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The human filarial parasite  Brugia malayi  harbors an endosymbiotic bacterium  Wolbachia  ( w Bm) that is required for parasite survival. Consequently, targeting  w Bm is a promising approach for anti-filarial drug development. The Type IV secretion system (T4SS) plays an important role in bacteria-host interactions and is under stringent regulation by transcription factors. In  w Bm, most T4SS genes are contained in two operons. We show the  w Bm is active since the essential assembly factor  virB8-1 , is transcribed in adult worms and larval stages, and VirB8-1 is present in parasite lysates. We also identify two transcription factors ( w BmxR1 and  w BmxR2) that bind to the promoter region of several genes of the T4SS. Gel shift assays show binding of  w BmxR1 to regions upstream of the  virB9-2  and  wBmxR2  genes, whereas  w BmxR2 binds to  virB4-2  and  wBmxR1  promoter regions. Interestingly, both transcription factors bind to the promoter of the  ribA  gene that precedes  virB8-1 , the first gene in operon 1 of the  w Bm T4SS. RT-PCR reveals  ribA  and  virB8-1  genes are co-transcribed as one operon, indicating the  ribA  gene and T4SS operon 1 are co-regulated by both  w BmxR1 and  w BmxR2.  RibA  encodes a bi-functional enzyme that catalyzes two essential steps in riboflavin (Vitamin B2) biosynthesis. Importantly, the riboflavin pathway is absent in  B. malayi . We demonstrate the pathway is functional in  w Bm, and observe vitamin B2 supplementation partially rescues filarial parasites treated with doxycycline, indicating  Wolbachia  may supply the essential vitamin to its worm host. This is the first characterization of a transcription factor(s) from  w Bm and first report of co-regulation of genes of the T4SS and riboflavin biosynthesis pathway. In addition, our results demonstrate a requirement of vitamin B2 for worm health and fertility, and imply a nutritional role of the symbiont for the filarial parasite host.

Characterization of Transcription Factors That Regulate the Type IV Secretion System and Riboflavin Biosynthesis in Wolbachia of Brugia malayi