same phenomenon could be observed in some cancer cells. These data prompt to reconsider the role of ERAP2 which might have been maintained in humans because fulfilling a relevant function as "short" form in specialized cells.

biochemistry↗