Identifying the correlates of protection against Streptococcus pneumoniae respiratory tract infection using a human challenge model

挑战：尽管现有的荚膜多糖疫苗得到广泛使用，但在英国，每年仍有92，000人因肺炎链球菌肺炎而入院，40，000人死亡。防治S.肺炎的肺部感染，这是我们的建议所面临的挑战。肺炎鼻咽定殖在整个生命增强免疫力对严重感染。因此，经鼻施用转基因S.不能引起严重感染的肺炎链球菌可预防S.肺炎我们用一个人的攻击模型来研究两个无毒力的S。肺炎突变株？fhs/pia和？proABC/piaA.鼻腔给药？fhs/pia突变体可防止野生型S.肺炎，而？proABC/piaA株则无。初步数据还确定了这些菌株之间的上皮和血清学反应的差异，但这些仍然很差的特点。目前，预防再定殖的机制、经鼻施用突变株对肺和全身免疫的额外作用以及这些与突变株和野生型株在与鼻咽上皮的相互作用中的差异之间的关系尚不清楚。肺炎的鼻咽、肺和全身免疫。肺炎，定义针对再定殖的保护机制，并将菌株之间的显著差异与鼻咽上皮反应联系起来。本研究结果对进一步开发减毒沙门氏菌具有重要意义。肺炎作为一种新的方法来预防肺炎。这些结果也将进一步加深我们对S.肺炎菌定殖影响随后的感染，这些数据与多种其它粘膜病原体相关。

Challenge:Despite widespread use of the existing capsular polysaccharide vaccines, in the UK there are still 92,000 admissions and 40,000 deaths per year due to Streptococcus pneumoniae pneumonia in adults. New approaches to prevent S. pneumoniae lung infections are needed, and this is the challenge our proposal addresses.Context:Recurrent S. pneumoniae nasopharyngeal colonisation throughout life boosts immunity against severe infections. Hence, nasal administration of genetically modified S. pneumoniae strains unable to cause severe infection could prevent S. pneumoniae pneumonia. We used a human challenge model to investigate two avirulent S. pneumoniaemutant strains ?fhs/pia and ?proABC/piaA. Nasal administration of the ?fhs/pia mutant protected against re-colonisation with wild-type S. pneumoniae, whereas the ?proABC/piaA strain did not. Preliminary data also identified differences in epithelial and serological responses between these strains, but these remain poorly characterised. At present the mechanism(s) that prevent re-colonisation, the additional effects of nasal administration of mutant strains on lung and systemic immunity, and how these relate to differences between mutant and wild type strains in their interactions with the nasopharyngeal epithelium are not known.Potential benefits:This proposal will characterise in depth the effects of nasal administration of wild type and mutant S. pneumoniaeon nasopharyngeal, lung and systemic immunity to S. pneumoniae, define mechanisms of protection against re-colonisation, and link significant differences between strains to nasopharyngeal epithelial responses. The results will be crucial for the further development of attenuated S. pneumoniae as a novel approach to prevent pneumonia. The results will also further our understanding of how S. pneumoniae colonisation affects subsequent infection, data which are relevant for multiple other mucosal pathogens.