Biology subjects

Herit, F.

Publications and source records attributed to Herit, F..

4 recordsLinked to original sources

bioRxiv2026

The lysosomal glutamine transporter SLC38A7/SNAT7 modulates SAMHD1 antiviral activity and promotes HIV-1 production in human macrophages

HIV-1 (Human Immunodeficiency Virus type 1) infects macrophages, which resist to the cytopathic effects of the virus and are considered as viral reservoirs. However, the cellular factors involved in viral production by human macrophages have not been fully identified. In this study, we focused on the amino acid transporter SNAT7 (small neutral amino-acid transporter 7), member of the SLC38 solute carrier family, which is the main lysosomal transporter of glutamine from the lysosome to the cytoplasm. Its expression was increased by HIV-1 infection. We revealed that the absence of SNAT7 inhibited viral production not only at the level of protein synthesis, but also early at the level of reverse transcription, without affecting global RNA or protein synthesis in the cells. The reduction in HIV expression upon SNAT7 depletion correlated with a reduction in the levels of an inactive form of the SAMHD1 (SAM domain- and HD domain-containing protein) restriction factor and was rescued following SAMHD1 degradation. Lastly, supplementation of the extracellular medium with glutamine in the absence of SNAT7 partially restored viral production. Together, our data reveal that glutamine extracted from lysosomes is involved in the early stages of the HIV-1 cycle and that the SNAT7 glutamine transporter acts as a dependency factor for HIV-1 in human macrophages.

microbiology↗

bioRxiv2025

The unique lipopolysaccharide composition of Salmonella Typhimurium ST313 dampens pyroptosis and inflammasome activation and suppresses host cell death

In humans, non-typhoidal Salmonella (NTS) serovars, such as Salmonella enterica Typhimurium cause self-limiting gastroenteritis. However, invasive non-typhoidal Salmonella (iNTS) isolates ST313 have emerged in sub-Saharan Africa that cause a severe bacteremia in immunocompromised individuals including HIV-positive adults. Despite a decade of studies comparing ST313 to the classical diarrheal S. Typhimurium ST19 pathovariant, the molecular basis of the differences of pathogenesis between these bacteria remains unclear. Here we used primary human macrophages infected with the invasive S. Typhimurium ST313 D23580 isolate and the reference ST19 4/74 isolate as an in vitro model of infection. Transcriptomic profiling revealed that primary human macrophages infected with ST313 bacteria had distinct patterns of host cell death and inflammation responses compared to ST19-infected cells. Specifically, infection with ST313 isolate induced significantly less pyroptotic cell death which was associated with minimal processing of Gasdermin-D. We discovered that S. Typhimurium ST313 stimulated reduced IL-1{beta} release and a low-level activation of the upstream inflammasome signaling cascade with reduced Caspase-4 and Caspase-1 cleavage. To investigate the molecular basis of this phenotype we purified lipopolysaccharide (LPS) species from ST313 to identify physical properties and structures that were distinct from ST19 LPS. The ST313-derived LPS was less pro- inflammatory than LPS from ST19, mirroring the low inflammatory phenotype of the live bacteria. Together, our data reveal that the unique LPS of ST313 is responsible for the reduced level of pyroptosis in human macrophages. This phenotype is consistent with the intracellular persistence and dissemination of these pathogenic bacteria. AUTHOR SUMMARYNon-typhoidal Salmonella (NTS) is a foodborne microbial pathogen that causes a self- limiting gastroenteritis in humans. However, in recent decades invasive non-typhoidal Salmonella (iNTS) isolates have emerged in sub-Saharan Africa, and are currently causing severe bloodstream infections responsible for about 66,000 deaths each year, largely in immunocompromised individuals. To investigate differences in pathogenicity between iNTS and NTS strains, we studied the infection of primary human macrophage with an iNTS ST313 isolate from Malawi in comparison to a gastroenteritis-associated ST19 reference strain. Primary macrophages play a key role in clearing Salmonella infections by recognizing bacterial components such as lipopolysaccharide (LPS). LPS induces immune responses including activation of cytokine release, inflammation and host cell death for effective bacterial elimination. Our study revealed that the iNTS isolate survived better in human primary macrophages than the NTS strain due to reduced inflammatory cell death, weakened inflammasome activation and lower cytokine release. We suggest that the distinct LPS structure is responsible for these dampened immune responses which aid the spread and persistence of S. Typhimurium ST313 in the human host.

microbiology↗

bioRxiv2025

HIV-1 and Chlamydia trachomatis restrict their respective growth but promote their survival in co-infected human macrophages

HIV-1 and Chlamydia trachomatis (CT) are two significant sexually transmitted pathogens that frequently co-infect individuals. However, the mechanisms by which these two obligate intracellular pathogens interact at the cellular level remain elusive, particularly in tissue macrophages, where persistent infections can occur. In this study, we demonstrate that CT generates inclusions in macrophages of murine and human origins. We also show that both HIV-1 and CT reciprocally restrict the growth and replication of each other within co-infected human macrophages, irrespective of whether the viral or bacterial infection is established first. Notably, the co-infection resulted in improved survival of the macrophage hosts, as the inflammatory cell death pathways induced by CT were prevented by the virus. Collectively, these findings demonstrate that HIV-1 and CT collaborate to persist in human macrophages. IMPORTANCEWhile HIV-1 and Chlamydia trachomatis (CT) infections are associated at the epidemiological level, very little is known at the cellular and molecular level on co-infections by these two intracellular pathogens. The significance of our research is in dissecting the impact of one pathogen on replication and production of infectious progeny by the other. For this, we studied human macrophages, which are targeted by both HIV-1 and CT and could play an important role in their intracellular persistence. This work reveals the close interplay between these two pathogens that benefit from each other to survive in human macrophages. Consequently, we emphasize the need to address these cells as a unique target during the co-infections.

microbiology↗

bioRxiv2018

Differential screening identifies molecules specifically inhibiting CCR5 transport to the cell surface and HIV infection

Proteins destined to the cell surface are conveyed through membrane-bound compartments using the secretory pathway. Multiple secretory routes exist in cells, which paves the way to the development of inhibitory molecules able to specifically perturb the transport of a chosen cargo. We used differential high-content screening of chemical libraries to identify molecules reducing the secretion of CCR5, the major co-receptor for HIV-1 entry. Three molecules strongly affected the anterograde transport of CCR5, without inhibiting the transport of the related G protein-coupled receptors CCR1 and CXCR4. These three molecules perturb the transport of endogenous CCR5 and decrease the entry of HIV in human primary target cells. Two molecules were found to share the same mode of action, inhibiting palmitoylation of CCR5. Our results demonstrate that secretory routes can be specifically targeted which allows to envisage novel strategies to provoke the intracellular retention or rerouting of secretory proteins involved in disease development.

cell biology↗