Communicable Ulcerative Colitis Induced by T-bet Deficiency in the Innate Immune System

Inflammatory bowel disease (IBD) has been attributed to overexuberant host immunity or the emergence of harmful intestinal flora. The transcription factor T-bet orchestrates inflammatory genetic programs in both adaptive and innate immunity. We describe a profound and unexpected function for T-bet in influencing the behavior of host inflammatory activity and commensal bacteria. T-bet deficiency in the innate immune system results in spontaneous and communicable ulcerative colitis in the absence of adaptive immunity and increased susceptibility to colitis in immunologically intact hosts. T-bet controls the response of the mucosal immune system to commensal bacteria by regulating TNF-α production in colonic dendritic cells, critical for colonic epithelial barrier maintenance. Loss of T-bet influences bacterial populations to become colitogenic, and this colitis is communicable to genetically intact hosts. These findings reveal a novel function for T-bet as a peacekeeper of host-commensal relationships and provide new perspectives on the pathophysiology of IBD

Actin-binding protein regulation by microRNAs as a novel microbial strategy to modulate phagocytosis by host cells: the case of N-Wasp and miR-142-3p

International audienc

Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation

The ability of Mycobacterium tuberculosis (Mtb) to persist inside host cells relies on metabolic adaptation, like the accumulation of lipid bodies (LBs) in the so-called foamy macrophages (FM), which are favorable to Mtb. The activation state of macrophages is tightly associated to different metabolic pathways, such as lipid metabolism, but whether differentiation towards FM differs between the macrophage activation profiles remains unclear. Here, we aimed to elucidate whether distinct macrophage activation states exposed to a tuberculosis-associated microenvironment or directly infected with Mtb can form FM. We showed that the triggering of signal transducer and activator of transcription 6 (STAT6) in interleukin (IL)-4-activated human macrophages (M(IL-4)) prevents FM formation induced by pleural effusion from patients with tuberculosis. In these cells, LBs are disrupted by lipolysis, and the released fatty acids enter the β-oxidation (FAO) pathway fueling the generation of ATP in mitochondria. Accordingly, murine alveolar macrophages, which exhibit a predominant FAO metabolism, are less prone to become FM than bone marrow derived-macrophages. Interestingly, direct infection of M(IL-4) macrophages with Mtb results in the establishment of aerobic glycolytic pathway and FM formation, which could be prevented by FAO activation or inhibition of the hypoxia-inducible factor 1-alpha (HIF-1α)-induced glycolytic pathway. In conclusion, our results demonstrate that Mtb has a remarkable capacity to induce FM formation through the rewiring of metabolic pathways in human macrophages, including the STAT6-driven alternatively activated program. This study provides key insights into macrophage metabolism and pathogen subversion strategies.Fil: Genoula, Melanie. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; ArgentinaFil: Marin Franco, Jose Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; ArgentinaFil: Maio, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Dolotowicz, Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Ferreyra Compagnucci, Malena María. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Milillo, María Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Mascarau, Rémi. Université de Toulouse; Francia. Centre National de la Recherche Scientifique; FranciaFil: Moraña, Eduardo José. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Palmero, Domingo Juan. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas "Dr. Francisco Javier Muñiz"; ArgentinaFil: Matteo, Mario José. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Tisioneumonología "raúl F. Vaccarezza".; ArgentinaFil: Fuentes, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: López, Beatriz. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán"; ArgentinaFil: Barrionuevo, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Neyrolles, Olivier. International Associated Laboratory; Argentina. Université de Toulouse; Francia. Centre National de la Recherche Scientifique; FranciaFil: Cougoule, Céline. Centre National de la Recherche Scientifique; Francia. Université de Toulouse; Francia. International Associated Laboratory; ArgentinaFil: Lugo Villarino, Geanncarlo. Centre National de la Recherche Scientifique; Francia. Université de Toulouse; Francia. International Associated Laboratory; ArgentinaFil: Vérollet, Christel. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; Argentina. Université de Toulouse; FranciaFil: Sasiain, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; ArgentinaFil: Balboa, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Centre National de la Recherche Scientifique; Francia. International Associated Laboratory; Argentin

