Nitrate Is an Environmental Cue in the Gut for Salmonella enterica Serovar Typhimurium Biofilm Dispersal through Curli Repression and Flagellum Activation via Cyclic-di-GMP Signaling

Miller, Amanda L.; Nicastro, Lauren K.; Bessho, Shingo; Grando, Kaitlyn; White, Aaron P.; Zhang, Yi; Queisser, Gillian; Buttaro, Bettina A.; Tükel, Çaǧla

doi:10.1128/mbio.02886-21

Cited by 21 publications

(15 citation statements)

References 72 publications

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“…During systemic infection, S. Typhimurium resides predominantly within the host macrophages [24]. Previous studies have reported that S. Typhimurium infection can stimulate iNOS and nitrate production in mouse macrophages [11], and the increase in nitrate levels in S. Typhimurium-infected RAW264.7 macrophages was also observed in this study. Concentrations of nitrate as high as 20 µM were detected in the supernatant of RAW264.7 cells during the 24 h infection period with S. Typhimurium (Figure 1a), and this is consistent with the data reported in previous studies.…”

Section: Nitrate Levels Are Increased During Systemic Infection By S ...supporting

confidence: 82%

“…As a stable derivative of NO, the levels of host-derived nitrate always increase due to the generation of NO upon S. Typhimurium infection. During infection of the intestine, S. Typhimurium can exploit this increased host nitrate to promote intestinal pathogenicity [11]. However, the functions of nitrate in the replication of S. Typhimurium within macrophages and in the systemic infection of S. Typhimurium are unknown.…”

Section: Discussionmentioning

confidence: 99%

“…S. Typhimurium employs nitrate as an electronic receptor to promote its growth in the intestinal tract [8,9], and it exploits nitrate as a signal to stimulate the expression of flagella to promote bacterial adhesion and invasion of intestinal epithelial cells [11] to thereby activate its intestinal pathogenicity. Our results indicate that nitrate also activates S. Typhimurium SPI-2 gene expression by inducing cytoplasmic acidification during systemic infection.…”

Section: Discussionmentioning

confidence: 99%

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Nitrate Utilization Promotes Systemic Infection of Salmonella Typhimurium in Mice

Yan

et al. 2022

IJMS

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Salmonella Typhimurium is an invasive enteric pathogen that causes gastroenteritis in humans and life-threatening systemic infections in mice. During infection of the intestine, S. Typhimurium can exploit nitrate as an electron acceptor to enhance its growth. However, the roles of nitrate on S. Typhimurium systemic infection are unknown. In this study, nitrate levels were found to be significantly increased in the liver and spleen of mice systemically infected by S. Typhimurium. Mutations in genes encoding nitrate transmembrane transporter (narK) or nitrate-producing flavohemoprotein (hmpA) decreased the replication of S. Typhimurium in macrophages and reduced systemic infection in vivo, suggesting that nitrate utilization promotes S. Typhimurium systemic virulence. Moreover, nitrate utilization contributes to the acidification of the S. Typhimurium cytoplasm, which can sustain the virulence of S. Typhimurium by increasing the transcription of virulence genes encoding on Salmonella pathogenicity island 2 (SPI-2). Furthermore, the growth advantage of S. Typhimurium conferred by nitrate utilization occurred only under low-oxygen conditions, and the nitrate utilization was activated by both the global regulator Fnr and the nitrate-sensing two-component system NarX-NarL. Collectively, this study revealed a novel mechanism adopted by Salmonella to interact with its host and increase its virulence.

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Section: Nitrate Levels Are Increased During Systemic Infection By S ...supporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Nitrate Utilization Promotes Systemic Infection of Salmonella Typhimurium in Mice

Yan

et al. 2022

IJMS

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“…Electron transport chain: proteins and organic molecules in the bacterial inner membrane that participate in redox reactions that translocate protons to the periplasm and ultimately shuttle electrons to a terminal electron acceptor. Energy metabolism: a set of biochemical reactions devoted to energy IR715 and increases motility, processes that may facilitate the spread of the pathogen in the inflamed gut [9]. In these examples, the ability of facultative anaerobic enterobacteria to use an array of AEAs represents a growth advantage over the native flora.…”

Section: Glossarymentioning

confidence: 99%

Respiration-induced biofilm formation as a driver for bacterial niche colonization

Martín‐Rodríguez¹

2023

Trends in Microbiology

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“…Similar biofilm control by the NarLX/NarPQ TCSs can be seen in human pathogen Burkholderia pseudomallei [ 71 , 89 ]. As nitrate and nitrite control and metabolism is central to many cellular processes, it is not surprising that many symbiotic and pathogenic bacteria have one or both of the previously described nitrogen-sensing TCSs or a homolog of these TCSs [ 22 , 25 , 90 ], though more detailed mechanistic research is necessary to link these nitrogen related TCSs directly to the modulation of virulence in more pathogens.…”

Section: Host Metabolic Products and Conditions As Tcs Triggersmentioning

confidence: 99%

Two-component systems regulate bacterial virulence in response to the host gastrointestinal environment and metabolic cues

2022

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Two-component systems are ubiquitous signaling mechanisms in bacteria that enable intracellular changes from extracellular cues. These bacterial regulatory systems couple external stimuli to control genetic expression via an autophosphorylation cascade that transduces membrane signals to intracellular locations, thereby allowing bacteria to rapidly adapt to the changing environmental conditions. Well known to control basic cellular processes, it is evident that two-component systems also exercise control over virulence traits, such as motility, secretion systems, and stress responses that impact the complex cascade of networks that alter virulence traits. In the gastrointestinal system, cues for activation of virulence-related two-component systems include metal ions, host-derived metabolites, and gut conditions. The diversity and origin of these cues suggest that the host can exert control over enteric pathogenicity via regulation in the gastrointestinal system. With the rise in multi-drug resistant pathogens, the potential control of pathogenicity with host cues via two-component systems presents a potential alternative to antimicrobials. Though the signaling mechanism itself is well studied, to date there is no systematic review compiling the host-associated cues of two-component systems and virulence traits. This review highlights the direct link between the host gastrointestinal environment and pathogenicity by focusing on two-component systems that are associated with the genetic expression of virulence traits, and that are activated by host-derived cues. The direct link between the host gastrointestinal environment, metabolites, and pathogenicity established in this review both underscores the importance of host-derived cues on bacterial activity and presents an enticing therapeutic target in the fight against antimicrobial resistant pathogens.

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Nitrate Is an Environmental Cue in the Gut for Salmonella enterica Serovar Typhimurium Biofilm Dispersal through Curli Repression and Flagellum Activation via Cyclic-di-GMP Signaling

Cited by 21 publications

References 72 publications

Nitrate Utilization Promotes Systemic Infection of Salmonella Typhimurium in Mice

Nitrate Utilization Promotes Systemic Infection of Salmonella Typhimurium in Mice

Respiration-induced biofilm formation as a driver for bacterial niche colonization

Two-component systems regulate bacterial virulence in response to the host gastrointestinal environment and metabolic cues

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