Insight into the Evolution of the Histidine Triad Protein (HTP) Family in Streptococcus

Abstract

The Histidine Triad Proteins (HTPs), also known as Pht proteins in Streptococcus pneumoniae, constitute a family of surface-exposed proteins that exist in many pathogenic streptococcal species. Although many studies have revealed the importance of HTPs in streptococcal physiology and pathogenicity, little is known about their origin and evolution. In this study, after identifying all htp homologs from 105 streptococcal genomes representing 38 different species/subspecies, we analyzed their domain structures, positions in genome, and most importantly, their evolutionary histories. By further projecting this information onto the streptococcal phylogeny, we made several major findings. First, htp genes originated earlier than the Streptococcus genus and gene-loss events have occurred among three streptococcal groups, resulting in the absence of the htp gene in the Bovis, Mutans and Salivarius groups. Second, the copy number of htp genes in other groups of Streptococcus is variable, ranging from one to four functional copies. Third, both phylogenetic evidence and domain structure analyses support the division of two htp subfamilies, designated as htp I and htp II. Although present mainly in the pyogenic group and in Streptococcus suis, htp II members are distinct from htp I due to the presence of an additional leucine-rich-repeat domain at the C-terminus. Finally, htp genes exhibit a faster nucleotide substitution rate than do housekeeping genes. Specifically, the regions outside the HTP domains are under strong positive selection. This distinct evolutionary pattern likely helped Streptococcus to easily escape from recognition by host immunity.

Overlapping Functionality of the Pht Proteins in Zinc Homeostasis of Streptococcus pneumoniae

“…Furthermore, such a recovery for strains lacking pht genes is also consistent with the Pht proteins not contributing to defense against Zn 2ϩ toxicity, as we found to be the case in vitro. In other streptococci, adcAII homologues are often found with only one pht gene in the genome (24). Given that we have shown that all four Pht proteins of S. pneumoniae have overlapping functionality with respect to aiding in delivery of Zn 2ϩ to AdcAII, it is not apparent what the advantage of producing four such proteins is, as opposed to perhaps simply producing a greater quantity of one Pht protein.…”

Defining the Role of the Streptococcus agalactiae Sht-Family Proteins in Zinc Acquisition and Complement Evasion

“…The overlapping roles of these zinc acquisition systems in S. agalactiae raise the question of the reason for the basis for the conservation of multiple zinc import pathways. Recently, it has been proposed that the Sht-family genes, which are frequently acquired as operons that also contain lmb and adcAII genes, were acquired prior to the emergence of the Streptococcus genus (10). As a consequence, maintenance or loss of Sht-family genes are presumed to arise from the competing selective pressures associated with their physiological function, such as zinc acquisition and evasion of host immune responses.…”

“…The presence of multiple zinc-specific SBPs is an unusual feature largely unique to the streptococci, since most prokaryotes employ only a single protein. This appears to have arisen due to the ancient acquisition of a genetic element containing Lmb (or AdcAII) and a histidine triad (HT) protein in the streptococcal genus (10). Subsequent gene duplication events have led to the emergence of multiple copies of the histidine triad proteins and Lmb/AdcAII-type SBPs.…”

Role of Pht Proteins in Attachment of Streptococcus pneumoniae to Respiratory Epithelial Cells

“…Homologs of pht genes have been identified in the human pathogens Streptococcus pyogenes (17,18) and Streptococcus agalactiae (19), but also among commensal streptococcal species and in some nonstreptococcal species (20). In S. pyogenes, this type of protein has been identified as an adhesin binding to extracellular matrix protein type I collagen (21).…”