Probing the Genome-Scale Metabolic Landscape of Bordetella pertussis, the Causative Agent of Whooping Cough
Authors: Branco dos Santos Filipe , Olivier Brett G. , Boele Joost , Smessaert Vincent , De Rop Philippe , Krumpochova Petra , Klau Gunnar W. , Giera Martin , Dehottay Philippe , Teusink Bas , Goffin Philippe 
Published: August 2017

Whooping cough is a highly contagious respiratory disease caused byBordetella pertussis. Despite widespread vaccination, its incidence has been rising alarmingly, and yet, the physiology ofB. pertussisremains poorly understood. We combined genome-scale metabolic reconstruction, a novel optimization algorithm, and experimental data to probe the full metabolic potential of this pathogen, usingB. pertussisstrain Tohama I as a reference. Experimental validation showed thatB. pertussissecretes a significant proportion of nitrogen as arginine and purine nucleosides, which may contribute to modulation of the host response. We also found thatB. pertussiscan be unexpectedly versatile, being able to metabolize many compounds while displaying minimal nutrient requirements. It can grow without cysteine, using inorganic sulfur sources, such as thiosulfate, and it can grow on organic acids, such as citrate or lactate, as sole carbon sources, providingin vivodemonstration that its tricarboxylic acid (TCA) cycle is functional. Although the metabolic reconstruction of eight additional strains indicates that the structural genes underlying this metabolic flexibility are widespread, experimental validation suggests a role of strain-specific regulatory mechanisms in shaping metabolic capabilities. Among five alternative strains tested, three strains were shown to grow on substrate combinations requiring a functional TCA cycle, but only one strain could use thiosulfate. Finally, the metabolic model was used to rationally design growth media with >2-fold improvements in pertussis toxin production. This study thus provides novel insights intoB. pertussisphysiology and highlights the potential, but also the limitations, of models based solely on metabolic gene content.

IMPORTANCEThe metabolic capabilities ofBordetella pertussis, the causative agent of whooping cough, were investigated from a systems-level perspective. We constructed a comprehensive genome-scale metabolic model forB. pertussisand challenged its predictions experimentally. This systems approach shed light on new potential host-microbe interactions and allowed us to rationally design novel growth media with >2-fold improvements in pertussis toxin production. Most importantly, we also uncovered the potential for metabolic flexibility ofB. pertussis(significantly larger range of substrates than previously alleged; novel active pathways allowing growth in minimal, nearly mineral nutrient combinations where only the carbon source must be organic), although our results also highlight the importance of strain-specific regulatory determinants in shaping metabolic capabilities. Deciphering the underlying regulatory mechanisms appears to be crucial for a comprehensive understanding ofB. pertussis's lifestyle and the epidemiology of whooping cough. The contribution of metabolic models in this context will require the extension of the genome-scale metabolic model to integrate this regulatory dimension.