Pseudomonas aeruginosa Protease IV Exacerbates Pneumococcal Pneumonia and Systemic Disease.
Pseudomonas aeruginosa Protease IV Exacerbates Pneumococcal Pneumonia and Systemic Disease.
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DOI：
10.1128/msphere.00212-18
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发表时间：
2018-05
期刊：
影响因子：
4.8
通讯作者：
McDaniel LS
中科院分区：
文献类型：
--
作者：
Bradshaw JL;Caballero AR;Bierdeman MA;Adams KV;Pipkins HR;Tang A;O'Callaghan RJ;McDaniel LS
肺炎链球菌仍然是细菌性肺炎的主要原因，尽管广泛使用肺炎球菌疫苗，迫使适当的治疗，以控制肺炎球菌感染的必要性。涉及肺炎链球菌与其他细菌病原体的合并感染威胁抗生素治疗策略和疾病结局。目前，对于菌血症之前的肺泡-毛细血管屏障功能障碍没有有效的治疗方法。了解单一和混合肺部感染期间宿主-病原体相互作用的动力学可以阐明预防或减少侵袭性疾病所需的适当治疗策略。抗生素治疗减少了肺中的细菌负荷，但也增加了急性病理学，这是由于通过抗生素诱导的细菌溶解释放的细胞毒素。因此，需要抑制或抵消细菌蛋白酶和毒素的作用的靶向治疗剂，以限制病理和疾病进展。本研究确定了PIV和Ply的协同作用，这两种单独的肺部病原体的产物可叠加改变肺部环境并促进侵袭性疾病。肺炎是一种影响所有年龄段人群的肺部疾病，一直是儿童死亡和成人住院的主要原因。肺炎链球菌和铜绿假单胞菌是常见的社区获得性和医院获得性肺炎的主要肺部病原体。此外，涉及这些细菌病原体的混合肺部感染的患病率正在增加，并且通常比单一感染更严重。这两种病原体的协同相互作用对肺部疾病严重程度的影响尚未得到充分研究。铜绿假单胞菌的主要分泌毒力因子蛋白酶IV（PIV）切割白细胞介素22（IL-22），白细胞介素22是维持针对细胞外病原体的先天粘膜防御所必需的细胞因子。在此，我们研究了PIV在C57 BL/6小鼠肺炎模型中增强具有有限毒力的肺炎球菌菌株（肺炎链球菌EF 3030）毒力的能力。我们证明，肺部合并感染涉及铜绿假单胞菌103-29和肺炎链球菌EF 3030的结果，在肺炎球菌合并感染与PIV缺陷株被废除。此外，外源性PIV和EF 3030的肺内给药导致大量免疫细胞浸润到肺中，形成大脓肿，以及严重的菌血症，导致100%死亡率。热灭活PIV不会加重肺炎或可靠地诱导菌血症，这表明需要PIV的比活性。我们的研究还表明，PIV在体内消耗IL-22。此外，PIV介导的肺炎和疾病严重程度的增强依赖于肺炎链球菌溶血素（Ply）的表达，这是肺炎链球菌的一种重要毒力因子。总之，我们揭示了PIV和Ply在肺部感染的小鼠模型中相加增强肺炎。重要性尽管肺炎球菌疫苗的广泛使用，肺炎链球菌仍然是细菌性肺炎的主要原因，迫使需要适当的治疗来控制肺炎球菌感染。涉及肺炎链球菌与其他细菌病原体的合并感染威胁抗生素治疗策略和疾病结局。目前，对于菌血症之前的肺泡-毛细血管屏障功能障碍没有有效的治疗方法。了解单一和混合肺部感染期间宿主-病原体相互作用的动力学可以阐明预防或减少侵袭性疾病所需的适当治疗策略。抗生素治疗减少了肺中的细菌负荷，但也增加了急性病理学，这是由于通过抗生素诱导的细菌溶解释放的细胞毒素。因此，需要抑制或抵消细菌蛋白酶和毒素的作用的靶向治疗剂，以限制病理和疾病进展。本研究确定了PIV和Ply的协同作用，这两种单独的肺部病原体的产物可叠加改变肺部环境并促进侵袭性疾病。
S. pneumoniae remains the leading cause of bacterial pneumonia despite widespread use of pneumococcal vaccines, forcing the necessity for appropriate treatment to control pneumococcal infections. Coinfections involving S. pneumoniae with other bacterial pathogens threaten antibiotic treatment strategies and disease outcomes. Currently, there is not an effective treatment for alveolar-capillary barrier dysfunction that precedes bacteremia. An understanding of the dynamics of host-pathogen interactions during single and mixed pulmonary infections could elucidate proper treatment strategies needed to prevent or reduce invasive disease. Antibiotic treatment decreases bacterial burden in the lung but also increases acute pathology due to cytotoxins released via antibiotic-induced bacterial lysis. Therefore, targeted therapeutics that inhibit or counteract the effects of bacterial proteases and toxins are needed in order to limit pathology and disease progression. This study identifies the cooperative effect of PIV and Ply, products of separate lung pathogens that additively alter the lung environment and facilitate invasive disease. Pneumonia is a pulmonary disease affecting people of all ages and is consistently a