Pre-conception maternal helminth infection transfers via nursing long-lasting cellular immunity against helminths to offspring

Maternal immune transfer is the most significant source of protection from early-life infection, but whether maternal transfer of immunity by nursing permanently alters offspring immunity is poorly understood. Here, we identify maternal immune imprinting of offspring nursed by mothers who had a pre-conception helminth infection. Nursing of pups by helminth-exposed mothers transferred protective cellular immunity to these offspring against helminth infection. Enhanced control of infection was not dependent on maternal antibody. Protection associated with systemic development of protective type 2 immunity in T helper 2 (TH2) impaired IL-4R-/- offspring. This maternally acquired immunity was maintained into maturity and required transfer (via nursing) to the offspring of maternally derived TH2-competent CD4 T cells. Our data therefore reveal that maternal exposure to a globally prevalent source of infection before pregnancy provides long-term nursing-acquired immune benefits to offspring mediated by maternally derived pathogen-experienced lymphocytes. © 2019 by the Authors

Astrophysics with the Laser Interferometer Space Antenna

Laser Interferometer Space Antenna (LISA) will be a transformative experiment for gravitational wave astronomy as it will offer unique opportunities to address many key astrophysical questions in a completely novel way. The synergy with ground-based and other space-based instruments in the electromagnetic domain, by enabling multi-messenger observations, will add further to the discovery potential of LISA. The next decade is crucial to prepare the astrophysical community for LISA's first observations. This review outlines the extensive landscape of astrophysical theory, numerical simulations, and astronomical observations that are instrumental for modeling and interpreting the upcoming LISA datastream. To this aim, the current knowledge in three main source classes for LISA is reviewed: ultra-compact stellar-mass binaries, massive black hole binaries, and extreme or intermediate mass ratio inspirals. The relevant astrophysical processes and the established modeling techniques are summarized. Likewise, open issues and gaps in our understanding of these sources are highlighted, along with an indication of how LISA could help make progress in the different areas. New research avenues that LISA itself, or its joint exploitation with studies in the electromagnetic domain, will enable, are also illustrated. Improvements in modeling and analysis approaches, such as the combination of numerical simulations and modern data science techniques, are discussed. This review is intended to be a starting point for using LISA as a new discovery tool for understanding our Universe

KANK2 links αVβ5 focal adhesions to microtubules and regulates sensitivity to microtubule poisons and cell migration

Integrins are heterodimeric glycoproteins that bind cells to extracellular matrix. Upon integrin clustering, multimolecular integrin adhesion complexes (IACs) are formed, creating links to the cell cytoskeleton. We have previously observed decreased cell migration and increased sensitivity to microtubule (MT) poisons, paclitaxel and vincristine, in the melanoma cell line MDA-MB-435S upon transfection with integrin alpha V specific siRNA, suggesting a link between adhesion and drug sensitivity. To elucidate the underlying mechanism, we determined alpha V-dependent changes in IAC composition. Using mass spectrometry (MS)-based proteomics, we analyzed the components of isolated IACs of MDA-MB-435S cells and two MDA-MB-435S-derived integrin alpha V specific shRNA-expressing cell clones with decreased expression of integrin alpha V. MS analysis showed that cells preferentially use integrin alpha V beta 5 for the formation of IACs. The differential analysis between MDA-MB-435S cells and clones with decreased expression of integrin alpha V identified key components of integrin alpha V beta 5 adhesion complexes as talins 1 and 2, alpha-actinins 1 and 4, filamins A and B, plectin and vinculin. The data also revealed decreased levels of several components of the cortical microtubule stabilization complex, which recruits MTs to adhesion sites (notably liprins alpha and beta, ELKS, LL5b, MACF1, KANK1, and KANK2), following alpha V knockdown. KANK2 knockdown in MDA-MB-435S cells mimicked the effect of integrin alpha V knockdown and resulted in increased sensitivity to MT poisons and decreased migration. Taken together, we conclude that KANK2 is a key molecule linking integrin alpha V beta 5 IACs to MTs, and enabling the actin-MT crosstalk that is important for both sensitivity to MT poisons and cell migration

