Control of Disease Tolerance to Malaria by Nitric Oxide and Carbon Monoxide

Abstract

Nitric oxide (NO) and carbon monoxide (CO) are gasotransmitters that suppress the development of severe forms of malaria associated with Plasmodium infection. Here, we addressed the mechanism underlying their protective effect against experimental cerebral malaria (ECM), a severe form of malaria that develops in Plasmodium-infected mice, which resembles, in many aspects, human cerebral malaria (CM). NO suppresses the pathogenesis of ECM via a mechanism involving (1) the transcription factor nuclear factor erythroid 2-related factor 2 (NRF-2), (2) induction of heme oxygenase-1 (HO-1), and (3) CO production via heme catabolism by HO-1. The protection afforded by NO is associated with inhibition of CD4(+) T helper (TH) and CD8(+) cytotoxic (TC) T cell activation in response to Plasmodium infection via a mechanism involving HO-1 and CO. The protective effect of NO and CO is not associated with modulation of host pathogen load, suggesting that these gasotransmitters establish a crosstalk-conferring disease tolerance to Plasmodium infection.

Disease tolerance and immunity in host protection against infection

“…The oxidative stress response orchestrated by the transcription factor, nuclear factor E2-related factor-2 (NRF2) 27,28 (Figure 2) can contribute critically to the establishment of disease tolerance to infection, as demonstrated for malaria 20,29 . Briefly, the blood stage of Plasmodium infection is associated with hemolysis and hence with generation of extracellular hemoglobin 20,21,29,30 . Upon oxidation, extracellular hemoglobin releases its prosthetic heme groups, which act as catalysts in the production of reactive oxygen species (ROS) and nitrogen species (RNS).…”

“…In some instances, administration of hemopexin, a plasma protein that binds avidly to labile heme and neutralizes its deleterious effects, confers tissue damage control and disease tolerance to sepsis in mice 16 . The pathological effects of labile heme can also be neutralized by gasotransmitters such as CO 21 or NO 29 , which bind avidly to ferrous heme-iron (Fe 2+ ) in hemoproteins. In the case of CO, this gasotransmitter blocks heme-iron oxidation (Fe 2+ ->Fe 3+ ) and inhibits heme release from hemoproteins, preventing its accumulation in plasma during bloodstream infections 20,21 .…”

“…An alternative approach is to quantify pathogen load in "whole body", as performed routinely in flies 5,9,10,127 . This is more challenging in other species, including rodents, but can be achieved, for example, using transgenic pathogens expressing reporter probes quantified throughout the course of an infection by whole body imaging 29 .…”

“…Presumably these effects are mediated via adenosine-driven signaling through transmembrane adenosine G proteincoupled cell surface receptors 109,163 . Lipid peroxidation is countered by several damage responses 50 that induce HO-1 31 , a heme catabolizing enzyme that degrades the lipophilic pro-oxidant heme into biliverdin, which is converted by biliverdin reductase into the lipophilic anti-oxidant bilirubin 164 and promotes disease tolerance to bloodstream infections 16,20,21,[29][30][31] .…”

Malaria Parasites in the Asymptomatic: Looking for the Hay in the Haystack

“…Nitric oxide (NO), which has been shown to be produced at higher levels by mononuclear cells in asymptomatic children [96], can suppress the pathogenesis of severe malaria through induction of heme oxygenase-1 (HO-1), CO production, and inhibition of T cell activation [97]. However, conflicting results have questioned the role for NO in mediating tolerance [98].…”