Development of an FhbB based chimeric vaccinogen that elicits antibodies that block Factor H binding and cleavage by the periopathogen Treponema denticola

Abstract

Treponema denticola is a proteolytic anaerobic spirochete and key contributor to periodontal disease of microbial etiology. As periodontal disease develops and progresses, T. denticola thrives in the hostile environment of the subgingival crevice by exploiting the negative regulatory activity of the complement protein, factor H (FH). FH bound to the cell surface receptor, FhbB (FH binding protein B), is competent to serve as a cofactor for the Factor I mediated‐cleavage of the opsonin C3b. However, bound FH is ultimately cleaved by the T. denticola protease, dentilisin. As the T. denticola population expands, the rate of FH cleavage may exceed its rate of replenishment leading to local FH depletion and immune dysregulation culminating in tissue and ligament destruction and tooth loss. The goal of this study was to develop a T. denticola FhbB based‐vaccine antigen that can block FH binding and cleavage and kill cells via antibody‐mediated bactericidal activity. Tetra (FhbB‐ch4) and pentavalent fhbB (FhbB‐ch5) chimerics were engineered to have attenuated FH binding ability. The chimerics were immunogenic and elicited high‐titer bactericidal and agglutinating antibody. Anti‐Fhb‐ch4 antisera blocked FH binding and cleavage by the T. denticola protease, dentilisin, in a dose dependent manner. Precedent for the use of FH binding proteins comes from the successful development of two FDA approved vaccines for type B Neiserria meningitidis. This study is the first to extend this approach to the development of a preventive or therapeutic vaccine (or monoclonal Ab) for periodontal disease.

The leptospiral OmpA-like protein (Loa22) is a surface-exposed antigen that elicits bactericidal antibody against heterologous Leptospira

“…PCR and cloning. PCR and cloning were performed as previously described [32] . Genes or gene fragments were PCR amplified from L. interrogans sv.…”

The Leptospiral General Secretory Protein D (GspD), a secretin, elicits complement-independent bactericidal antibody against diverse Leptospira species and serovars

“…PCR and cloning were performed using standard conditions as previously described [22] . LipL32, gspD, qlp42 and gspD gene fragments were PCR amplified from L. interrogans serovar Copenhageni strain Fiocruz L1-130 genomic DNA using Phusion polymerase (Thermo Scientific) and primers that harbor restriction sites for cloning ( Table 2 ).…”

The role of bacterial infections in rheumatoid arthritis development and novel therapeutic interventions: Focus on oral infections

“…Treponema denticola , an anaerobic oral spirochete, could be the main contributor to periodontal disease 66 . T. denticola Eno is a virulence factor, with higher degrees of homology with the human Eno.…”

“…63 Treponema denticola, an anaerobic oral spirochete, could be the main contributor to periodontal disease. 66 T. denticola Eno is a virulence factor, with higher degrees of homology with the human Eno. It is also served as a plasminogen-binding receptor, which assists in inflammatory cell invasion.…”