Nitric Oxide and Salmonella Pathogenesis

Abstract

Nitric oxide (NO) and its congeners contribute to the innate immune response to Salmonella. This enteric pathogen is exposed to reactive nitrogen species (RNS) in the environment and at different anatomical locations during its infectious cycle in vertebrate hosts. Chemical generation of RNS enhances the gastric barrier to enteropathogenic bacteria, while products of the Salmonella pathogenicity island 1 type III secretion system and Salmonella-associated molecular patterns stimulate transcription of inducible NO synthase (iNOS) by cells of the mononuclear phagocytic cell lineage. The resulting NO, or products that arise from its interactions with oxygen (O2) or iron and low-molecular weight thiols, are preferentially bacteriostatic against Salmonella, while reaction of NO and superoxide (O2−) generates the bactericidal compound peroxynitrite (ONOO−). The anti-Salmonella activity of RNS emanates from the modification of redox active thiols and metal prosthetic groups of key molecular targets of the electron transport chain, central metabolic enzymes, transcription factors, and DNA and DNA-associated proteins. In turn, Salmonella display a plethora of defenses that modulate the delivery of iNOS-containing vesicles to phagosomes, scavenge and detoxify RNS, and repair biomolecules damaged by these toxic species. Traditionally, RNS have been recognized as important mediators of host defense against Salmonella. However, exciting new findings indicate that Salmonella can exploit the RNS produced during the infection to foster virulence. More knowledge of the primary RNS produced in response to Salmonella infection, the bacterial processes affected by these toxic species, and the adaptive bacterial responses that protect Salmonella from nitrosative and oxidative stress associated with NO will increase our understanding of Salmonella pathogenesis. This information may assist in the development of novel therapeutics against this common enteropathogen.

Expression of STM4467 -Encoded Arginine Deiminase Controlled by the STM4463 Regulator Contributes to Salmonella enterica Serovar Typhimurium Virulence

“…The results indicated that infection by wild-type Salmonella dramatically increased the NO levels in macrophages (Fig. 6), in accordance with the observation that NOS activity is inducible upon bacterial infection (26). We found that the levels of NO production stimulated by Salmonella bacteria with the STM4467 deletion were comparable to those occurring upon infection with the wild-type strain (Fig.…”

The Nramp (Slc11) proteins regulate development, resistance to pathogenic bacteria and iron homeostasis in Dictyostelium discoideum

“…Although Fe 2+ in phagolysosomes can produce hydroxyl radicals via Fenton reaction, thus potentially killing bacteria, depletion of the iron pool from the phagosome deprives pathogenic bacteria of metal ions that are critical for their survival. Invasive bacteria, such as Legionella pneumophila, Mycobacterium tuberculosis or Salmonella enterica serovar Typhimurium are known to absorb large amounts of iron, while at the same time they are resistant to oxygen radicals (Henard and Vazquez-Torres, 2011;Johnson and Wessling-Resnick, 2012;Kortman et al, 2012;Moalem et al, 2004;Robey and Cianciotto, 2002;Slauch, 2011). Recently, we also showed that L. pneumophila hinders recruitment of the V-H + -ATPase, but not Nramp1, in the Legionella-containing vacuole in a process apparently involving inhibition of phosphatidylinositol-3-phosphate formation.…”

Ferric Uptake Regulator-Dependent Antinitrosative Defenses in Salmonella enterica Serovar Typhimurium Pathogenesis

“…For example, Fur is a positive regulator of the sufABCDSE operon that encodes an enzymatic pathway for the repair of oxidized [4Fe-4S] clusters (42). As mentioned earlier, [4Fe-4S] clusters in dehydratases are some of the preferred targets of NO and some of its oxidative products, such as peroxynitrite (38,43). Low levels of expression of SufABCDSE in fur mutant bacteria could have devastating effects on the repair of dehydratases, such as aconitase, the nuo-encoded NADH dehydrogenase, glutamate synthetase, and dihydroxy acid dehydratase, which are responsible for key aspects of central metabolism.…”

“…Second, lower concentrations of the cytochrome bd oxidase, which is known to detoxify NO (31), might have contributed to the slow detoxification of this diatomic radical in fur mutant Salmonella. The lingering concentrations of NO noted in cultures of fur mutant Salmonella could exert lasting cytotoxicity to critical enzymes, such as ribonucleotide reductase and dihydroxy acid dehydratase (38). Low concentrations of cytochrome bd oxidase could also explain why the doubling time of fur mutant Salmonella undergoing nitrosative stress is less than the one recorded for wild-type controls.…”

“…In this context, cytochromes were recently found to add to the pathogenicity of S. aureus (37). Copper and iron cofactors in quinol cytochrome oxidases are some of the preferred targets of the cytotoxicity of NO (38). Therefore, the extended inhibition of respiration experienced by fur mutant bacteria undergoing nitrosative stress could have a particularly devastating effect on ATP synthesis, cell growth, and Salmonella pathogenesis.…”