A RIVETing story

Abstract

In both love and war, making the wrong move at the wrong time can have very detrimental effects. This concept also holds true for bacterial pathogens attempting to colonize their animal hosts. The expression of virulence factors by pathogenic bacteria must be coordinated both temporally and spatially to ensure the establishment and persistence of an invading microorganism. At present, we have little knowledge regarding the regulation of bacterial virulence factors in vivo. However, recent studies, exemplified by the work of Lee et al.1xRegulation and temporal expression patterns of Vibrio cholerae virulence genes during infection. Lee, S.H. et al. Cell. 1999; 99: 625–634Abstract | Full Text | Full Text PDF | PubMedSee all References1, are beginning to shed light on this area of bacterial pathogenesis.Using an infant mouse model and recombinase-based in vivo expression technology (RIVET), Lee and co-workers monitored the transcriptional induction patterns of two virulence genes (ctxA and tcpA) in Vibrio cholerae, the causative agent of cholera. ctxA encodes the catalytic subunit of cholera toxin (CT), whereas tcpA encodes a pilin subunit of the toxin-coregulated pilus (TCP). In vitro studies have indicated that both TCP and CT, in addition to other virulence factors, are coordinately regulated by three proteins, ToxR, TcpP and ToxT. The RIVET analyses by Lee et al., however, suggest a model whereby TCP and CT are differentially regulated and expressed sequentially during infection.The data indicate that, after oral ingestion of V. cholerae, undefined host signals within the lumen of the stomach or proximal small intestine activate the transcription factors ToxR and TcpP. This process is dependent upon basal levels of TcpA and leads to induction of the transcriptional activator, ToxT. Elevated TcpP levels boost the transcription of tcpA further, leading to increased expression of TCP and facilitating the ability of V. cholerae to colonize the intestinal epithelium. Once in close proximity to the intestinal host cells, a second set of as-yet-undefined signals leads to further induction of ToxR. The increased ToxR and ToxT levels at this point induce expression of CT. This scenario ensures that CT is released only after bacteria come into close proximity with the targeted host cells. As new experimental approaches and technologies such as RIVET are developed, the regulation of virulence genes in the context of bona fide host–pathogen interactions should continue to come into sharper focus.