Chapter 27 : The Way Forward

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We have observed a vertical leap into our understanding of EHEC’s virulence. In the past edition of this book, the locus of enterocyte effacement (LEE) and its encoded type 3 secretion system (T3SS) had been recently discovered ( ). However, few effectors were known at the time, with Tir ( ) and intimin ( ) dominating research on the molecular mechanisms involved in the formation of attaching and effacing (AE) lesions. Structural insights into T3SS came later, with the description of the EscF needle ( ) and the EspA filament ( ) forming the unique translocon of the EHEC and EPEC T3SSs. The number of effectors quickly expanded from the six LEE-encoded effectors, to the first hints that effectors encoded outside of the LEE existed ( ), to the large expansion of their repertoire ( ). Next-generation sequencing of many EHEC genomes also highlighted the fact that different strains of EHEC and enteropathogenic (EPEC) carry different combination of these effectors ( ). Vigorous research was initially devoted to understanding the mechanism through which EHEC engaged the actin cytoskeleton to form AE lesions. These studies involved Tir and intimin interactions, but also extensive studies in the EspFu/TccP effectors ( ). More recently, studies of non-AE-related effectors and their role in more discrete actin rearrangements, as well in modulation of the host immune response, have taken the front seat ( ). Looking forward, we need to understand how different combinations of T3SS effectors affect the virulence potential of EHEC strains. We are also starting to study the hierarchy of secretion of these effectors ( ) and how they work in concert. Knowledge of which effectors are acting within a mammalian cell at any given time, and how their functions amplify or antagonize their phenotypes, is the next frontier in understanding the role of these proteins in the bacterial/host interplay. Another still unresolved issue is how the T3SS is regulated to shift from secreting the translocon proteins (EspA, EspB, and EspD) to secreting effectors within epithelial cells. There is also the question of how the EspA filament is disassembled during the infection process to allow the close contact between the bacteria and the host. Finally, the big question that remains open is, how does EHEC cause diarrhea in the human intestine, and which are the main players in this disease process?

Citation: Sperandio V. 2015. The Way Forward, p 541-552. In Sperandio V, Hovde C (ed), Enterohemorrhagic and Other Shiga Toxin-Producing . ASM Press, Washington, DC. doi: 10.1128/9781555818791.ch27
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