Biology subjects

Rivault, A.

Publications and source records attributed to Rivault, A..

3 recordsLinked to original sources

bioRxiv2026

HIV-1 Tat protects macrophages from killing by the Exoenzyme U from Pseudomonas aeruginosa

People living with HIV (PLWH) have a higher risk of developing other diseases, such as bacterial pneumonia. While Pseudomonas aeruginosa (PAE) is a common cause of pneumonia in humans, PLWHs are infrequently infected by PAE. The reasons for this relative resistance of PLWH to PAE are not known. The most virulent PAE strains produce ExoU which is a key effector of PAE cytotoxicity. Upon injection into the target cell cytosol by the type III secretion system, ExoU binds to PI(4,5)P2 on the inner leaflet of the plasma membrane. Its phospholipase activity then induces a loss of plasma membrane integrity, rapidly leading to cell death. HIV-Tat is secreted by HIV-infected cells, leading to nanomolar concentrations of Tat in the sera of PLWH, even under antiretroviral therapy. Circulating Tat can be endocytosed by uninfected cells, translocate to the cytosol and bind to PI(4,5)P2 at the plasma membrane. In uninfected cells only, Tat is palmitoylated, enabling Tat to become resident on PI(4,5)P2. We found that Tat can interfere with the recruitment of ExoU by PI(4,5)P2, thereby protecting macrophages from PAE toxicity. HIV Tat could therefore be involved in the relative protection of PLWH against the most aggressive PAE isolates and their ExoU type III effector. Tat nevertheless enhances the toxicity of ExoU-deficient PAE strains toward macrophages. ImportancePeople living with HIV (PLWH) are at risk of developing bacterial pneumonia. A widespread cause of pneumonia is Pseudomonas aeruginosa (PAE) but, for unknown reasons, PLWHs are infrequently infected by PAE. A key effector of PAE cytotoxicity is ExoU that is injected by PAE into the target cell cytosol, then binds to PI(4,5)P2 on the inner leaflet of the plasma membrane. The potent phospholipase activity of ExoU then induces a loss of plasma membrane integrity, rapidly leading to cell death. HIV-Tat is present in the serum of PLWH. Circulating Tat is endocytosed by cells, translocates to the cytosol and bind to PI(4,5)P2 at the plasma membrane with a very high affinity. This study indicates that Tat interferes with the recruitment of ExoU by PI(4,5)P2, thereby protecting macrophages from ExoU+ PAE. HIV Tat could therefore be involved in the relative protection of PLWH against the most aggressive PAE isolates.

microbiology↗

bioRxiv2025

Non-canonical caspase-8 activation by cathepsin B drives anti-inflammatory human macrophage polarization

Anti-inflammatory monocyte-derived macrophages are essential to maintain tissue homeostasis but can also contribute to disease progression, notably in cancer and fibrosis. Deciphering the signaling pathways that govern their generation could therefore unlock new therapeutic opportunities. Here we uncover a previously unrecognized, non-apoptotic function of caspase-8 in driving both monocyte-to-macrophage differentiation and anti-inflammatory macrophages polarization. We identified cathepsin B as a novel upstream activator of caspase-8 activation through a non-canonical cleavage mechanism, conferring to caspase-8 an original activity profile distinct from its apoptotic role. Disruption of this cathepsin-B-caspase-8 axis, either genetically or pharmacologically, not only impairs the generation of anti-inflammatory macrophages but also reprograms these cells towards a pro-inflammatory phenotype. Our findings position the cathepsin-B-caspase-8 axis as a critical regulatory node in macrophage fate decisions and a promising target for therapeutic reprogramming of human macrophages in cancer, inflammation and fibrotic diseases.

immunology↗

bioRxiv2025

HIV-1 Tat favors the multiplication of Mycobacterium tuberculosis and toxoplasma by inhibiting clathrin-mediated endocytosis and autophagy

AbstractHIV-1 and Mycobacterium tuberculosis (Mtb) coinfections are a major public health problem but are not well characterized. HIV-1 Tat is secreted by infected cells, generating nanomolar concentrations of Tat in the sera of people living with HIV. Circulating Tat enters cells, binds to PI(4,5)P2 then undergoes palmitoylation, thereby becoming resident on this phosphoinositide. Here, we found that Tat favors the multiplication of Mtb in macrophages. Moreover, Tat renders zebrafish larvae more sensitive to mycobacterial infection. We found that Tat binding to PI(4,5)P2 and palmitoylation enable Tat to inhibit the recruitment of the AP-2 adaptor, thereby inhibiting clathrin-mediated endocytosis and in turn autophagy. This inhibition prevents the degradation of intracellular pathogens such as Mtb and opsonized Toxoplasma gondii, but also of lipid droplets, thereby facilitating the access of these pathogens to lipids. We thus identified a mechanism enabling HIV Tat to favor the multiplication of intracellular pathogens such as Mtb.

microbiology↗