Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens

Abstract

This review summarizes recent evidence from knock-out mice on the role of reactive oxygen intermediates and reactive nitrogen intermediates (RNI) in mammalian immunity. Reflections on redundancy in immunity help explain an apparent paradox: the phagocyte oxidase and inducible nitric oxide synthase are each nonredundant, and yet also mutually redundant, in host defense. In combination, the contribution of these two enzymes appears to be greater than previously appreciated. The remainder of this review focuses on a relatively new field, the basis of microbial resistance to RNI. Experimental tuberculosis provides an important example of an extended, dynamic balance between host and pathogen in which RNI play a major role. In diseases such as tuberculosis, a molecular understanding of host-pathogen interactions requires characterization of the defenses used by microbes against RNI, analogous to our understanding of defenses against reactive oxygen intermediates. Genetic and biochemical approaches have identified candidates for RNI-resistance genes in Mycobacterium tuberculosis and other pathogens.

Figure 1

ROI and RNI production in mammalian cells via phox and NOS: parallel but connecting paths. Nitroxyl anion (NO⁻), a one-electron reduction product of nitric oxide (^⋅NO), is unlikely to arise from ^⋅NO under physiologic conditions, but is considered by some investigators to be a primary and more toxic product of NOS (91). Reaction of RNI with cysteine sulfhydryls can lead either to S-nitrosylation or to oxidation to the sulfenic acid, as well as to disulfide bond formation (not shown), all of which are potentially reversible. Peroxynitrite anion (OONO⁻) and peroxynitrous acid (OONOH) have distinct patterns of reactivity (92), but for simplicity, the text refers to both as peroxynitrite. OONOH spontaneously decomposes via species resembling the reactive radicals, hydroxyl (OH^⋅) and/or nitrogen dioxide (^⋅NO₂). When l-arginine is limiting, NOS can produce superoxide (O_2⨪) along with ^⋅NO, favoring the formation of peroxynitrite (5).