Hypervirulent (hvKp) Klebsiella pneumoniae is one of two main pathotypes of Klebsiella pneumoniae. It is considered a critical public health threat as it is more virulent and can cause community-acquired infection. Siderophores are a major virulence factor secreted by hvKp to acquire iron to overcome iron limitation. Four different siderophores (aerobactin, yersiniabactin, enterobactin and salmochelin) can be produced in a single hvKp strain; production of all four is strongly predictive of hypervirulence suggesting non-redundant functions. Expression of the siderophores must be under tight regulatory control to maintain an appropriate amount of intracellular iron to avoid adverse effects to the cells. Though the impact of iron limitation on siderophore expression has been well studied, the contribution of other cues and regulators is not well understood.
In this study, we aimed to understand the regulatory networks governing bacterial iron acquisition in hvKp. Transcriptomics for the hvKp bacterium in 11 infection-relevant stress conditions showed a dynamic response to the stresses by regulating 1.7-43% of the genes in each condition. The higher fractions (32.6-43%) of differential expression genes were observed in anaerobic, virulence inducing, nutritional downshift and stationary phase, and conditions. Notably, expression of the siderophore genes was induced by oxidative stress and nutritional downshift whereas they were repressed in low oxygen and other conditions. Growing the bacterium under increasing levels of iron starvation showed a sequential siderophore induction, with aerobactin produced first followed by enterobactin, yersiniabactin and, lastly, salmochelin. In vivo expression of the four siderophores was investigated and they were found to be differentially expressed in the different host niches.
Overall, our findings support the hypothesis that K. pneumoniae uses distinct regulatory mechanisms to control each of its four siderophores. Further laboratory work will explore the mechanisms underpinning their differential expression in different environmental and niches.