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Flavin Reductase Contributes to Pneumococcal Virulence by Protecting from Oxidative Stress and Mediating Adhesion and Elicits Protection Against Pneumococcal Challenge
Authors:Morozov, Giora I | Porat, Nurith | Kushnir, Tatyana | Najmuldeen, Hastyar | Adawi, Asad | Chalifa-Caspi, Vered | Benisty, Rachel | Ohayon, Ariel | Liron, Ofir | Azriel, Shalhevet | Malka, Itai | Dotan, Shahar | Portnoi, Maxim | Piotrowski, Andrew A | Kafka, Daniel | Hajaj, Barak | Fishilevich, Tali | Shagan, Marilou | Tal, Michael | Ellis, Ron | Morrison, Donald A | Mitchell, Andrea | Dagan, Ron | Yesilkaya, Hasan | Nebenzahl, Yaffa Mizrachi | Mitchell, Tim
Pneumococcal flavin reductase (FlaR) is known to be cell-wall associated and possess age dependent antigenicity in children. This study aimed at characterizing FlaR and elucidating its involvement in pneumococcal physiology and virulence. Bioinformatic analysis of FlaR sequence identified three-conserved cysteine residues, suggesting a transition metal-binding capacity. Recombinant FlaR (rFlaR) bound Fe2+ and exhibited FAD-dependent NADP-reductase activity, which increased in the presence of cysteine or excess Fe2+ and inhibited by divalent-chelating agents. flaR mutant was highly susceptible to H2O2 compared to its wild type (WT) and complemented strains, suggesting a role for FlaR in pneumococcal oxidative stress resistance. Additionally, flaR mutant demonstrated significantly decreased mice mortality following intraperitoneal infection. Interestingly, lack of FlaR did not affect the extent of phagocytosis by primary mouse peritoneal macrophages but reduced adhesion to A549 cells compared to the WT and complemented strains. Noteworthy are the findings that immunization with rFlaR elicited protection in mice against intraperitoneal lethal challenge and anti-FlaR antisera neutralized bacterial virulence. Taken together, FlaR's roles in pneumococcal physiology and virulence, combined with its lack of significant homology to human proteins, point towards rFlaR as a vaccine candidate.
Article (Peer-reviewed) -- 2018