Endothelial nitric oxide synthase limits host immunity to control disseminated Candida albicans infections in mice

Abstract

Three isoforms of nitric oxide synthase (NOS) occur in mammals. High levels of NO produced by NOS2/iNOS can protect against bacterial and parasitic infections, but the role of NOS in fungal innate immunity is less clear. Compared to wild type mice, Nos3-/- mice showed significantly higher survival of candidemia caused by Candida albicans SC5314. NOS3/eNOS is expressed by endothelial cells in the kidney, and colonization of this organ was decreased during the sub-acute stage of disseminated candidiasis. Nos3-/- mice more rapidly eliminated Candida from the renal cortex and exhibited more balanced local inflammatory reactions, with similar macrophage but less neutrophil infiltration than in infected wild type. Levels of the serum cytokines IL-9, IL-12, IL-17 and chemokines GM-CSF, MIP1α, and MIP1β were significantly elevated, and IL-15 was significantly lower in infected Nos3-/- mice. Spleens of infected Nos3-/- mice had significantly more Th2 and Th9 but not other CD4+ T cells compared with wild type. Inflammatory genes associated with leukocyte chemotaxis, IL-1 signaling, TLR signaling and Th1 and Th2 cell differentiation pathways were significantly overexpressed in infected Nos3-/- kidneys, with Nos2 being the most strongly induced. Conversely, the general NOS inhibitor NG-nitro-L-arginine methyl ester increased virulence in the mouse candidemia model, suggesting that iNOS contributes to the protective mechanism in infected Nos3-/- mice. By moderating neutrophil infiltration, the absence of eNOS may reduce the collateral damage to kidney cortex, and Th-9 CD4+ cells may enhance clearance of the infection. These data suggest that selective eNOS inhibition could mitigate candidemia by a combination of systemic and local responses that promote a more effective host immune response.

Renal CD169++resident macrophages are crucial for protection against acute systemic candidiasis

“…Our data showed that kidney is the primary target organ where C. albicans persists, and this is consistent with previous reports that indicate the importance of renal immunity in experimental disseminated candidiasis and subsequent mouse mortality ( Spellberg et al, 2003 ; MacCallum & Odds, 2005 ; Lionakis et al, 2011 ; Navarathna et al, 2012 , 2019 ; Hebecker et al, 2016 ). In particular, despite the ablation of TRMs in all peripheral organs in CD169-DTR mice, kidneys remained as the only organ with persisting C. albicans , hence highlighting the distinctive role of kidney TRMs in systemic Candida immunity.…”

Candida albicanssuppression of neutrophil reactive nitrogen species is rescued by host Hif-1αin vivo

“…(Brown, 2011), supporting our conclusion that neutrophil suppression is an important strategy of C. albicans during infection that, if rescued, could represent an exciting therapeutic opportunity. RNS has well characterised, highly candidacidal effects (Rementería, García-Tobalina and Sevilla, 1995; Vazquez-Torres et al ., 1995; Tillmann, Gow and Brown, 2011; Navarathna, Lionakis and Roberts, 2019). Similarly, Macherla et al .…”

“…Following recruitment, neutrophils have multiple mechanisms of eliminating C. albicans , including the production of reactive oxygen (ROS) and nitrogen (RNS) species (Winterbourn et al ., 2006). Inhibition of inducible nitric oxide synthase (iNOS) leads to increased mortality in mouse models of C. albicans infections, showing the importance of RNS mediated fungicidal activity (Tillmann, Gow and Brown, 2011; Wagener et al ., 2017; Navarathna, Lionakis and Roberts, 2019).…”

Toll-Like Receptors Regulate the Development and Progression of Renal Diseases

“…TLR1, TLR2, and TLR6 were regarded as critical mediators for fungal colonization and inflammatory responses in the candidemia kidney. As expression of these TLRs in the kidney could be enhanced by deficiency of nitric oxide synthase 3, NOS inhibition might mitigate candidemia [44].…”