Interrelationship between type three secretion system and metabolism in pathogenic bacteria

Abstract

Before the advent of molecular biology methods, studies of pathogens were dominated by analyses of their metabolism. Development of molecular biology techniques then enabled the identification and functional characterisation of the fascinating toolbox of virulence factors. Increasing, genomic and proteomic approaches form the basis for a more systemic view on pathogens' functions in the context of infection. Re-emerging interest in the metabolism of pathogens and hosts further expands our view of infections. There is increasing evidence that virulence functions and metabolism of pathogens are extremely intertwined. Type three secretion systems (T3SSs) are major virulence determinants of many Gram-negative pathogens and it is the objective of this review to illustrate the intertwined relationship between T3SSs and the metabolism of the pathogens deploying them.

Keywords: Pseudomonas; Salmonella; T3SS; Yersinia; cross-talk; metabolism; type three secretion system; virulence.

Figure 1

Interrelations between virulence factors and metabolism in Yersinia. The type 3 secretion system (T3SS; red), encoded by the pCD virulence plasmid (called pYV in Y. enterocolitica) interferes with the anaplerotic enzyme phosphoenolpyruvate carboxylase (PEPC, blue) via the T3SS regulator LcrQ (YscM1 in Y. enterocolitica; inhibitor of PEPC); lcrG, another component of the low calcium response regulon, controls transcription of aceAB and aspA. The glyoxylate cycle enzymes isocitrate lyase and malate synthase, encoded by aceAB, fulfill an anaplerotic function required for fatty acid degradation (FA, fatty acid; FA-CoA, fatty acyl-CoA). AspA, an aspartase generating fumarate from aspartate can also be regarded as an anaplerotic enzyme. AspA seems to be catalytically inactive in Y. pestis. In an unknown way, plasmid pCD seems to be involved in fatty acid uptake together with another virulence plasmid, pPCP. Production of the pPCP-encoded virulence factors Pla (plasminogen activator) and Pst (pesticin) is controlled by cAMP (cyclic adenosine monophosphate) via the cAMP receptor protein CRP (“catabolite repression”). The cAMP/CRP complex represses the T3SS effector gene ypkA (yopO in Y. enterocolitica). SycO, the chaperone of YpkA, directly interacts with LcrQ/YscM1. Cross-talk between fatty acid metabolism, glyoxylate shunt and the PEPC reaction also occurs via allosteric effectors (FA, FA-CoA, malate; interactions not illustrated for reasons of clarity).

Figure 2

Salmonellae recruit new nutrients for their brothers by means of self-destructive deployment of a T3SS. T3SS-1 mediated invasion of the gut tissue is mostly a kamikaze mission but the inflammatory response induced comprises the release of reactive oxygen species (ROS) which results in the formation of tetrathionate, an alternative electron acceptor. Surviving salmonellae can then use tetrathionate to metabolize ethanolamine to proliferate and outcompete the normal gut flora.