VJ wrote the first version of the manuscript.

JM provided statistical support for the design of the study and performed the statistical analyses. TC supervised the laboratory analytical procedures and validated the laboratory results. TC, HS, SA and RV set up and carried out the qPCRs. SP and LH participated in the design and clinical coordination of the study. All authors contributed to the editing, and approved the final paper.”
“Background Iron and zinc are recognized as important micronutrients for bacteria, but excess of iron can catalyze the Fenton reactions, resulting in formation of toxic hydroxyl radicals [1]. Similarly, an excess KU 57788 of zinc ions can also trigger the formation of hydroxyl radicals p38 MAPK inhibitors clinical trials [2]. Besides hydroxyl radicals, reactive oxygen species (ROS) such as superoxide radical and H2O2 are inevitably generated as byproducts of aerobic metabolism in bacteria [3]. Additionally, during infection, ROS can be generated

by the innate immune system[4]. ROS can cause damage to many macromolecules including DNA, proteins and lipids [5, 6]. It is clear that oxidative stress and metal homeostasis are closely related. However, bacteria have evolved efficient mechanisms to maintain metal ion homeostasis and protect themselves from oxidative damage [7]. Fur family proteins are present widely in bacteria and play crucial roles in cellular processes. This family contains more than six Angiogenesis inhibitor different proteins. They are the sensors of iron (Fur and Irr) [8][9], zinc (Zur) [10], manganese [11] and nickel (Nur) [12], and the peroxide Liothyronine Sodium regulon repressor (PerR) [13]. In the Gram-negative Escherichia coli, there are two Fur family proteins Fur and Zur. In contrast, there are three Fur-like proteins (Fur, Zur and PerR) in many Gram-positive bacteria such as Bacillus subtilis Clostridium acetobutylicum and Staphylococcus aureus. In B. subtilis, Fur regulates iron uptake and siderophore biosynthesis; Zur regulates two ABC zinc transporters; and PerR regulates the oxidative stress response [13, 14]. Streptococcus suis is economically a very important

Gram-positive and facultative anaerobic bacterium that causes severe diseases in pigs and humans. As an emerging zoonotic pathogen, S. suis serotype 2 has become the predominant causative agent of adult human meningitis in Vietnam and Hong Kong [15]. Two large outbreaks of human infections were reported in China in 1998 and 2005, resulting in 229 infections and 52 deaths [16, 17]. Like other bacterial pathogens, S. suis may also encounter both oxidative stress and metal starvation during infection. Thus, the regulation on the responses to oxidative stress and metal starvation by Fur-like proteins could be particularly important for S. suis survival in vivo and pathogenesis. However, only a single gene encoding a Fur-like protein has been found in each sequenced genome of S. suis, even in the genomes of most species of the genus Streptococcus.