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Dysfunction of phagocytes is a relevant risk factor for staphylococcal infection. The most common hereditary phagocyte dysfunction is chronic granulomatous disease (CGD), characterized by impaired generation of reactive oxygen species (ROS) due to loss of function mutations within the phagocyte NADPH oxidase NOX2. Phagocytes ROS generation is fundamental to eliminate pathogens and to regulate the inflammatory response to infection. CGD is characterized by recurrent and severe bacterial and fungal infections, with Staphylococcus aureus as the most frequent pathogen, and skin and lung abscesses as the most common clinical entities. Staphylococcus aureus infection may occur in virtually any human host, presumably because of the many virulence factors of the bacterium. However, in the presence of functional NOX2, staphylococcal infections remain rare and are mainly linked to breaches of the skin barrier. In contrast, in patients with CGD, S. aureus readily survives and frequently causes clinically apparent disease. Astonishingly, little is known why S. aureus, which possesses a wide range of antioxidant enzymes (e.g. catalase, SOD), is particularly sensitive to control through NOX2. In this review, we will evaluate the discovery of CGD and our present knowledge of the role of NOX2 in S. aureus infection.

Reactive oxygen species (ROS) play a crucial role in the cellular defense against S. aureus, as evidenced by the importance of this pathogen in patients lacking the ROS-generating phagocyte NADPH oxidase NOX2. ROS concentrations required to kill S. aureus in vitro are much higher than those found in the phagosome. We therefore hypothesized that sublethal ROS concentrations may play a role in S. aureus gene dysregulation and investigated the in vitro transcriptomic response of S. aureus to sublethal concentrations of hydrogen peroxide (H2O2). A striking observation of these experiments was a coordinated and massive downregulation of genes involved in pyrimidine metabolism. Using transposon insertion mutants, we demonstrated that deletion of carA, a gene involved in pyrimidine synthesis, led to a significant growth defect and to an increased sensitivity of S. aureus to added H2O2. The phenotype of the carA mutant could be reversed through supplementation with the pyrimidine precursor uracil, or with a multicopy vector encoding carA. As opposed to the impact of ROS on extracellular survival, carA deletion did not affect the intracellular survival in neutrophils. Our results raise the possibility that ROS-dependent downregulation of pyrimidine metabolism might be a survival strategy of S. aureus, allowing colonization through intracellular survival, while decreasing the risk of killing the host through dampened extracellular growth.

Background Coronary artery disease (CAD) is in part genetically determined. Aging is accentuated in people with HIV (PLWH). It is unknown whether genetic CAD event prediction in PLWH is improved by applying individual polygenic risk scores (PRS) and by considering genetic variants associated with successful aging and longevity. Methods In Swiss HIV Cohort Study participants of self-reported European descent, we determined univariable and multivariable odds ratios (OR) for CAD events, based on traditional CAD risk factors, adverse antiretroviral exposures, and different validated genome-wide PRS. PRS were built from CAD-associated single nucleotide polymorphisms (SNPs), longevity-associated SNPs, or both. Results We included 269 cases with CAD events between 2000-2017 (Median age 54 years, 87% male, 82% with suppressed HIV RNA) and 567 event-free controls. Clinical (i.e. traditional and HIV-related) risk factors, and PRS built from CAD-associated SNPs, longevity-associated SNPs, or both, each contributed independently to CAD events (p<0.001). Participants with the most unfavorable clinical risk factor profile (top quintile) had adjusted CAD-OR=17.82 (8.19-38.76), compared to participants in the bottom quintile. Participants with the most unfavorable CAD-PRS (top quintile) had adjusted CAD-OR=3.17 (1.74-5.79), compared to the bottom quintile. After adding longevity-associated SNPs to the CAD-PRS, participants with the most unfavorable genetic background (top quintile) had adjusted CAD-OR=3.67 (2.00-6.73), compared to the bottom quintile. Conclusions In Swiss PLWH, CAD prediction based on traditional and HIV-related risk factors was superior to genetic CAD prediction based on longevity- and CAD-associated PRS. Combining traditional, HIV-related and genetic risk factors provided the most powerful CAD prediction.

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