title: Identification of an atypical zinc metalloproteinase, ZmpC, from an epidemic conjunctivitis-causing strain of Streptococcus pneumoniae.
abstract: Streptococcus pneumoniae is a pathogen associated with a range of invasive and noninvasive infections. Despite the identification of the majority of virulence factors expressed by S. pneumoniae, knowledge of the strategies used by this bacterium to trigger infections, especially those originating at wet-surfaced epithelia, remains limited. In this regard, we recently reported a mechanism used by a nonencapsulated, epidemic conjunctivitis-causing strain of S. pneumoniae (strain SP168) to gain access into ocular surface epithelial cells. Mechanistically, strain SP168 secretes a zinc metalloproteinase, encoded by a truncated zmpC gene, to cleave off the ectodomain of a vital defense component - the membrane mucin MUC16 - from the apical glycocalyx barrier of ocular surface epithelial cells and, thereby invades underlying epithelial cells. Here, we compare the truncated SP168 ZmpC to its highly conserved archetype from S. pneumoniae serotype 4 (TIGR4), which has been linked to pneumococcal virulence in previous studies. Comparative nucleotide sequence analyses revealed that the zmpC gene corresponding to strain SP168 has two stretches of DNA deleted near its 5' end. A third 3 bp in-frame deletion, resulting in the elimination of an alanine residue, was found towards the middle segment of the SP168 zmpC. Closer examination of the primary structure revealed that the SP168 ZmpC lacks the canonical LPXTG motif - a signature typical of several surface proteins of gram-positive bacteria and of other pneumococcal zinc metalloproteinases. Surprisingly, in vitro assays performed using recombinant forms of ZmpC indicated that the truncated SP168 ZmpC induces more cleavage of the MUC16 ectodomain than its TIGR4 counterpart. This feature may help explain, in part, why S. pneumoniae strain SP168 is better equipped at abrogating the MUC16 glycocalyx barrier en route to causing epidemic conjunctivitis.
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, 20 Staniford St., Boston, MA 02114, USA. raj.menon@schepens.harvard.edu
authors.forename: Balaraj B
authors.initials: BB
authors.lastname: Menon
authors.forename: Bharathi
authors.initials: B
authors.lastname: Govindarajan
mesh_terms: D018394:CA-125 Antigen / Q000378:metabolism*; D003231:Conjunctivitis / Q000453:epidemiology / Q000382:microbiology*; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D058872:Epidemics; D006868:Hydrolysis; D008565:Membrane Proteins / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011008:Pneumococcal Infections / Q000453:epidemiology / Q000382:microbiology*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018394:CA-125 Antigen; D004269:DNA, Bacterial; C451759:MUC16 protein, human; D008565:Membrane Proteins; D037521:Virulence Factors; D008666:Metalloendopeptidases; C478168:ZmpC protein, Streptococcus pneumoniae