| 1. |
- Liu, Yan, et al.
(författare)
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Dynamic niche-specific adaptations in Neisseria meningitidis during infection
- 2016
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Ingår i: Microbes and infection. - : Elsevier BV. - 1286-4579 .- 1769-714X. ; 18:2, s. 109-117
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Tidskriftsartikel (refereegranskat)abstract
- Neisseria meningitidis is an opportunistic human pathogen that usually colonizes the nasopharyngeal mucosa asymptomatically. Upon invasion into the blood and central nervous system, this bacterium triggers a fulminant inflammatory reaction with the manifestations of septicemia and meningitis, causing high morbidity and mortality. To reveal the bacterial adaptations to specific and dynamic host environments, we performed a comprehensive proteomic survey of N. meningitidis isolated from the nasal mucosa, CSF and blood of a mouse disease model. We could identify 51 proteins whose expression pattern has been changed during infection, many of which have not yet been characterized. The abundance of proteins was markedly lower in the bacteria isolated from the nasal mucosa compared to the bacteria from the blood and CSF, indicating that initiating adhesion is the harshest challenge for meningococci. The high abundance of the glutamate dehydrogenase (GdhA) and Opa1800 proteins in all bacterial isolates suggests their essential role in bacterial survival in vivo. To evaluate the biological relevance of our proteomic findings, four candidate proteins from representative functional groups, such as the bacterial chaperone GroEL, IMP dehydrogenase GuaB, and membrane proteins PilQ and NMC0101, were selected and their impact on bacterial fitness was investigated by mutagenesis assays. This study provides an integrated picture of bacterial niche-specific adaptations during consecutive infection processes.
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| 2. |
- Wang, Xiao, et al.
(författare)
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CD46 accelerates macrophage-mediated host susceptibility to meningococcal sepsis in a murine model
- 2017
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 47:1, s. 119-130
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Tidskriftsartikel (refereegranskat)abstract
- CD46, a membrane cofactor expressed on all nucleated human cells, plays an essential role in suppressing autoimmune reactions and protecting host cells from complement-mediated attack. Human transgenic CD46 homozygousmice (CD46(+/+)) are prone to lethal sepsis upon infection with Neisseria meningitidis (N. meningitidis). However, the underlying mechanisms are poorly understood. Here, we determined thatCD46(+/+) mice produce large numbers of M1 type macrophages with enhanced surface expression of MHC II and production of pro-inflammatory mediators such as IL-6, TNF, IL-12, and IL-1 beta In the presence of M-CSF or GM-CSF, CD46 signaling enhances monocyte-macrophage differentiation. Additionally, CD46(+/+) macrophages rapidly undergo apoptosis upon LPS challenge or meningococcal infection, which could contribute to uncontrolled bacterial dissemination in vivo. Adoptive transfer of CD46(+/+) peritoneal macrophages aggravated septic responses in wild-type mice, but the depletion of macrophages partially alleviated septic reactions in CD46(+/+) mice after N. meningitidis infection. Our findings reveal a novel role of CD46 in accelerating inflammatory responses upon meningococcal infection or LPS stimulation by regulating the functional polarization and survival of macrophages.
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| 3. |
- Wang, Xiao, et al.
(författare)
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Immune Homeostatic Macrophages Programmed by the Bacterial Surface Protein NhhA Potentiate Nasopharyngeal Carriage of Neisseria meningitidis
- 2016
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Ingår i: mBio. - 2161-2129 .- 2150-7511. ; 7:1
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Tidskriftsartikel (refereegranskat)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 CD200Rhi phenotype (NhhA-MΦ). In response to meningococcal stimulation, NhhA-MΦ failed to produce proinflammatory mediators. Instead, they upregulated IL-10 and Th2/Treg-attracting chemokines, such as CCL-17, CCL-18, and CCL-22. Moreover, NhhA-MΦ cells 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. 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 (TLR)1/TLR2 signaling and ERK and JNK activation and required endogenously produced IL-10 and TNF-α. Our findings reveal a strategy that might be adopted by N. meningitidis to maintain asymptomatic nasopharyngeal colonization.
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