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The opportunistic pathogen  Burkholderia cenocepacia  is particularly life-threatening for cystic fibrosis (CF) patients. Chronic lung infections with these bacteria can rapidly develop into fatal pulmonary necrosis and septicaemia. We have recently shown that macrophages are a critical site for replication of  B .  cenocepacia  K56-2 and the induction of fatal pro-inflammatory responses using a zebrafish infection model. Here, we show that ShvR, a LysR-type transcriptional regulator that is important for biofilm formation, rough colony morphotype and inflammation in a rat lung infection model, is also required for the induction of fatal pro-inflammatory responses in zebrafish larvae. ShvR was not essential, however, for bacterial survival and replication in macrophages. Temporal, rhamnose-induced restoration of  shvR  expression in the  shvR  mutant during intramacrophage stages unequivocally demonstrated a key role for ShvR in transition from intracellular persistence to acute fatal pro-inflammatory disease. ShvR has been previously shown to tightly control the expression of the adjacent  afc  gene cluster, which specifies the synthesis of a lipopeptide with antifungal activity. Mutation of  afcE , encoding an acyl-CoA dehydrogenase, has been shown to give similar phenotypes as the  shvR  mutant. We found that, like  shvR ,  afcE  is also critical for the switch from intracellular persistence to fatal infection in zebrafish. The closely related  B .  cenocepacia  H111 has been shown to be less virulent than K56-2 in several infection models, including  Galleria mellonella  and rats. Interestingly, constitutive expression of  shvR  in H111 increased virulence in zebrafish larvae to almost K56-2 levels in a manner that absolutely required  afc . These data confirm a critical role for  afc  in acute virulence caused by  B .  cenocepacia  that depends on strain-specific regulatory control by ShvR. We propose that ShvR and AFC are important virulence factors of the more virulent Bcc species, either through pro-inflammatory effects of the lipopeptide AFC, or through AFC-dependent membrane properties.

plos pathogens

The afc antifungal activity cluster, which is under tight regulatory control of ShvR, is essential for transition from intracellular persistence of Burkholderia cenocepacia to acute pro-inflammatory infection