Bacillary replication and macrophage necrosis are determinants of neutrophil recruitment in tuberculosis |
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| Institution: | 1. Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA;2. Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester, MA, USA;1. Therapeutic Immunology Division, Department of Laboratory Medicine, Karolinska Institutet, Hälsövägen F79, Huddinge, SE-14186 Stockholm, Sweden;2. Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden;3. Henry M Jackson Foundation-Division of AIDS, Tuberculosis Clinical Research Branch, National Institute of Allergy and infectious Diseases, National Institutes of Health, Bethesda, MD, USA;4. Division of Infection and Immunity, University College London, London, UK;5. Department of Medical Microbiology, University College London Hospitals NHS Trust, London, UK;1. School of Physics and Materials Science, Thapar University, Patiala 147004, India;2. UGC-DAE Consortium for Scientific Research, University Campus, Indore 452017, India;1. Laboratory of Immunology, Robert-Debré Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Univ. Paris Diderot, Sorbonne Paris Cité, 75019 Paris, France;2. Department of Pediatric Infectious Disease, Robert-Debré Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Univ. Paris Diderot, Sorbonne Paris Cité, 75019 Paris, France;3. Department of Anesthesiology and Intensive Care Unit, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Univ. Paris Descartes, Sorbonne Paris Cité, 75015 Paris, France;4. Department of Pediatric Intensive Care Unit, Robert-Debré Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Univ. Paris Diderot, Sorbonne Paris Cité, 75019 Paris, France;5. Department of Pediatric Gastroenterology, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Univ. Paris Diderot, Sorbonne Paris Cité, 75019 Paris, France;6. INSERM U1141, Robert-Debré Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Univ. Paris Diderot, Sorbonne Paris Cité, 75019 Paris, France;1. Moscow Institute of Physics and Technology, Institutsky Pereulok 9, Dolgoprudny, Moscow Region 141700, Russia;2. The Schmidt Institute of Physics of Earth, B. Gruzinskaya Street 10-11, Moscow 123995, Russia |
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| Abstract: | We previously determined that burst size necrosis is the chief mode of mononuclear cell death in the lungs of mice with tuberculosis. The present study explored the link between infection-induced necrosis of mononuclear phagocytes and neutrophil accumulation in the lungs of mice challenged with one of four Mycobacterium tuberculosis strains of increasing virulence (RvΔphoPR mutant, H37Ra, H37Rv and Erdman). At all time points studied, Erdman produced the highest bacterial load and the highest proportion and number of M. tuberculosis-infected neutrophils. These parameters, and the proportion of TUNEL-positive cells, tracked with virulence across all strains tested. Differences in neutrophil infection were not reflected by levels of chemoattractant cytokines in bronchoalveolar lavage fluid, while interferon-γ (reported to suppress neutrophil trafficking to the lung in tuberculosis) was highest in Erdman-infected mice. Treating Erdman-infected mice with ethambutol decreased the proportion of mononuclear phagocytes with high bacterial burden and the ratio of infected neutrophils to infected mononuclear cells in a dose-dependent manner. We propose that faster replicating M. tuberculosis strains cause more necrosis which in turn promotes neutrophil recruitment. Neutrophils infected with M. tuberculosis constitute a biomarker for poorly controlled bacterial replication, infection-induced mononuclear cell death, and increased severity of immune pathology in tuberculosis. |
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| Keywords: | Tuberculosis Neutrophils Macrophages Cell death |
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