Glutamate utilization promotes meningococcal survival <i>in vivo</i> through avoidance of the neutrophil oxidative burst

Talà, Adelfia; Monaco, Caterina; Nagorska, Krzysztofa; Exley, Rachel M.; Corbett, Anne; Zychlinsky, Arturo; Alifano, Pietro; Tang, Christoph M.

doi:10.1111/j.1365-2958.2011.07766.x

Cited by 27 publications

(38 citation statements)

References 72 publications

(105 reference statements)

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“…Confirming our results, articles various inflammation modulating effects of L-glutamate [27] and L-arginine [28] were observed in vivo.…”

Section: Discussionsupporting

confidence: 76%

“…In conclusion, our in vivo and ex vivo experimental data suggest that the L-amino acids, independent of their metabolic significance, may continuosly and quickly modify the activity of human peripheral neutrophil granulocytes and also the outcome of various immunologic reactions [27,28]. Both the mTORC1 and mTORC2 axises of mTOR signaling pathway can be involved in these processes, as the activation mTORC1 complex by the amino acids involves a transient impairment in the function of mTORC2 complex in these processes.…”

Section: Resultsmentioning

confidence: 99%

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Effects of L-amino Acids on Human Peripheral Neutrophil Granulocyte Activation

Sipka¹,

Keresztes²,

Kovács³

et al. 2014

TONUTRJ

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Objective:The objective was to investigate the early (20 minutes) effects of 21 L-amino acids on the activation of human neutrophils and to determine in healthy individuals the effects of a meal on the 1) number and relative luminescence unit (RLU) of peripheral neutrophils, 2) serum glutamate and glucose levels and 3) mTOR signaling network. Methods:The RLU of neutrophils stimulated by Ca 2+ ionophor (CaI) and phorbol myristate acetate (PMA) following amino acid supplementation (3 x 10 -4 M) or after consuming a meal was determined. L-glutamate was measured by HPLC.Results: All amino acids resulted in significant inhibitions of neutrophil RLU, except for arginine, which stimulated neutrophils. The ratios of amino acid induced inhibition were significantly higher in the cells stimulated by PMA than by CaI. The consumption of a meal resulted in a significant serum glutamate elevation compared to baseline (2.3 versus 0.9 x10 -4 M) 90 minutes after ingestion of the meal. It was independent of the body mass index and returned near fasting levels after 150 minutes. The number of neutrophils was significantly elevated 90 minutes after the meal but the PMA induced RLU was significantly decreased. Conclusion:Our ex vivo and in vivo results suggest that the L-amino acids, independent of their metabolic significance, may continuosly and quickly modify the activity of human peripheral neutrophils, and also the outcome of various immunologic reactions. The activation of the mTORC1 complex likely involves a transient impairment in the function of mTORC2 complex in these processes.

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“…Confirming our results, articles various inflammation modulating effects of L-glutamate [27] and L-arginine [28] were observed in vivo.…”

Section: Discussionsupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Effects of L-amino Acids on Human Peripheral Neutrophil Granulocyte Activation

Sipka¹,

Keresztes²,

Kovács³

et al. 2014

TONUTRJ

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“…N. meningitidis reportedly resists neutrophil oxidative burst by synthesizing glutathione, a key molecule in the control of the redox state in all living cells (48,49), from L-glutamate obtained via GltT-GltM (29). Since endothelial cells produce oxygen radicals, such as ROS, upon microbial infection (31,33,34), we speculated that a relationship might exist between glutathione synthesis and HBMEC invasion ability under our experimental conditions.…”

Section: Resultsmentioning

confidence: 99%

“…In N. meningitidis, glutamate is essential for growth in chemically defined medium (26), as well as in the intracellular milieu (27). N. meningitidis has two glutamate transporters: the high-sodium (Na ϩ )-dependent glutamate transporter GltS (28,29) and the Lglutamate ABC-type transporter GltT-GltM, which functions under low-Na ϩ conditions (28-30). GltT-GltM is reportedly required for survival in HeLa cells (27,28), as well as for resistance to neutrophil oxidative burst (29).…”

mentioning

confidence: 99%

Multiple Functions of Glutamate Uptake via Meningococcal GltT-GltM l -Glutamate ABC Transporter in Neisseria meningitidis Internalization into Human Brain Microvascular Endothelial Cells

