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已被广泛使用，但在英国，每年仍有92,000人因成人肺炎链球菌肺炎入院，40,000人死亡。预防肺炎链球菌肺部感染的新方法是必要的，这是我们的建议所解决的挑战。背景：一生中反复出现的肺炎链球菌鼻咽定植增强了对严重感染的免疫力。因此，鼻腔给药不能引起严重感染的转基因肺炎链球菌菌株可以预防肺炎链球菌肺炎。我们使用人体攻击模型研究了两种无毒的肺炎突变链球菌菌株。fhs/pia和？proABC/piaA。鼻腔给药？fhs/pia突变体可以防止野生型肺炎链球菌的再定植，而？proABC/piaA菌株则没有。初步数据还确定了这些菌株之间在上皮和血清学反应上的差异，但这些差异仍然不明确。目前，预防再定植的机制、经鼻给药突变菌株对肺和全身免疫的额外影响，以及这些与突变型和野生型菌株与鼻咽上皮相互作用的差异之间的关系尚不清楚。潜在益处：该提案将深入描述野生型和突变型肺炎链球菌鼻咽、肺和全身免疫对肺炎链球菌的影响，定义防止再定植的保护机制，并将菌株之间的显著差异与鼻咽上皮反应联系起来。该结果将对进一步开发减毒肺炎链球菌作为预防肺炎的新方法至关重要。这些结果也将进一步加深我们对肺炎链球菌定植如何影响后续感染的理解，这些数据与多种其他粘膜病原体相关。

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.