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      Offspring born to influenza A virus infected pregnant mice have increased susceptibility to viral and bacterial infections in early life

      research-article
      1 , 1 , 1 , 1 , 2 , 3 , 2 , 3 , 4 , 1 , 1 , 1 , 1 , 1 , 5 , 6 , 7 , 8 , 9 , 8 , 9 , 10 , 10 , 10 , 10 , 11 , 12 , 13 , 13 , 14 , 15 , 2 , 16 , 17 , 18 , 4 , 19 , 14 , 1 , 20 , 21 ,
      Nature Communications
      Nature Publishing Group UK
      Immunological surveillance, Alveolar macrophages, Mucosal immunology, Pathogens, Virus-host interactions

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          Abstract

          Influenza during pregnancy can affect the health of offspring in later life, among which neurocognitive disorders are among the best described. Here, we investigate whether maternal influenza infection has adverse effects on immune responses in offspring. We establish a two-hit mouse model to study the effect of maternal influenza A virus infection (first hit) on vulnerability of offspring to heterologous infections (second hit) in later life. Offspring born to influenza A virus infected mothers are stunted in growth and more vulnerable to heterologous infections (influenza B virus and MRSA) than those born to PBS- or poly(I:C)-treated mothers. Enhanced vulnerability to infection in neonates is associated with reduced haematopoetic development and immune responses. In particular, alveolar macrophages of offspring exposed to maternal influenza have reduced capacity to clear second hit pathogens. This impaired pathogen clearance is partially reversed by adoptive transfer of alveolar macrophages from healthy offspring born to uninfected dams. These findings suggest that maternal influenza infection may impair immune ontogeny and increase susceptibility to early life infections of offspring.

          Abstract

          Influenza infection during pregnancy can affect health of offspring but it is not clear how this affects immune responses. Here the authors use a mouse model to show that influenza infection during pregnancy can increase susceptibility to secondary infection and alter immune cell function in offspring.

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          Most cited references40

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          Estimates of global seasonal influenza-associated respiratory mortality: a modelling study

          Estimates of influenza-associated mortality are important for national and international decision making on public health priorities. Previous estimates of 250 000-500 000 annual influenza deaths are outdated. We updated the estimated number of global annual influenza-associated respiratory deaths using country-specific influenza-associated excess respiratory mortality estimates from 1999-2015.
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            Alveolar macrophages: plasticity in a tissue-specific context.

            Alveolar macrophages exist in a unique microenvironment and, despite historical evidence showing that they are in close contact with the respiratory epithelium, have until recently been investigated in isolation. The microenvironment of the airway lumen has a considerable influence on many aspects of alveolar macrophage phenotype, function and turnover. As the lungs adapt to environmental challenges, so too do alveolar macrophages adapt to accommodate the ever-changing needs of the tissue. In this Review, we discuss the unique characteristics of alveolar macrophages, the mechanisms that drive their adaptation and the direct and indirect influences of epithelial cells on them. We also highlight how airway luminal macrophages function as sentinels of a healthy state and how they do not respond in a pro-inflammatory manner to antigens that do not disrupt lung structure. The unique tissue location and function of alveolar macrophages distinguish them from other macrophage populations and suggest that it is important to classify macrophages according to the site that they occupy.
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              The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring.

              Viral infection during pregnancy has been correlated with increased frequency of autism spectrum disorder (ASD) in offspring. This observation has been modeled in rodents subjected to maternal immune activation (MIA). The immune cell populations critical in the MIA model have not been identified. Using both genetic mutants and blocking antibodies in mice, we show that retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt)-dependent effector T lymphocytes [for example, T helper 17 (TH17) cells] and the effector cytokine interleukin-17a (IL-17a) are required in mothers for MIA-induced behavioral abnormalities in offspring. We find that MIA induces an abnormal cortical phenotype, which is also dependent on maternal IL-17a, in the fetal brain. Our data suggest that therapeutic targeting of TH17 cells in susceptible pregnant mothers may reduce the likelihood of bearing children with inflammation-induced ASD-like phenotypes.
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                Author and article information

