A host metabolite promotes <em>Salmonella</em> survival

doi:10.1126/science.abf8414

GSTDTAP > 气候变化

DOI	10.1126/science.abf8414
	*A host metabolite promotes Salmonella* survival**
	Jason P. Lynch; Cammie F. Lesser
	2021-01-22
发表期刊	Science
出版年	2021
英文摘要	The Krebs cycle is a key metabolic pathway that is common to bacteria and mitochondria, often referred to as the central hub of aerobic metabolism. However, on recognition of invading bacteria and other proinflammatory stimuli, the Krebs cycle of macrophages is reprogrammed, shifting from oxidative phosphorylation to glycolysis, resulting in accumulation of intermediate metabolites. These metabolites, which include succinate, act to induce expression of genes involved in promoting inflammation. On page 400 of this issue, Rosenberg et al. ([ 1 ][1]) provide evidence that the bacterium Salmonella enterica serovar Typhimurium ( S. Tm), in response to increases in succinate, induces the expression of virulence determinants that promote survival within reprogrammed inflammatory macrophages. ![Figure][2] Succinate promotes expression of virulence determinants The invasion of Salmonella enterica serovar Typhimurium ( S. Tm) into macrophages triggers reprogramming of the Krebs cycle. The subsequent accumulation of succinate is sensed by S. Tm within Salmonella -containing vacuoles (SCVs), resulting in increased expression of the Salmonella pathogenicity island 2 type III secretion system (SPI2 T3SS) and polymixin resistance (PMR) regulons that promote intracellular bacterial replication. GRAPHIC: KELLIE HOLOSKI/ SCIENCE S. Tm is a highly versatile enteric pathogen and one of the most common bacterial causes of gastroenteritis. S. Tm is considered an intracellular pathogen that establishes a replicative niche in phagosomes of either intestinal epithelial cells or macrophages. In addition, S. Tm colonizes the lumen of the large intestines, ensuring its successful transmission by a fecal-oral route. The pathogenesis of S. Tm is dependent on the coordinated regulation of a variety of virulence determinants controlled by complicated regulatory networks that integrate numerous environmental cues, including temperature, oxygenation, osmolarity, and nutrient availability ([ 2 ][3]). Macrophages are critical mediators of the host innate immune response. They recognize, engulf, and kill invading pathogens, as well as produce proinflammatory cytokines and chemokines to initiate inflammation. Part of this response involves metabolic reprogramming whereby the Krebs cycle in macrophages is broken at multiple steps ([ 3 ][4]). An important consequence of this is the accumulation of Krebs cycle metabolites, including succinate, aketoglutarate, citrate, and itaconate, each of which can act as a signaling molecule to modulate the inflammatory response. To investigate whether S. Tm within infected macrophages adapt to host cell metabolic reprogramming, Rosenberg et al. used dual RNA sequencing to assess gene expression of both infected macrophages and intracellular bacteria. Analyses of bacterial gene expression changes led to the discovery of enhanced expression of two regulons that promote the survival of intracellular S. Tm. The first induced regulon, the Salmonella pathogenicity island 2 (SPI2) type III secretion system (T3SS), promotes the expression of a protein delivery vehicle that injects proteins into host cells that promote the remodeling of a S. Tm–containing phagosome. The second regulon, called the polymixin resistance (PMR) regulon, mediates the expression of genes that promote S. Tm resistance to antimicrobial peptides by promoting lipopolysaccharide modifications. Rosenberg et al. found that succinate alone was sufficient to induce expression of both regulons in S. Tm and that S. Tm cells that lack succinate transporters were impaired in their ability to replicate within infected macrophages. Furthermore, the succinate-mediated effects were unaltered in the absence of an intact bacterial Krebs cycle, suggesting that succinate directly modulates the expression of S. Tm regulons akin to how it regulates macrophage gene expression, as opposed to utilizing succinate for metabolic purposes (see the figure). Prior to invading macrophages and intestinal epithelial cells, S. Tm establishes a replicative niche within the large intestines. This is an inhospitable environment to S. Tm because this pathogen prefers to grow in the presence of oxygen, and the large intestines are anoxic and densely colonized by obligate anaerobes primarily of the classes Clostridia and Bacteroidia . However, the recognition of S. Tm by intestinal epithelial cells leads to the initiation of innate immune responses and the development of an inflammatory milieu in the gut that promotes S. Tm replication. Neutrophils recruited to the gut release elastase and reactive oxygen species (ROS), reagents to which S. Tm is