Abstract
Itaconic acid is an immunoregulatory metabolite produced by macrophages in response to pathogen invasion. It also exhibits antibacterial activity because it is an uncompetitive inhibitor of isocitrate lyase, whose activity is required for the glyoxylate shunt to be operational. Some bacteria, such as Yersinia pestis, encode enzymes that can degrade itaconic acid and therefore eliminate this metabolic inhibitor. Studies, primarily with Salmonella enterica subspecies enterica serovar Typhimurium, have demonstrated the presence of similar genes in this pathogen and the importance of these genes for the persistence of the pathogen in murine hosts. This minireview demonstrates that, based on Blast searches of 1063 complete Salmonella genome sequences, not all Salmonella serovars possess these genes. It is also shown that the growth of Salmonella isolates that do not possess these genes is sensitive to the acid under glucose-limiting conditions. Interestingly, most of the serovars without the three genes, including serovar Typhi, harbor DNA at the corresponding genomic location that encodes two open reading frames that are similar to bacteriocin immunity genes. It is hypothesized that these genes could be important for Salmonella that finds itself in strong competition with other Enterobacteriacea in the intestinal tract—for example, during inflammation.
Highlights
Itaconic acid is an immunoregulatory metabolite produced by macrophages in response to pathogen invasion
It is hypothesized that these genes could be important for Salmonella that finds itself in strong competition with other Enterobacteriacea in the intestinal tract—for example, during inflammation
Itaconic acid and bacteriocins are among the many compounds that Salmonella species must contend with in their environments and hosts
Summary
Itaconic acid and bacteriocins are among the many compounds that Salmonella species must contend with in their environments and hosts. Though, Salmonella species will encounter the acid when near or inside activated macrophages, since these cells produce and secrete itaconic acid upon stimulation by γ-interferon and lipopolysaccharide [5]. Cellular concentrations of the acid within lipopolysaccharide (LPS)-treated RAW264.7 mouse macrophages were estimated to be about 8 mM and 3 mM in BV2 retroviral-immortalized microglia cells [6]. The full TCA cycle is operational and isocitrate lyase is dispensable; when only fatty acids or acetate are available, isocitrate dehydrogenase is phosphorylated, causing its activity to cease, and isocitrate lyase, the enzyme sensitive to itaconic acid, is able to utilize the accumulating isocitrate for the glyoxylate shunt
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