BrpA in Virulence Modulation of Streptococcus mutans

描述（由申请人提供）：变形链球菌是龋齿的主要病原，龋齿是世界范围内普遍存在的健康问题。这种生物引起疾病的能力取决于它附着在牙齿表面、形成坚韧的生物膜和耐受口腔内酸和其他有害条件的能力。我们之前的研究表明，生物膜调控蛋白A （BrpA）在突变链球菌的酸和氧化胁迫耐受性和生物膜形成的调控中起主要作用。缺乏BrpA显著增加了缺乏突变体对酸杀和过氧化氢的易感性。brpa缺陷突变体能够结合并在表面形成微菌落，但不能积累和发育成熟的生物膜。作为一种表面相关蛋白，BrpA是一种糖蛋白，其组成和结构特征似乎是口腔菌群中变形链球菌所特有的。因此，BrpA作为药物和疫苗生产的候选物具有很大的潜力，可以在不破坏菌群中其他有益微生物的情况下从斑块中消除变形链球菌。本研究旨在进一步研究BrpA在以下方面的作用：(i)细胞定位和结构-功能关系，（ii）环境刺激下的表达调节，以及（iii）在混合物种生物膜中生长时变形链球菌的粘附性、持久性和竞争力中的作用。本研究结果将有助于更好地理解BrpA在突变链球菌致病性调控中的作用和潜在机制，并将丰富我们对口腔菌群生态学的认识。更重要的是，从这项研究中获得的数据可以促进治疗和预防策略的设计，以对抗龋齿和可能的感染性心内膜炎。

DESCRIPTION (provided by applicant): Streptococcus mutans is the primary etiological agent of dental caries, a costly and ubiquitous health problem worldwide. The ability of this organism to cause disease depends on its abilities to adhere to the tooth surface, form tenacious biofilms and tolerate acid and other detrimental conditions in the oral cavity. We previously showed that the biofilm regulatory protein A (BrpA) plays a major role in regulation of acid- and oxidative-stress tolerance and biofilm formation in S. mutans. Deficiency of BrpA dramatically increased the susceptibility of the deficient mutants to acid-killing and hydrogen peroxide challenge. The BrpA-deficient mutant was able to bind to and form microcolonies on a surface, but failed to accumulate and develop mature biofilms. Predicted as a surface-associated protein, BrpA is a glycoprotein and possesses compositional and structural features that appear to be unique to S. mutans in the oral flora. Therefore, BrpA has great potential as a candidate for drug and vaccine production that may eliminate S. mutans from the plaque without disrupting other beneficial microorganisms in the flora. This study is designed to further investigate BrpA in regards to the (i) cellular location and structure-function relationships, (ii) regulation of expression in response to environmental stimuli, and (iii) role in the adherence, persistence and competitiveness of S. mutans when grown in mixed-species biofilms. The information derived from this study will contribute to a better understanding of the role and the underlying mechanism of BrpA in regulation of S. mutans pathogenicity and will enrich our knowledge on the ecology of the oral flora. More importantly, the data derived from this study could facilitate the design of therapeutic and preventive strategies to combat dental caries and possibly infective endocarditis. PUBLIC HEALTH RELEVANCE: The ability of Streptococcus mutans to cause dental caries depends on its ability to adhere to and form tenacious biofilms on the tooth surface and to tolerate detrimental conditions in the oral cavity. Glycoprotein BrpA in S. mutans plays major roles in environmental stress tolerance and formation of biofilms. This study will further investigate the role and the underlying mechanisms of BrpA in regulation of S. mutans pathogenicity and the potential for targeting BrpA in anti-caries strategy.