inherently resistant, but to which the Clostridia and Bacteroides are sensitive ([ 4 ][5]–[ 6 ][6]). The depletion of these anaerobes by neutrophils leads to loss of a source of bacterial short-chain fatty acids, nutrients that promote the viability of intestinal epithelial cells ([ 7 ][7]). Starved of these metabolites, intestinal epithelial cells become dysfunctional, shifting from oxidative phosphorylation to glycolysis, which diminishes their consumption of oxygen. Consequently, oxygen passively diffuses across the epithelium from the surrounding vasculature into the gut lumen. The increased oxygen tension results in expression of all of the enzymes of the S. Tm Krebs cycle ([ 8 ][8]). This enables S. Tm to perform a complete Krebs cycle, which is fed by microbiota-derived metabolites, including succinate. This promotes aerobic metabolism and results in a burst of S. Tm replication within the intestinal lumen. These studies, together with the findings of Rosenberg et al. , demonstrate that S. Tm can respond to succinate in two distinct ways. Within the gut lumen, S. Tm utilizes microbiota-derived succinate as a nutrient source, whereas within metabolically reprogrammed macrophages, succinate is used as an activation signal. These findings also provide examples of how the Krebs cycle of both host cells and bacteria can be reprogrammed in the context of an infection. There is growing evidence for microbiota-driven metabolites influencing the growth of invading pathogens. For example, microbiota-derived succinate can also promote blooms of the pathogen Clostridium difficile ([ 9 ][9]), and the growth of multiple intracellular pathogens, including Legionella, Francisella, Shigella , and Anaplasma species, is driven by host-derived amino acids or metabolites ([ 10 ][10]). Given the intricate ways that successful bacterial pathogens have evolved to combat host defense pathways, it seems likely that succinate and/or other Krebs cycle metabolites are sensed by other pathogens. In this regard, succinate has been reported to induce expression of at least one component of the T3SS of Citrobacter rodentium , an extracellular intestinal pathogen, through the regulation of Cra, a global transcriptional regulator ([ 11 ][11]). It will also be interesting to discover how a single metabolite, succinate, is able to regulate the expression of two distinct S. Tm regulons. Is it through the modulation of a yet-to-be-identified common regulator? Is it due to the direct binding to one or more transcription factors or regulatory small RNAs? Perhaps succinate acts within the invading pathogen to promote post-translational succinylation of regulatory proteins and thereby alters their function ([ 12 ][12]). More research is needed to understand succinate-mediated gene regulation. 1. [↵][13]1. G. Rosenberg, 2. D. Yehezkel, 3. D. Hoffman , Science 371, 400 (2021). [OpenUrl][14][Abstract/FREE Full Text][15] 2. [↵][16]1. A. Fàbrega, 2. J. Vila , Clin. Microbiol. Rev. 26, 308 (2013). [OpenUrl][17][Abstract/FREE Full Text][18] 3. [↵][19]1. D. G. Ryan, 2. L. A. J. O'Neill , Annu. Rev. Immunol. 38, 289 (2020). [OpenUrl][20] 4. [↵][21]1. N. Gill et al ., PLOS ONE 7, e49646 (2012). [OpenUrl][22][CrossRef][23][PubMed][24] 5. 1. I. Sekiro et al ., Gut Microbes 1, 30 (2010). [OpenUrl][25][CrossRef][26][PubMed][27] 6. [↵][28]1. C. C. Gillis et al ., Cell Host Microbe 23, 54 (2018). [OpenUrl][29][CrossRef][30][PubMed][31] 7. [↵][32]1. F. Rivera-Chávez et al ., Cell Host Microbe 19, 443 (2016). [OpenUrl][33][CrossRef][34][PubMed][35] 8. [↵][36]1. L. Spiga et al ., Cell Host Microbe 22, 291 (2017). [OpenUrl][37][CrossRef][38][PubMed][39] 9. [↵][40]1. J. A. Ferreyra et al ., Cell Host Microbe 16, 770 (2014). [OpenUrl][41][CrossRef][42][PubMed][43] 10. [↵][44]1. A. Best, 2. Y. Abu Kwaik , Trends Microbiol. 27, 550 (2019). [OpenUrl][45][CrossRef][46] 11. [↵][47]1. M. M. Curtis et al ., Cell Host Microbe 16, 759 (2014). [OpenUrl][48][CrossRef][49][PubMed][50] 12. [↵][51]1. J. Liu, 2. C. Qian, 3. X. Cao , Immunity 45, 15 (2016). [OpenUrl][52][CrossRef][53][PubMed][54] Acknowledgments: The authors are supported by the National Institutes of Health (R01DK113599, R01AI128360, R21AI144716) and the Kenneth Rainin Foundation. C.F.L. is also the Brit d'Arbeloff MGH research scholar and J.P.L. a Crohn's and Colitis Foundation Association Postdoctoral Scholar. C.F.L. is on the scientific advisory board of Synlogic Therapeutics. 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领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/312353
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Jason P. Lynch,Cammie F. Lesser. A host metabolite promotes Salmonella survival[J]. Science,2021.
APA	Jason P. Lynch,&Cammie F. Lesser.(2021).A host metabolite promotes Salmonella survival.Science.
MLA	Jason P. Lynch,et al."A host metabolite promotes Salmonella survival".Science (2021).