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16(+) monocyte population via the IL-10/STAT3 axis

The human CD14+ monocyte compartment is composed by two subsets based on CD16 expression. We previously reported that this compartment is perturbed in tuberculosis (TB) patients, as reflected by the expansion of CD16+ monocytes along with disease severity. Whether this unbalance is beneficial or detrimental to host defense remains to be elucidated. Here in the context of active TB, we demonstrate that human monocytes are predisposed to differentiate towards an anti-inflammatory (M2-like) macrophage activation program characterized by theCD16+CD163+MerTK+pSTAT3+ phenotype and functional properties such as enhanced protease-dependent motility, pathogen permissivity and immunomodulation. This process is dependent on STAT3 activation, and loss-of-function experiments point towards a detrimental role in host defense against TB. Importantly, we provide a critical correlation between the abundance of the CD16+CD163+MerTK+pSTAT3+ cells and the progression of the disease either at the local level in a non-human primate tuberculous granuloma context, or at the systemic level through the detection of the soluble form of CD163 in human sera. Collectively, this study argues for the pathogenic role of the CD16+CD163+MerTK+pSTAT3+ monocyte-to-macrophage differentiation program and its potential as a target for TB therapy,and promotes the detection of circulating CD163 as a potential biomarker for disease progression and monitoringof treatment efficacy.Fil: Lastrucci, Claire. Centre National de la Recherche Scientifique; FranciaFil: Bénard, Alan. Centre National de la Recherche Scientifique; FranciaFil: Balboa, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Pingris, Karine. Centre National de la Recherche Scientifique; FranciaFil: Souriant, Shanti. Centre National de la Recherche Scientifique; FranciaFil: Poincloux, Renaud. Centre National de la Recherche Scientifique; FranciaFil: Al Saati, Talal. Inserm; FranciaFil: Rasolofo, Voahangy. Pasteur Institute in Antananarivo; MadagascarFil: González Montaner, Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas ; ArgentinaFil: Inwentarz, Sandra. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas ; ArgentinaFil: Moraña, Eduardo José. Gobierno de la Ciudad de Buenos Aires. Hospital de Infecciosas ; ArgentinaFil: Kondova, Ivanela. Biomedical Primate Research Centre; Países BajosFil: Verreck, Franck A. W.. Biomedical Primate Research Centre; Países BajosFil: Sasiain, María del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Neyrolles, Olivier. Centre National de la Recherche Scientifique; FranciaFil: Maridonneau Parini, Isabel. Centre National de la Recherche Scientifique; FranciaFil: Lugo Villarino, Geanncarlo. Centre National de la Recherche Scientifique; FranciaFil: Cougoule, Celine. Centre National de la Recherche Scientifique; Franci

Dissemination of <i>Mycobacterium tuberculosis</i> is associated to a <i>SIGLEC1</i> null variant that limits antigen exchange via trafficking extracellular vesicles

The identification of individuals with null alleles enables studying how the loss of gene function affects infection. We previously described a non‐functional variant in SIGLEC1, which encodes the myeloid‐cell receptor Siglec‐1/CD169 implicated in HIV‐1 cell‐to‐cell transmission. Here we report a significant association between the SIGLEC1 null variant and extrapulmonary dissemination of Mycobacterium tuberculosis (Mtb) in two clinical cohorts comprising 6,256 individuals. Local spread of bacteria within the lung is apparent in Mtb‐infected Siglec‐1 knockout mice which, despite having similar bacterial load, developed more extensive lesions compared to wild type mice. We find that Siglec‐1 is necessary to induce antigen presentation through extracellular vesicle uptake. We postulate that lack of Siglec‐1 delays the onset of protective immunity against Mtb by limiting antigen exchange via extracellular vesicles, allowing for an early local spread of mycobacteria that increases the risk for extrapulmonary dissemination

Circulating CD14brightCD16+ 'intermediate' monocytes exhibit enhanced parasite pattern recognition in human helminth infection.

