Flavin Reductase Contributes to Pneumococcal Virulence by Protecting from Oxidative Stress and Mediating Adhesion and Elicits Protection Against Pneumococcal Challenge
| Autor: | Giora I. Morozov, Shalhevet Azriel, Andrea M. Mitchell, Tatyana Kushnir, Timothy J. Mitchell, Ofir Liron, Shahar Dotan, Barak Hajaj, Hastyar Najmuldeen, Itai Malka, Ronald J. Ellis, Andrew Piotrowski, Marilou Shagan, Daniel Kafka, Vered Chalifa-Caspi, Hasan Yesilkaya, Ron Dagan, Rachel Benisty, Ariel Ohayon, Michael Tal, Donald A. Morrison, Nurith Porat, Yaffa Mizrachi Nebenzahl, Maxim Portnoi, Asad Adawi, Tali Fishilevich |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Antigenicity FMN Reductase Phagocytosis 030106 microbiology Mutant lcsh:Medicine Virulence Biology medicine.disease_cause Article Bacterial Adhesion Microbiology Mice 03 medical and health sciences Bacterial Proteins Cell Line Tumor Flavin reductase Streptococcus pneumoniae medicine Animals Humans lcsh:Science Cells Cultured Mice Inbred BALB C Multidisciplinary lcsh:R Wild type 3. Good health Oxidative Stress Cell culture Mutation Macrophages Peritoneal Mice Inbred CBA Female lcsh:Q |
| Zdroj: | Scientific Reports, Vol 8, Iss 1, Pp 1-17 (2018) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-017-18645-8 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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