Neutrophils to the ROScue: Mechanisms of NADPH Oxidase Activation and Bacterial Resistance

Abstract

Reactive oxygen species (ROS) generated by NADPH oxidase play an important role in antimicrobial host defense and inflammation. Their deficiency in humans results in recurrent and severe bacterial infections, while their unregulated release leads to pathology from excessive inflammation. The release of high concentrations of ROS aids in clearance of invading bacteria. Localization of ROS release to phagosomes containing pathogens limits tissue damage. Host immune cells, like neutrophils, also known as PMNs, will release large amounts of ROS at the site of infection following the activation of surface receptors. The binding of ligands to G-protein-coupled receptors (GPCRs), toll-like receptors, and cytokine receptors can prime PMNs for a more robust response if additional signals are encountered. Meanwhile, activation of Fc and integrin directly induces high levels of ROS production. Additionally, GPCRs that bind to the bacterial-peptide analog fMLP, a neutrophil chemoattractant, can both prime cells and trigger low levels of ROS production. Engagement of these receptors initiates intracellular signaling pathways, resulting in activation of downstream effector proteins, assembly of the NADPH oxidase complex, and ultimately, the production of ROS by this complex. Within PMNs, ROS released by the NADPH oxidase complex can activate granular proteases and induce the formation of neutrophil extracellular traps (NETs). Additionally, ROS can cross the membranes of bacterial pathogens and damage their nucleic acids, proteins, and cell membranes. Consequently, in order to establish infections, bacterial pathogens employ various strategies to prevent restriction by PMN-derived ROS or downstream consequences of ROS production. Some pathogens are able to directly prevent the oxidative burst of phagocytes using secreted effector proteins or toxins that interfere with translocation of the NADPH oxidase complex or signaling pathways needed for its activation. Nonetheless, these pathogens often rely on repair and detoxifying proteins in addition to these secreted effectors and toxins in order to resist mammalian sources of ROS. This suggests that pathogens have both intrinsic and extrinsic mechanisms to avoid restriction by PMN-derived ROS. Here, we review mechanisms of oxidative burst in PMNs in response to bacterial infections, as well as the mechanisms by which bacterial pathogens thwart restriction by ROS to survive under conditions of oxidative stress.

<b><i>Salmonella</i></b> and Reactive Oxygen Species: A Love-Hate Relationship

“…However, salmonella expresses a lipopolysaccharide with an O antigen; the latter is an important virulence determinant in protection against complement opsonization and phagocytosis [31]. However, the lipid A portion of the LPS molecule is also an activator of innate immunity responses, including induction of iNOS expression [32] and enforcement of the oxidative burst [33]. In addition, salmonella is capable of expressing multiple adhesins that in concert contribute to infection of the mouse [34] and to biofilm formation that adds to the persistent carriage state [35, 36].…”

Unraveling the factors and mechanism involved in persistence: Host‐pathogen interactions in Helicobacter pylori

“…In a study, it has been reported that phagocytosis of nonopsonized H. pylori cell by neutrophil is incompetent rather than phagocytosis of latex coated beads . Nonopsonized H. pylori cells have the ability to resist phagocytosis because it targets the NADPH oxidase and disrupts it, which leads to phagosome dysfunction because superoxide ions do not collocate in the phagosome, rather they diffuse into the extracellular space . Catalase‐dependent mechanism also helps in the evasion of this immune response …”

The Role of Complement in Transfusion-Related Acute Lung Injury

“…The ROS response mediated by IgG is influenced by the combination of FcγRIIa and FcγRIIIb isoforms expressed on PMNs [55]. PMNs that are activated by IgG elicit a robust ROS response [56]. It has been shown that blocking of PMN-FcγRIIIb is sufficient to inhibit immune complex-mediated ROS production in a setting of autoimmune arthritis [57].…”