Abstract
The acquisition of transition metal ions is essential for the viability and in some cases the expression of virulence genes in bacteria. The fimCBA operon of Streptococcus parasanguinis FW213 encodes a Mn2+/Fe2+-specific ATP-binding cassette transporter. FimA, a lipoprotein in the system, is essential for the development of endocarditis, presumably by binding to fibrin monolayers on the damaged heart tissue. Recent sequence analysis revealed that Spaf_0344 was homologous to Streptococcus gordonii scaR, encoding a metalloregulatory protein for the Sca Mn2+-specific transporter. Based on the homology, Spaf_0344 was designated fimR. By using various fim promoter (pfim) derivatives fused with a promoterless chloramphenicol acetyltransferase gene, the functions of the cis-elements of pfim were analyzed in the wild-type and fimR-deficient hosts. The result indicated that FimR represses the expression of pfim and the palindromic sequences 5′ to fimC are involved in repression of pfim. A direct interaction between FimR and the palindromic sequences was further confirmed by in vitro electrophoresis gel mobility shift assay and in vivo chromatin immunoprecipitation assay (ChIP)-quantitative real-time PCR (qPCR). The result of the ChIP-qPCR analysis also indicated that FimR is activated by Mn2+ and, to a lesser degree, Fe2+. Functional analysis indicated that the expression of FimA in S. parasanguinis was critical for wild-type levels of survival against oxidative stress and within phagocytes, but not for acid tolerance. Taken together, in addition to acting as an adhesin (FimA), the expression of the fim operon is critical for the pathogenic capacity of S. parasanguinis.
Highlights
Streptococcus parasanguinis is a primary colonizer of the tooth surface and an important member of the dental plaque [1,2]
Identification of fimR Sequence analysis of the 39 flanking region of fim operon revealed two open reading frames (ORFs), Spaf_0345 and Spaf_0344, in opposite orientations (Figure 1). Both ORFs began with an ATG translation start codon and were preceded by a putative ribosomal binding site (RBS)
Spaf_0344 shares significant homology at the deduced aa level with ScaR (65% identity) of S. gordonii CH1 (AF182402_1) and with SloR (55% identity) of S. mutans UA159 (NP_720655.1). Both ScaR and SloR belong to the Diphtheria toxin repressor (DtxR) family proteins, which are composed of an N-terminal helixturn-helix (HTH) motif, followed by a metal binding and dimerization domain
Summary
Streptococcus parasanguinis is a primary colonizer of the tooth surface and an important member of the dental plaque [1,2]. S. parasanguinis and other viridians streptococci can enter the bloodstream, causing a transient bacteremia and infective endocarditis on native and prosthetic heart valves [3,4]. The significance of S. parasanguinis in the oral ecosystem and systemic infection is well established, far the only known virulence factor associated with endocarditis is FimA of the FimCBA Mn2+/Fe3+ ATP-binding cassette (ABC) transporter [5]. A FimAdeficient S. parasanguinis is avirulent in an animal model [6]. Immunization with the purified FimA protein prior to infection with S. parasanguinis FW213 reduces the frequency and severity of infection in the rat model [7], further confirming the impact of FimA in disease development
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