leading cause of childhood mortality and adult hospitalizations. Streptococcus pneumoniae and Pseudomonas aeruginosa are major lung pathogens commonly associated with community-acquired and nosocomial pneumonia. Additionally, mixed lung infections involving these bacterial pathogens are increasing in prevalence and are frequently more severe than single infections. The cooperative interactions of these two pathogens that impact pulmonary disease severity are understudied. A major secreted virulence factor of P. aeruginosa, protease IV (PIV), cleaves interleukin 22 (IL-22), a cytokine essential for maintaining innate mucosal defenses against extracellular pathogens. Here, we investigate the ability of PIV to augment the virulence of a pneumococcal strain with limited virulence, S. pneumoniae EF3030, in a C57BL/6 murine model of pneumonia. We demonstrate that pulmonary coinfection involving P. aeruginosa 103-29 and S. pneumoniae EF3030 results in pneumococcal bacteremia that is abrogated during pneumococcal coinfection with a PIV-deficient strain. Furthermore, intratracheal administration of exogenous PIV and EF3030 resulted in abundant immune cell infiltration into the lung with large abscess formation, as well as severe bacteremia leading to 100% mortality. Heat-inactivated PIV did not worsen pneumonia or reliably induce bacteremia, suggesting that the specific activity of PIV is required. Our studies also show that PIV depletes IL-22 in vivo. Moreover, PIV-mediated enhancement of pneumonia and disease severity was dependent on the expression of pneumolysin (Ply), a prominent virulence factor of S. pneumoniae. Altogether, we reveal that PIV and Ply additively potentiate pneumonia in a murine model of lung infection. IMPORTANCE S. pneumoniae remains the leading cause of bacterial pneumonia despite widespread use of pneumococcal vaccines, forcing the necessity for appropriate treatment to control pneumococcal infections. Coinfections involving S. pneumoniae with other bacterial pathogens threaten antibiotic treatment strategies and disease outcomes. Currently, there is not an effective treatment for alveolar-capillary barrier dysfunction that precedes bacteremia. An understanding of the dynamics of host-pathogen interactions during single and mixed pulmonary infections could elucidate proper treatment strategies needed to prevent or reduce invasive disease. Antibiotic treatment decreases bacterial burden in the lung but also increases acute pathology due to cytotoxins released via antibiotic-induced bacterial lysis. Therefore, targeted therapeutics that inhibit or counteract the effects of bacterial proteases and toxins are needed in order to limit pathology and disease progression. This study identifies the cooperative effect of PIV and Ply, products of separate lung pathogens that additively alter the lung environment and facilitate invasive disease.