Takahashi

Yanagisawa²,

Kim

et al. 2015

Infect Immun

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cWe previously reported that Neisseria meningitidis internalization into human brain microvasocular endothelial cells (HBMEC) was triggered by the influx of extracellular L-glutamate via the GltT-GltM L-glutamate ABC transporter, but the underlying mechanism remained unclear. We found that the ⌬gltT ⌬gltM invasion defect in assay medium (AM) was alleviated in AM without 10% fetal bovine serum (FBS) [AM(؊S)]. The alleviation disappeared again in AM(؊S) supplemented with 500 M glutamate. Glutamate uptake by the ⌬gltT ⌬gltM mutant was less efficient than that by the wild-type strain, but only upon HBMEC infection. We also observed that both GltT-GltM-dependent invasion and accumulation of ezrin, a key membrane-cytoskeleton linker, were more pronounced when N. meningitidis formed larger colonies on HBMEC under physiological glutamate conditions. These results suggested that GltT-GltM-dependent meningococcal internalization into HBMEC might be induced by the reduced environmental glutamate concentration upon infection. Furthermore, we found that the amount of glutathione within the ⌬gltT ⌬gltM mutant was much lower than that within the wild-type N. meningitidis strain only upon HBMEC infection and was correlated with intracellular survival. Considering that the L-glutamate obtained via GltT-GltM is utilized as a nutrient in host cells, L-glutamate uptake via GltT-GltM plays multiple roles in N. meningitidis internalization into HBMEC. N eisseria meningitidis is a Gram-negative microorganism and an exclusive human pathogen. It usually exists in an asymptomatic nasopharyngeal carriage state at a rate of 0.4% to 25% in human populations (1, 2). However, N. meningitidis can cause devastating invasive diseases, such as septicemia or meningitis, by penetration of the mucosal tissue, invasion of the bloodstream, and colonization of the meninges. Human genome-wide association studies (3, 4) identified single nucleotide polymorphisms in complement factor H (CFH) and CFH-related protein 3 (CFHR3), and CFHR3 promotes immune activation by acting as an antagonist of CFH (5). Environmental conditions, such as smoking (6, 7) and climate (8), are also likely to be important in determining the outcome of infection. However, the exact reasons why the diseases occur in some individuals and not in others remain unclear.Many attempts to identify bona fide virulence factors in N. meningitidis have been reported. Surface molecules, such as Opa, Opc, pili, lipooligosaccharide, and the polysaccharide capsule, have been identified as adhesive and invasive factors in N. meningitidis (9-12). In addition, genome informatics also revealed several minor adhesion and invasion proteins, such as App (13), NhhA (14), MspA (15), and NadA (16). Other attempts to find meningococcal virulence factors by genome informatics involved comparisons between commensal and pathogenic bacteria (17) and the modes of bacterial virulence evolution (18). However, many of the so-called meningococcal "virulence genes" are also present in commensal neisserial species (19,...

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“…[25][26][27]. N. meningitidis lacks a functional glutamate synthase gene, hence lacks glutamine synthase enzyme for the synthesis of glutamate [28]. The organism takes in glutamate either from the external environment or synthesized in NADPH specific glutamate dehydrogenase in presence of high external NH…”

Section: Cultivation Media and Bacterial Growthmentioning

confidence: 99%

Optimization of Media and Feeding Strategy for Improved Capsular Polysaccharide Yield for Neisseria meningitidis W-135

Kambrath¹,

Reddy²

2017

THE IJES

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has turned out to be the reason for recent outbreak of meningitis in the sub-Saharan regions of Africa including Cameroon, Chad, Gambia, Burkina Faso, and other countries. The capsular polysaccharide (PS) of Neisseria meningitidis serogroups A, C, X, Y, and W-135 are excellent vaccine targets against meningitis caused by this bacterium. This study promotes a novel feed solution including amino acids, vitamins, and glucose along with an optimal fermentation medium; and feeding strategy to cultivate high yield polysaccharide at harvest level. The study is based on the hypothesis that glucose is one of the major growth determining factors with the combinations of nitrogen sources. In this study, fed-batch cultivation was performed in a 2L fermenter, maintaining the following conditions: (i) Temperature = 37ºC (ii) pH = 7.0 (iii) Agitation frequency in the range 150 rotations per minute (rpm) to 500 rpm, and (iv) Dissolved oxygen (DO) 20%-25%. The bacterial growth and polysaccharide production were found to be enhanced when the feed flow was increased periodically from late lag phase to early decline phase. The polysaccharide production was found to be maximum in the early decline phase of the bacterial growth. The said method produced polysaccharide of about 1000mg/L, which is twice the reported method. There is limited research information available on fed-batch cultivation and feeding strategy for growing Neisseria meningitidis W-135. The major findings of this study can provide significant contribution in the field of capsular polysaccharide production from which MenW polysaccharide vaccines are manufactured.

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Glutamate utilization promotes meningococcal survival in vivo through avoidance of the neutrophil oxidative burst

Cited by 27 publications

References 72 publications

Effects of L-amino Acids on Human Peripheral Neutrophil Granulocyte Activation

Effects of L-amino Acids on Human Peripheral Neutrophil Granulocyte Activation

Multiple Functions of Glutamate Uptake via Meningococcal GltT-GltM l -Glutamate ABC Transporter in Neisseria meningitidis Internalization into Human Brain Microvascular Endothelial Cells

Optimization of Media and Feeding Strategy for Improved Capsular Polysaccharide Yield for Neisseria meningitidis W-135

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