Type IV pilus retraction enables sustained bacteremia and plays a key role in the outcome of meningococcal sepsis in a humanized mouse model
| Autor: | Mathieu Coureuil, Taliah Schmitt, Xavier Nassif, Sandrine Bourdoulous, Mohamed El Behi, Daniel Euphrasie, Olivier Join-Lambert, Mathilde Audry, Sophia Schönherr-Hellec, Jean-Philippe Barnier |
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| Přispěvatelé: | Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Bourdoulous, Sandrine |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Bacterial Diseases
Bacterial Lethality Physiology Bacteremia Mice SCID Meningococcal Disease Pilus retraction Neisseria meningitidis Pathology and Laboratory Medicine medicine.disease_cause Bacterial Adhesion Pilus Mice Medical Conditions [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases Medicine and Health Sciences Biology (General) Immune Response 0303 health sciences Skin Transplantation Bacterial Pathogens Body Fluids 3. Good health Infectious Diseases Blood Medical Microbiology [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases Female Fimbriae Proteins Pathogens Cellular Structures and Organelles Anatomy medicine.symptom Neisseria Research Article Pathogen Motility QH301-705.5 Virulence Factors Immunology Inflammation Biology Meningococcal disease Microbiology Sepsis 03 medical and health sciences Signs and Symptoms Virology Genetics medicine Animals Humans Microbial Pathogens Molecular Biology 030304 developmental biology Bacteria 030306 microbiology Organisms Endothelial Cells Biology and Life Sciences Bacteriology Cell Biology RC581-607 medicine.disease [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology Meningococcal Infections Disease Models Animal Pili and Fimbriae Fimbriae Bacterial Humanized mouse Parasitology Immunologic diseases. Allergy Clinical Medicine [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Public Library of Science, 2021, 17 (2), pp.e1009299. ⟨10.1371/journal.ppat.1009299⟩ PLoS Pathogens, 2021, 17 (2), pp.e1009299. ⟨10.1371/journal.ppat.1009299⟩ PLoS Pathogens, Vol 17, Iss 2, p e1009299 (2021) |
| ISSN: | 1553-7366 1553-7374 |
| DOI: | 10.1371/journal.ppat.1009299⟩ |
| Popis: | Neisseria meningitidis (the meningococcus) remains a major cause of bacterial meningitis and fatal sepsis. This commensal bacterium of the human nasopharynx can cause invasive diseases when it leaves its niche and reaches the bloodstream. Blood-borne meningococci have the ability to adhere to human endothelial cells and rapidly colonize microvessels. This crucial step enables dissemination into tissues and promotes deregulated inflammation and coagulation, leading to extensive necrotic purpura in the most severe cases. Adhesion to blood vessels relies on type IV pili (TFP). These long filamentous structures are highly dynamic as they can rapidly elongate and retract by the antagonistic action of two ATPases, PilF and PilT. However, the consequences of TFP dynamics on the pathophysiology and the outcome of meningococcal sepsis in vivo have been poorly studied. Here, we show that human graft microvessels are replicative niches for meningococci, that seed the bloodstream and promote sustained bacteremia and lethality in a humanized mouse model. Intriguingly, although pilus-retraction deficient N. meningitidis strain (ΔpilT) efficiently colonizes human graft tissue, this mutant did not promote sustained bacteremia nor induce mouse lethality. This effect was not due to a decreased inflammatory response, nor defects in bacterial clearance by the innate immune system. Rather, TFP-retraction was necessary to promote the release of TFP-dependent contacts between bacteria and, in turn, the detachment from colonized microvessels. The resulting sustained bacteremia was directly correlated with lethality. Altogether, these results demonstrate that pilus retraction plays a key role in the occurrence and outcome of meningococcal sepsis by supporting sustained bacteremia. These findings open new perspectives on the role of circulating bacteria in the pathological alterations leading to lethal sepsis. Author summary Invasive meningococcal diseases remain a major cause of fatal sepsis. A specific feature of Neisseria meningitidis is its ability to colonize the blood microvessels in a type IV pilus (TFP)-dependent mechanism. TFP are filamentous appendages that undergo retraction through a mechanism dependent on the PilT ATPase. Here, we assess the role of TFP retraction in the pathophysiology of meningococcal infection using a humanized model of SCID mice grafted with human skin. We show that human skin graft microvessels are replicative niches for N. meningitidis that promote sustained bacteremia and subsequent lethality. Intriguingly, although pilus retraction-deficient N. meningitidis (ΔpilT) efficiently colonizes human grafts, this mutant strain did not promote sustained bacteremia nor induce mouse lethality. This drastic decrease in virulence was not due to a decreased inflammatory response or to a defect in bacterial clearance by the innate immune system. Rather, we demonstrate that pilus retraction was crucial to obtain a sustained bacteremia by allowing the release of bacteria from colonized microvessels and that lethality was directly linked to sustained bacteremia. Altogether, these data demonstrate the important role of pilus retraction in meningococcal pathogenesis and infection outcome and open new questions regarding the impact of circulating bacteria on the host during lethal sepsis. |
| Databáze: | OpenAIRE |
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