Circulating monocyte sub-sets have recently emerged as mediators of divergent immune functions during infectious disease but their role in helminth infection has not been investigated. In this study we evaluated whether 'classical' (CD14brightCD16-), 'intermediate' (CD14brightCD16+), and 'non-classical' (CD14dimCD16+) monocyte sub-sets from peripheral blood mononuclear cells varied in both abundance and ability to bind antigenic material amongst individuals living in a region of Northern Senegal which is co-endemic for Schistosoma mansoni and S. haematobium. Monocyte recognition of excretory/secretory (E/S) products released by skin-invasive cercariae, or eggs, of S. mansoni was assessed by flow cytometry and compared between S. mansoni mono-infected, S. mansoni and S. haematobium co-infected, and uninfected participants. Each of the three monocyte sub-sets in the different infection groups bound schistosome E/S material. However, 'intermediate' CD14brightCD16+ monocytes had a significantly enhanced ability to bind cercarial and egg E/S. Moreover, this elevation of ligand binding was particularly evident in co-infected participants. This is the first demonstration of modulated parasite pattern recognition in CD14brightCD16+ intermediate monocytes during helminth infection, which may have functional consequences for the ability of infected individuals to respond immunologically to infection

The therapeutic potential of epigenetic manipulation during infectious diseases.

Epigenetic modifications are increasingly recognized as playing an important role in the pathogenesis of infectious diseases. They represent a critical mechanism regulating transcriptional profiles in the immune system that contributes to the cell-type and stimulus specificity of the transcriptional response. Recent data highlight how epigenetic changes impact macrophage functional responses and polarization, influencing the innate immune system through macrophage tolerance and training. In this review we will explore how post-translational modifications of histone tails influence immune function to specific infectious diseases. We will describe how these may influence outcome, highlighting examples derived from responses to acute bacterial pathogens, models of sepsis, maintenance of viral latency and HIV infection. We will discuss how emerging classes of pharmacological agents, developed for use in oncology and other settings, have been applied to models of infectious diseases and their potential to modulate key aspects of the immune response to bacterial infection and HIV therapy

Mannan core branching of lipo(arabino)mannan is required for mycobacterial virulence in the context of innate immunity

The causative agent of tuberculosis (TB), Mycobacterium tuberculosis, remains an important worldwide health threat. Although TB is one of the oldest infectious diseases of man, a detailed understanding of the mycobacterial mechanisms underlying pathogenesis remains elusive. Here, we studied the role of the α(1→2) mannosyltransferase MptC in mycobacterial virulence, using the Mycobacterium marinum zebrafish infection model. Like its M. tuberculosis orthologue, disruption of M. marinum mptC (mmar_3225) results in defective elongation of mannose caps of lipoarabinomannan (LAM) and absence of α(1→2)mannose branches on the lipomannan (LM) and LAM mannan core, as determined by biochemical analysis (NMR and GC-MS) and immunoblotting. We found that the M. marinum mptC mutant is strongly attenuated in embryonic zebrafish, which rely solely on innate immunity, whereas minor virulence defects were observed in adult zebrafish. Strikingly, complementation with the Mycobacterium smegmatis mptC orthologue, which restored mannan core branching but not cap elongation, was sufficient to fully complement the virulence defect of the mptC mutant in embryos. Altogether our data demonstrate that not LAM capping, but mannan core branching of LM/LAM plays an important role in mycobacterial pathogenesis in the context of innate immunit

Resident immunity in tissue repair and maintenance: The zebrafish model coming of age

The zebrafish has emerged as an exciting vertebrate model to study different aspects of immune system development, particularly due to its transparent embryonic development, the availability of multiple fluorescent reporter lines, efficient genetic tools and live imaging capabilities. However, the study of immunity in zebrafish has largely been limited to early larval stages due to an incomplete knowledge of the full repertoire of immune cells and their specific markers, in particular, a lack of cell surface antibodies to detect and isolate such cells in living tissues. Here we focus on tissue resident or associated immunity beyond development, in the adult zebrafish. It is our view that, with our increasing knowledge and the development of improved tools and protocols, the adult zebrafish will be increasingly appreciated for offering valuable insights into the role of immunity in tissue repair and maintenance, in both health and disease throughout the lifecourse