                Contributors
                guelsah.gabriel@leibniz-hpi.de
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                16 August 2021
                16 August 2021
                2021
                : 12
                : 4957
                Affiliations
                [1 ]GRID grid.418481.0, ISNI 0000 0001 0665 103X, Department of Viral Zoonoses – One Health, , Leibniz Institute for Experimental Virology, ; Hamburg, Germany
                [2 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Comprehensive Cancer Center Hamburg, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany
                [3 ]GRID grid.13648.38, ISNI 0000 0001 2180 3484, Department of Tumor Biology, Center of Experimental Medicine, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany
                [4 ]GRID grid.418187.3, ISNI 0000 0004 0493 9170, Early Life Origins of Chronic Lung Disease, Research Center Borstel, Leibniz Lung Center, , Member of the German Center for Lung Research (DZL), ; Borstel, Germany
                [5 ]GRID grid.7490.a, ISNI 0000 0001 2238 295X, Department of Computational Biology of Infection Research, , Helmholtz Centre for Infection Research, ; Braunschweig, Germany
                [6 ]GRID grid.418481.0, ISNI 0000 0001 0665 103X, Flow Cytometry/FACS Unit, , Leibniz-Institute for Experimental Virology, ; Hamburg, Germany
                [7 ]GRID grid.418481.0, ISNI 0000 0001 0665 103X, Microscopy and Image Analysis Unit, , Leibniz-Institute for Experimental Virology, ; Hamburg, Germany
                [8 ]GRID grid.4567.0, ISNI 0000 0004 0483 2525, Comprehensive Pneumology Center (CPC), Institute of Lung Biology and Disease, , Helmholtz Center Munich, German Research Center for Environmental Health, ; Neuherberg, Germany
                [9 ]Member of The German Center for Lung Research (DZL), Borstel, Germany
                [10 ]GRID grid.4567.0, ISNI 0000 0004 0483 2525, German Mouse Clinic, Institute of Experimental Genetics, , Helmholtz Center Munich, German Research Center for Environmental Health, ; Neuherberg, Germany
                [11 ]GRID grid.6936.a, ISNI 0000000123222966, Chair of Experimental Genetics, School of Life Science Weihenstephan, , Technische Universität München, ; Freising, Germany
                [12 ]GRID grid.452622.5, German Center for Diabetes Research (DZD), ; Neuherberg, Germany
                [13 ]GRID grid.411544.1, ISNI 0000 0001 0196 8249, Institute for Pathology and Neuropathology, , University Hospital Tübingen, ; Tübingen, Germany
                [14 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, National Heart and Lung Institute, , Imperial College London, ; London, UK
                [15 ]GRID grid.418187.3, ISNI 0000 0004 0493 9170, Core Facility Fluorescence Cytometry, , Research Center Borstel, Leibniz Lung Center, ; Borstel, Germany
                [16 ]GRID grid.7497.d, ISNI 0000 0004 0492 0584, Division of Personalized Medical Oncology (A420), , German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [17 ]GRID grid.411778.c, ISNI 0000 0001 2162 1728, Department of Personalized Oncology, , University Hospital Mannheim, University of Heidelberg, ; Mannheim, Germany
                [18 ]GRID grid.418187.3, ISNI 0000 0004 0493 9170, Junior Research Group Coinfection, Priority Research Area Infections, , Research Center Borstel, Leibniz Lung Center, ; Borstel, Germany
                [19 ]GRID grid.9764.c, ISNI 0000 0001 2153 9986, Institute of Experimental Medicine, , Christian-Albrechts-Universität zu Kiel, ; Kiel, Germany
                [20 ]GRID grid.412970.9, ISNI 0000 0001 0126 6191, Institute for Virology, , University for Veterinary Medicine Hannover, ; Hannover, Germany
                [21 ]GRID grid.452463.2, German Center for Infection Research (DZIF), ; Braunschweig, Germany
                Author information
                http://orcid.org/0000-0003-0035-8726
                http://orcid.org/0000-0003-0991-4442
                http://orcid.org/0000-0003-1969-480X
                http://orcid.org/0000-0002-5143-2677
                http://orcid.org/0000-0002-6076-0111
                http://orcid.org/0000-0002-7898-2353
                http://orcid.org/0000-0001-5208-4259
                http://orcid.org/0000-0002-0648-8911
                http://orcid.org/0000-0002-7220-2555
                http://orcid.org/0000-0003-0542-8033
                Article
                25220
                10.1038/s41467-021-25220-3
                8368105
                34400653
                1a1be6da-347a-48ac-be35-1a38787de659
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 19 August 2020
                : 21 July 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft (German Research Foundation);
                Funded by: FundRef https://doi.org/10.13039/100010663, EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council);
                Funded by: FundRef https://doi.org/10.13039/501100001923, DH | NIHR | Health Services Research Programme (NIHR Health Services Research Programme);
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                © The Author(s) 2021

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                immunological surveillance,alveolar macrophages,mucosal immunology,pathogens,virus-host interactions

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