The Alternative Sigma Factor RpoE2 Is Involved in the Stress Response to Hypochlorite and in vivo Survival of Haemophilus influenzae

Extracytoplasmic function (ECF) sigma factors underpin the ability of bacteria to adapt to changing environmental conditions, a process that is particularly relevant in human pathogens that inhabit niches where human immune cells contribute to high levels of extracellular stress. Here, we have characterized the previously unstudied RpoE2 ECF sigma factor from the human respiratory pathogen (Hi) and its role in hypochlorite-induced stress. Exposure of to oxidative stress (HOCl, H O ) increased gene expression, and the activity of RpoE2 was controlled by a cytoplasmic 67-aa anti-sigma factor, HrsE. RpoE2 regulated the expression of the periplasmic MsrAB peptide methionine sulfoxide reductase that, in , is required for HOCl resistance, thus linking RpoE2 to HOCl stress. Interestingly, a HiΔ strain had wild-type levels of resistance to oxidative stress , but HiΔ survival was reduced 26-fold in a mouse model of lung infection, demonstrating the relevance of this sigma factor for pathogenesis. The HiRpoE2 system has some similarity to the ECF sigma factors described in and sp. that also control the expression of genes. However, HiRpoE2 regulation extended to genes encoding other periplasmic damage repair proteins, an operon containing a DoxX-like protein, and also included selected OxyR-controlled genes. Based on our results, we propose that the highly conserved HiRpoE2 sigma factor is a key regulator of responses to oxidative damage in the cell envelope region that controls a variety of target genes required for survival in the host.