title: Immune Homeostatic Macrophages Programmed by the Bacterial Surface Protein NhhA Potentiate Nasopharyngeal Carriage of Neisseria meningitidis.
abstract: Neisseria meningitidis colonizes the nasopharyngeal mucosa of healthy populations asymptomatically, although the bacterial surface is rich in motifs that activate the host innate immunity. What determines the tolerant host response to this bacterium in asymptomatic carriers is poorly understood. We demonstrated that the conserved meningococcal surface protein NhhA orchestrates monocyte (Mo) differentiation specifically into macrophage-like cells with a CD200R(hi) phenotype (NhhA-Mφ). In response to meningococcal stimulation, NhhA-Mφ failed to produce proinflammatory mediators. Instead, they upregulated interleukin-10 (IL-10) and Th2/regulatory T cell (Treg)-attracting chemokines, such as CCL17, CCL18, and CCL22. Moreover, NhhA-Mφ were highly efficient in eliminating bacteria. The in vivo validity of these findings was corroborated using a murine model challenged with N. meningitidis systematically or intranasally. The NhhA-modulated immune response protected mice from septic shock; Mo/Mφ depletion abolished this protective effect. Intranasal administration of NhhA induced an anti-inflammatory response, which was associated with N. meningitidis persistence at the nasopharynx. In vitro studies demonstrated that NhhA-triggered Mo differentiation occurred upon engaged Toll-like receptor 1 (TLR1)/TLR2 signaling and extracellular signal-regulated kinase (ERK) and Jun N-terminal protein kinase (JNK) activation and required endogenously produced IL-10 and tumor necrosis factor alpha (TNF-α). Our findings reveal a strategy that might be adopted by N. meningitidis to maintain asymptomatic nasopharyngeal colonization.
  
  
  OBJECTIVE
  Neisseria meningitidis is an opportunistic human-specific pathogen that colonizes the nasopharyngeal mucosa asymptomatically in approximately 10% of individuals. Very little is known about how this bacterium evades immune activation during the carriage stage. Here, we observed that N. meningitidis, via the conserved surface protein NhhA, skewed monocyte differentiation into macrophages with a CD200R(hi) phenotype. Both in vivo and in vitro data demonstrated that these macrophages, upon meningococcal infection, played an important role in forming a homeostatic immune microenvironment through their capacity to eliminate invading bacteria and to generate anti-inflammatory mediators. This work provides novel insight into the mechanisms underlying the commensal persistence of N. meningitidis.
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Sjölinder
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden hong.sjolinder@su.se.
authors.forename: Hong
authors.initials: H
authors.lastname: Sjölinder
mesh_terms: D018829:Adhesins, Bacterial / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002353:Carrier State / Q000382:microbiology*; D002454:Cell Differentiation; D054414:Chemokine CCL17 / Q000235:genetics; D054422:Chemokine CCL22 / Q000235:genetics; D019742:Chemokines, CC / Q000235:genetics; D004195:Disease Models, Animal; D006706:Homeostasis; D006801:Humans; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008589:Meningococcal Infections / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000502:physiology; D009305:Nasopharynx / Q000382:microbiology*; D009345:Neisseria meningitidis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D013559:Symbiosis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018829:Adhesins, Bacterial; C106230:CCL17 protein, human; C111792:CCL18 protein, human; C515482:CCL22 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D019742:Chemokines, CC; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10