GM-CSF targeted immunomodulation affects host response to M. tuberculosis infection

International audienceHost directed immunomodulation represents potential new adjuvant therapies in infectious diseases such as tuberculosis. Major cytokines like TNFα exert a multifold role in host control of mycobacterial infections. GM-CSF and its receptor are over-expressed during acute M. tuberculosis infection and we asked how GM-CSF neutralization might affect host response, both in immunocompetent and in immunocompromised TNFα-deficient mice. GM-CSF neutralizing antibodies, at a dose effectively preventing acute lung inflammation, did not affect M. tuberculosis bacterial burden, but increased the number of granuloma in wild-type mice. We next assessed whether GM-CSF neutralization might affect the control of M. tuberculosis by isoniazid/rifampicin chemotherapy. GM-CSF neutralization compromised the bacterial control under sub-optimal isoniazid/rifampicin treatment in TNFα-deficient mice, leading to exacerbated lung inflammation with necrotic granulomatous structures and high numbers of intracellular M. tuberculosis bacilli. In vitro, GM-CSF neutralization promoted M2 anti-inflammatory phenotype in M. bovis BCG infected macrophages, with reduced mycobactericidal NO production and higher intracellular M. bovis BCG burden. Thus, GM-CSF pathway overexpression during acute M. tuberculosis infection contributes to an efficient M1 response, and interfering with GM-CSF pathway in the course of infection may impair the host inflammatory response against M. tuberculosis

Deletion of Mocos induces xanthinuria with obstructive nephropathy and major metabolic disorders in mice

International audienceBackground : Xanthinuria type II is a rare autosomal purine disorder. This recessive defect of purine metabolism remains an underrecognized disorder. Methods : Mice with targeted disruption of the molybdenum cofactor sulfurase (Mocos) gene were generated to enable an integrated understanding of purine disorders and evaluate pathophysiological functions of this gene found in large number of pathways and known to be associated with autism. Results : Mocos deficient mice die with 4 weeks of age due to renal failure of distinct obstructive nephropathy with xanthinuria, xanthine deposits, cystic tubular dilatation, Tamm Horsfall (uromodulin) protein deposits, tubular cell necrosis with neutrophils and occasionally hypdronephrosis with urolithiasis. Obstructive nephropathy is associated with moderate interstitial inflammatory and fibrotic responses, anemia, reduced detoxification systems and important alterations of the metabolism of purines, amino acids and phospholipids.Conversely, heterozygous mice expressing reduced MOCOS protein are healthy with no apparent pathology

Acetylcholine production by type 2 innate lymphoid cells promotes mucosal immunity to helminth parasites

International audienceInnate lymphoid cells (ILCs) are critical mediators of immunological and physiological responses at mucosal barrier sites. While neurotransmitters can stimulate ILCs, the synthesis of small-molecule neurotransmitters by these cells has only recently begun to be appreciated. Type 2 innate lymphoid cells (ILC2s) are shown here to synthesise and release acetylcholine (ACh) during parasitic nematode infection. The cholinergic phenotype of pulmonary ILC2s was associated with their activation state, could be induced by in vivo exposure to extracts of Alternaria alternata or the alarmin cytokines interleukin (IL)-33 and IL-25, and was augmented by IL-2 in vitro. Genetic disruption of ACh synthesis by murine ILC2s resulted in increased parasite burdens, impaired ILC2 proliferation, and reduced features of lung and gut barrier responses following Nippostrongylus brasiliensis infection. These data demonstrate a functional role for ILC2-derived ACh in expansion of ILC2s for maximal induction of type 2 immunity

Chronic Lung Infection Is IL-1R Independent, but Relies on MyD88 Signaling.

