Showing papers by "Jean-Pierre Gorvel published in 2021"

Brucella : Reservoirs and Niches in Animals and Humans.

Abstract: Brucella is an intracellular bacterium that causes abortion, reproduction failure in livestock and leads to a debilitating flu-like illness with serious chronic complications if untreated in humans. As a successful intracellular pathogen, Brucella has developed strategies to avoid recognition by the immune system of the host and promote its survival and replication. In vivo, Brucellae reside mostly within phagocytes and other cells including trophoblasts, where they establish a preferred replicative niche inside the endoplasmic reticulum. This process is central as it gives Brucella the ability to maintain replicating-surviving cycles for long periods of time, even at low bacterial numbers, in its cellular niches. In this review, we propose that Brucella takes advantage of the environment provided by the cellular niches in which it resides to generate reservoirs and disseminate to other organs. We will discuss how the favored cellular niches for Brucella infection in the host give rise to anatomical reservoirs that may lead to chronic infections or persistence in asymptomatic subjects, and which may be considered as a threat for further contamination. A special emphasis will be put on bone marrow, lymph nodes, reproductive and for the first time adipose tissues, as well as wildlife reservoirs.

From Species to Regional and Local Specialization of Intestinal Macrophages.

Abstract: Initially intended for nutrient uptake, phagocytosis represents a central mechanism of debris removal and host defense against invading pathogens through the entire animal kingdom. In vertebrates and also many invertebrates, macrophages (MFs) and MF-like cells (e.g., coelomocytes and hemocytes) are professional phagocytic cells that seed tissues to maintain homeostasis through pathogen killing, efferocytosis and tissue shaping, repair, and remodeling. Some MF functions are common to all species and tissues, whereas others are specific to their homing tissue. Indeed, shaped by their microenvironment, MFs become adapted to perform particular functions, highlighting their great plasticity and giving rise to high population diversity. Interestingly, the gut displays several anatomic and functional compartments with large pools of strikingly diversified MF populations. This review focuses on recent advances on intestinal MFs in several species, which have allowed to infer their specificity and functions.

The Brucella effector BspL targets the ER-associated degradation (ERAD) pathway and delays bacterial egress from infected cells.

Abstract: Perturbation of the endoplasmic reticulum (ER), a central organelle of the cell, can have critical consequences for cellular homeostasis. An elaborate surveillance system known as ER quality control ensures that cells can respond and adapt to stress via the unfolded protein response (UPR) and that only correctly assembled proteins reach their destination. Interestingly, several bacterial pathogens hijack the ER to establish an infection. However, it remains poorly understood how bacterial pathogens exploit ER quality-control functions to complete their intracellular cycle. Brucella spp. replicate extensively within an ER-derived niche, which evolves into specialized vacuoles suited for exit from infected cells. Here we present Brucella-secreted protein L (BspL), a Brucella abortus effector that interacts with Herp, a central component of the ER-associated degradation (ERAD) machinery. We found that BspL enhances ERAD at the late stages of the infection. BspL targeting of Herp and ERAD allows tight control of the kinetics of autophagic Brucella-containing vacuole formation, delaying the last step of its intracellular cycle and cell-to-cell spread. This study highlights a mechanism by which a bacterial pathogen hijacks ERAD components for fine regulation of its intracellular trafficking.

PTX Instructs the Development of Lung-Resident Memory T Cells in Bordetella pertussis Infected Mice.

Abstract: Whooping cough is a severe, highly contagious disease of the human respiratory tract, caused by Bordetellapertussis. The pathogenicity requires several virulence factors, including pertussis toxin (PTX), a key component of current available vaccines. Current vaccines do not induce mucosal immunity. Tissue-resident memory T cells (Trm) are among the first lines of defense against invading pathogens and are involved in long-term protection. However, the factors involved in Trm establishment remain unknown. Comparing two B.pertussis strains expressing PTX (WT) or not (ΔPTX), we show that the toxin is required to generate both lung CD4+ and CD8+ Trm. Co-administering purified PTX with ΔPTX is sufficient to generate these Trm subsets. Importantly, adoptive transfer of lung CD4+ or CD8+ Trm conferred protection against B. pertussis in naive mice. Taken together, our data demonstrate for the first time a critical role for PTX in the induction of mucosal long-term protection against B. pertussis.

The uniqueBrucellaeffectors NyxA and NyxB target SENP3 to modulate the subcellular localisation of nucleolar proteins

Abstract: The cell nucleus is a primary target for intracellular bacterial pathogens to counteract immune responses and hijack host signalling pathways to cause disease. The mechanisms controlling nuclear protein localisation in the context of stress responses induced upon bacterial infection are still poorly understood. Here we show that the Brucella abortus effectors NyxA and NyxB interfere with the host sentrin specific protease 3 (SENP3), which is essential for intracellular replication. Translocated Nyx effectors directly interact with SENP3 via a defined acidic patch identified from the crystal structure of NyxB, preventing its nucleolar localisation at the late stages of the infection. By sequestering SENP3, the Nyx effectors induce the cytoplasmic accumulation of the nucleolar AAA-ATPase NVL, the large subunit ribosomal protein L5 (RPL5) and the ribophagy receptor NUFIP1 in Nyx-enriched structures in the vicinity of replicating bacteria. This shuttling of ribosomal biogenesis-associated nucleolar proteins is negatively regulated by SENP3 and dependent on the autophagy-initiation protein Beclin1, indicative of a ribophagy-derived process induced during Brucella infection. Our results highlight a new nucleomodulatory function by two unique Brucella effectors, and reveal that SENP3 is a critical regulator of the subcellular localisation of multiple nucleolar proteins during Brucella infection, promoting intracellular replication.