Role of cdGMP in Francisella novicida biofilm formation

Francisella tularensis is a gram-negative intracellular pathogen that is highly virulent in humans causing the disease tularemia. F. novicida is closely-related to F. tularensis but is avirulent in humans. Within a cluster of six genes that is specific to F. novicida are two genes, cdgA and cdgB, that encode proteins with diguanylate cyclase (DGC) and phosphodiesterase (PDE) domains. The F. tularensis genome does not encode any DGC or PDE containing proteins. DGCs and PDEs modulate the synthesis and degradation of cyclic di-GMP (cdGMP). cdGMP is a signaling molecule involved in the shift between planktonic and biofilm growth phases. An F. novicida mutant strain lacking both cdgA and cdgB is defective for biofilm formation. Although they contain both CDG and PDE domains, biofilm studies suggest that CdgA acts primarily as a PDE, while CdgB acts primarily as a DGC. Expressing CdgB from a plasmid stimulates F. novicida biofilm formation, even in a strain lacking the biofilm regulator qseB. qRT-PCR analysis confirmed that QseB regulates cdgA and cdgB transcription, suggesting a signaling cascade controlling cdGMP levels. We suggest that differences in cdGMP signaling may contribute to the relative virulence of Francisella species.