The Mechanisms by Which Salmonella Interferes with Nitric Oxide Production in Macrophages. IntroductionThis paper shows the postulated mechanisms through which Salmonella species manages to survive in macrophages irrespective of the stressful conditions in those cells. Salmonella species cause gastrointestinal and so many life threatening systemic infections in different hosts. It is classified as one of the leading causes (Lahiri et al 1166). The ability of Salmonella species to survive in macrophages and even proliferate in such innate immune cells shows their capacity to cause disease (Gilberthorpe et al 1756). The immune system of hosts infected by different pathogens has reactive mechanisms through which such pathogens are removed from the body.
After infection, the immune system responds by producing mechanisms and cells that can fight the pathogen. One of the immune response is the production of macrophages intracellular. Macrophages produce NO (Nitric Oxide) that limits the growth of intracellular pathogens. Salmonella as has been indicated is one of the intracellular pathogens but has the capability to withstand NO produced by the macrophages. Gilberthorpe et al note that Salmonella typhimurium can resist stressful environment created by the macrophages which include; production of reactive Oxygen Species such as superoxide anion (Oˉ2) and production of Reactive Nitrogen Species for example NO (1756).
Oxygen reactive species are produced by NAD(P)H Oxidase (Phox) while Reactive Nitrogen Species are produced by inducible Nitric Oxide Synthase (iNOS) (Gilberthorpe et al 1756). One important knowledge is that macrophages produce NO that acts to limit the growth of pathogens within the cells, but the mechanisms through which some pathogenic cells manage to withstand the NO is still unknown. Researchers have proposed several methods which are related but an exact method seems not clear.
Some mechanisms proposed indicate that Salmonella species avoid NO toxicity by use of detoxifying protein while some suggest that the pathogens up regulate enzymes involved in the modulation of NO. Some studies have even shown that Salmonella pathogenicity island 2 (SPI-2) acts as an intermediary in the protection of intracellular Salmonella from the toxic RNI (Lahiri et al 1167; Uchiya & Nikai 2004). According to Gilberthorpe et al, Salmonella species interfere with Nitric Oxide production by use of a protein flavohaemoglobin Hmp, which is encoded for by an hmp gene regulated by NsrR (1756).
This protein is said to detoxify Nitric oxide and produces a non toxic product to the bacteria N Oˉ3 making the pathogen to continue surviving in the macrophages. In a research titled “NsrR: a key regulator circumventing Salmonella enterica serovar Typhimurium oxidative and nitrosative stress in vitro and in IFN-c-stimulated J774.2 macrophages” (Gilberthorpe et al 1756), the researchers aim to prove that Salmonella enterica serovar Typhimurium has a genetic regulator that ensures production of the protein flavohaemoglobin Hmp, which results in detoxification of NO produced by the macrophages (Gilberthorpe et al 1756).
In another research, researchers try to show that Salmonella species avoid Nitric Oxide toxicity by up regulating arginase II. According to this research Salmonella pathogenicity island (SPI-2) is an intermediary in the protection of Salmonella pathogens from nitrosative stress in macrophages. Up-regulation of arginase II is due to the nature of competition between enzymes that modulate the fate of pathogens in cells. There are two enzymes involved in such modulation, these are iNOS and arginase.
Arginase has two forms, arginase I and arginase II. These enzymes use L-arginine as a substrate in the production of Nitric Oxide (Lahiri et al 1166-1167).