Question

In: Biology

An experimental mouse model of Leishmania infection was used by Nathan and Miller to investigate the...

An experimental mouse model of Leishmania infection was used by
Nathan and Miller to investigate the relative contribution of reactive
oxygen intermediates (ROIs) and reactive nitrogen intermediates
(RNIs) in the control of leishmaniasis.
i) How did the authors establish that RNIs but not ROIs are essential and
sufficient to limit an infection?
ii) How are these toxic intermediates generated by redox reactions
and what mechanisms protect the parasite against their toxicity?

Solutions

Expert Solution

i.) Nathan and Miller experiments on Leishmania donovani was done in experimental mouse models in order to determine the relative contributions of respiratory burst-derived reactive oxygen intermediates (ROI) versus reactive nitrogen intermediates (RNI) to macrophage-mediated intracellular host defense. They used mice genetically deficient in these mechanisms and were challenged with Leishmania donovani, a protozoan that selectively parasitizes visceral tissue macrophages. The experimental mice were either lacking mechanism for producing ROI or the mechanism for producing iNOS (RNI). When the mice were experimentally infected they found that ROI mediated defense mechanism is dispensable that means the mouse which was producing RNI but not producing ROI was recovered and infection was limited. while the mice lacking RNI the infection was unrestrained. and thus proving RNI was essential in limiting the Leishmania infection.

ii.) Main ROI generating enzymes are oxidoreductases like cytochromes involved in electron transport chain. nearly 10% oxygen is converted into free radicles or ROI. NADPH oxidases are also a major source of ROI and are associated with macrophages, monocytes, and neutrophils. NADPH oxidase is responsible for respiratory burst during the activation of these cells.

RNI is generated by NOS (nitric oxide synthase) activity. there are three main NOS: NOS I, NOS II, NOS III. in any case RNI is generated by five electron reduction of arginine, an amino acid. the reaction is catalyzed by NOS and is dependent on the presence of NADPH, FMN, FAD, and biopterin.

There are at least three different categories of mechanisms how an intracellular pathogen might become phenotypically resistant to effector pathways of host phagocytes: (i) synthesis of antioxidants that directly detoxify (i.e. neutralize or degrade) the effector molecules; (ii) the rapid degradation of microbial proteins that have been modified by the host cell?derived effector molecules and thereby became non?functional or toxic to the pathogen; and (iii) the adaptation of the microbial metabolism that helps the pathogen to bypass the effect of killer molecules or nutrient restrictions in the host cell. In the case of Leishmania parasites partial resistance to ROI or reactive nitrogen intermediates (RNI) has been described for the extracellular (promastigote) and for the intracellular (amastigote) stage of certain Leishmania species. Reported underlying mechanisms are the putative ROI?scavenging function of phosphoglycans and the expression of superoxide dismutase, catalase and/or peroxiredoxins most of which were directly shown to support the survival of Leishmania within macrophages.


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