Howlader Debaki R, Das Sayan, Lu Ti, Mandal Rahul Shubhra, Hu Gang, Varisco David J, Dietz Zackary K, Ratnakaram Siva Sai Kumar, Ernst Robert K, Picking William D, Picking Wendy L
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, 66047, USA.
Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, 65211, USA.
NPJ Vaccines. 2023 Mar 14;8(1):37. doi: 10.1038/s41541-023-00618-w.
The opportunistic pathogen Pseudomonas aeruginosa (Pa) causes severe nosocomial infections, especially in immunocompromised individuals and the elderly. Increasing drug resistance, the absence of a licensed vaccine and increased hospitalizations due to SARS-CoV-2 have made Pa a major healthcare risk. To address this, we formulated a candidate subunit vaccine against Pa (L-PaF), by fusing the type III secretion system tip and translocator proteins with LTA1 in an oil-in-water emulsion (ME). This was mixed with the TLR4 agonist (BECC438b). Lung mRNA sequencing showed that the formulation activates genes from multiple immunological pathways eliciting a protective Th1-Th17 response following IN immunization. Following infection, however, the immunized mice showed an adaptive response while the PBS-vaccinated mice experienced rapid onset of an inflammatory response. The latter displayed a hypoxic lung environment with high bacterial burden. Finally, the importance of IL-17 and immunoglobulins were demonstrated using knockout mice. These findings suggest a need for a balanced humoral and cellular response to prevent the onset of Pa infection and that our formulation could elicit such a response.
机会致病菌铜绿假单胞菌（Pa）会引发严重的医院感染，尤其是在免疫功能低下的个体和老年人中。耐药性增加、缺乏获批疫苗以及因严重急性呼吸综合征冠状病毒2（SARS-CoV-2）导致的住院人数增加，使得铜绿假单胞菌成为主要的医疗健康风险因素。为解决这一问题，我们通过将III型分泌系统尖端蛋白和转运蛋白与脂磷壁酸1（LTA1）融合在水包油乳剂（ME）中，制备了一种针对铜绿假单胞菌的候选亚单位疫苗（L-PaF）。将其与Toll样受体4（TLR4）激动剂（BECC438b）混合。肺部mRNA测序显示，该制剂可激活多种免疫途径的基因，在经鼻内（IN）免疫后引发保护性的Th1-Th17反应。然而，在感染后，免疫小鼠表现出适应性反应，而接种磷酸盐缓冲盐水（PBS）的小鼠则迅速出现炎症反应。后者表现出低氧肺环境且细菌载量高。最后，利用基因敲除小鼠证明了白细胞介素-17（IL-17）和免疫球蛋白的重要性。这些发现表明，需要一种平衡的体液和细胞反应来预防铜绿假单胞菌感染的发生，并且我们的制剂可以引发这样的反应。
