Metabolism and Virulence

Funded by a Discovery Grant from the Natural Sciences and Research Council of Canada

When bacteria cause infection, they utilize host nutrients for growth. The type and availability of nutrients found by pathogenic bacteria can influence their virulence, but the mechanisms are not always understood. Most species of the Bcc colonize the lungs of people with cystic fibrosis producing a spectrum of clinical manifestations, ranging from asymptomatic carriage to the lethal “cepacia syndrome.” Despite intense clinical research, the reasons why some cystic fibrosis patients succumb to Bcc infections while others do not are unknown. A major source of carbon and nitrogen source supporting the cystic fibrosis microbiota are the amino acids present in the cystic fibrosis mucus. Using a species of Bcc, B. cenocepacia, we are elucidating how this bacterium senses changes in amino acid availability eliciting different pathogenic responses.

We have identified that a protein that forms the flagellum, flagellin is one of the most upregulated proteins of a species of Bcc, B. cenocepacia in conditions that mimic the nutrients of the cystic fibrosis mucus. We further confirmed that the cystic fibrosis nutritional conditions induced swimming motility and flagellin expression (Kumar and Cardona, 2016). Notably, B. cenocepacia K56-2 exhibited an increase in the number of flagella per cell. On the contrary, when grown in minimal medium with glucose, cells presented only one polar flagellum. Intriguingly, arginine and glutamate-induced swimming motility and protease activity and this response was mediated by a decrease of a global messenger molecule in bacteria, c-di-GMP (Kumar et al., 2018).

Taken together, we have found three overlapping virulence mechanisms that are triggered by amino acids: i) The number of flagella increases in media containing amino acids; ii) Swimming motility and protease activity is upregulated in response to arginine and glutamate by a decrease of c-di-GMP signaling; and iii) pathogenicity is dependent on phenylalanine and phenylacetic acid degradation because accumulation of phenylacetyl-CoA reduces quorum sensing-related virulence. The intertwining of mechanisms with different effects on pathogenicity in response to amino acid content suggests that host and microbiome-derived variations in amino acid content may be factors that play a role in the variable clinical outcomes observed in Bcc infections.