Cystic fibrosis is associated with chronic colonization and inflammation. The role of MyD88, the shared adapter protein of the proinflammatory TLR and IL-1R families, in chronic biofilm lung infection is unknown. We report that chronic lung infection with the clinical RP73 strain is associated with uncontrolled lung infection in complete MyD88-deficient mice with epithelial damage, inflammation, and rapid death. Then, we investigated whether alveolar or myeloid cells contribute to heightened sensitivity to infection. Using cell-specific, MyD88-deficient mice, we uncover that the MyD88 pathway in myeloid or alveolar epithelial cells is dispensable, suggesting that other cell types may control the high sensitivity of MyD88-deficient mice. By contrast, IL-1R1-deficient mice control chronic RP73 infection and IL-1β Ab blockade did not reduce host resistance. Therefore, the IL-1R1/MyD88 pathway is not involved, but other IL-1R or TLR family members need to be investigated. Our data strongly suggest that IL-1 targeted neutralizing therapies used to treat inflammatory diseases in patients unlikely reduce host resistance to chronic infection

Libre accès aux publications et sciences ouvertes en débat

« Libre accès aux publications et sciences ouvertes en débat »…Le titre du dossier coordonné par Ghislaine Chartron et Joachim Schöpfel dit bien les choses. De fait, les Sciences de l’Information et de la Communication « sont doublement concernées par l’Open access, en tant que communauté scientifique et en tant que discipline intéressée par la production et la circulation de l’information au sein des structures et organisations scientifiques », en tant que sujet et objet en quelque sorte. Fermeture ou ouverture ? S’il y a fermeture, secret pour dire autrement, c’est qu’il y a quelque chose à cacher. Que le rire est le propre de l’Homme, par exemple. Ou bien que la Terre tourne autour du Soleil. Mais, là déjà, un scientifique, Galilée, a… tourné la difficulté : au lieu de parler Latin, il se met à parler Italien, histoire de mobiliser des alliés, les ingénieurs de Venise, entre autres… [en savoir +

Astrophysics with the Laser Interferometer Space Antenna

submitted to Living Reviews In RelativityLaser Interferometer Space Antenna (LISA) will be a transformative experiment for gravitational wave astronomy as it will offer unique opportunities to address many key astrophysical questions in a completely novel way. The synergy with ground-based and other space-based instruments in the electromagnetic domain, by enabling multi-messenger observations, will add further to the discovery potential of LISA. The next decade is crucial to prepare the astrophysical community for LISA's first observations. This review outlines the extensive landscape of astrophysical theory, numerical simulations, and astronomical observations that are instrumental for modeling and interpreting the upcoming LISA datastream. To this aim, the current knowledge in three main source classes for LISA is reviewed: ultra-compact stellar-mass binaries, massive black hole binaries, and extreme or intermediate mass ratio inspirals. The relevant astrophysical processes and the established modeling techniques are summarized. Likewise, open issues and gaps in our understanding of these sources are highlighted, along with an indication of how LISA could help make progress in the different areas. New research avenues that LISA itself, or its joint exploitation with studies in the electromagnetic domain, will enable, are also illustrated. Improvements in modeling and analysis approaches, such as the combination of numerical simulations and modern data science techniques, are discussed. This review is intended to be a starting point for using LISA as a new discovery tool for understanding our Universe

Astrophysics with the Laser Interferometer Space Antenna

submitted to Living Reviews In RelativityLaser Interferometer Space Antenna (LISA) will be a transformative experiment for gravitational wave astronomy as it will offer unique opportunities to address many key astrophysical questions in a completely novel way. The synergy with ground-based and other space-based instruments in the electromagnetic domain, by enabling multi-messenger observations, will add further to the discovery potential of LISA. The next decade is crucial to prepare the astrophysical community for LISA's first observations. This review outlines the extensive landscape of astrophysical theory, numerical simulations, and astronomical observations that are instrumental for modeling and interpreting the upcoming LISA datastream. To this aim, the current knowledge in three main source classes for LISA is reviewed: ultra-compact stellar-mass binaries, massive black hole binaries, and extreme or intermediate mass ratio inspirals. The relevant astrophysical processes and the established modeling techniques are summarized. Likewise, open issues and gaps in our understanding of these sources are highlighted, along with an indication of how LISA could help make progress in the different areas. New research avenues that LISA itself, or its joint exploitation with studies in the electromagnetic domain, will enable, are also illustrated. Improvements in modeling and analysis approaches, such as the combination of numerical simulations and modern data science techniques, are discussed. This review is intended to be a starting point for using LISA as a new discovery tool for understanding our Universe