Outer Membrane Vesicles Displaying a Heterologous PcrV-HitA Fusion Antigen Promote Protection against Pulmonary Pseudomonas aeruginosa Infection.
Outer Membrane Vesicles Displaying a Heterologous PcrV-HitA Fusion Antigen Promote Protection against Pulmonary Pseudomonas aeruginosa Infection.
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DOI：
10.1128/msphere.00699-21
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发表时间：
2021-10-27
期刊：
影响因子：
4.8
通讯作者：
Sun W
中科院分区：
文献类型：
--
作者：
Li P;Wang X;Sun X;Guan Z;Sun W
随着卫生保健机构中铜绿假单胞菌的威胁和抗生素耐药性的激增，开发针对铜绿假单胞菌感染的有效疫苗势在必行。在这项研究中，我们利用重组假结核耶尔森菌突变体的Asd（天冬氨酸-半醛脱氢酶）平衡致死宿主载体系统产生自佐剂外膜囊泡（omv）。以omv为载体，传递铜绿假单胞菌PcrV-HitAT （PH）融合抗原，进行疫苗评价。携带PH抗原（rOMV-PH）的omv肌内疫苗接种对5 × 106（25 50%致死剂量）细胞毒性PA103菌株的鼻内攻击具有73%的保护作用，对非细胞毒性PAO1菌株具有完全的保护作用。相比之下，单独接种PH缺陷的omv或PH抗原未能提供有效的保护以抵御相同的挑战。免疫分析显示，与PH接种相比，rOMV-PH接种可诱导强效的体液应答和Th1/Th17应答。在小鼠中，rOMV-PH疫苗快速清除了铜绿假单胞菌负担，并协调了促炎细胞因子的产生。此外，抗原特异性CD4+和CD8+ T细胞及其产生的细胞因子（肿瘤坏死因子α和白细胞介素- 17a），而不是抗体，对预防肺炎铜绿假单胞菌感染至关重要。我们的研究表明，传递异源铜绿假单胞菌抗原的重组假结核杆菌omv可能是一种新的有希望的预防耐药铜绿假单胞菌传播的疫苗候选物。重要性：医院和社区获得性铜绿假单胞菌感染在有基础疾病的患者中引起很高的发病率和死亡率。耐多药铜绿假单胞菌菌株的传播正成为抗生素治疗的一大挑战。因此，迫切需要一种疫苗作为替代策略之一来预防铜绿假单胞菌感染。
Along with surging threats and antibiotic resistance of Pseudomonas aeruginosa in health care settings, it is imperative to develop effective vaccines against P. aeruginosa infection. In this study, we used an Asd (aspartate-semialdehyde dehydrogenase)-based balanced-lethal host-vector system of a recombinant Yersinia pseudotuberculosis mutant to produce self-adjuvanting outer membrane vesicles (OMVs). The OMVs were used as a carrier to deliver the heterologous PcrV-HitAT (PH) fusion antigen of P. aeruginosa for vaccine evaluation. Intramuscular vaccination with OMVs carrying the PH antigen (referred to rOMV-PH) afforded 73% protection against intranasal challenge with 5 × 106 (25 50% lethal doses) of the cytotoxic PA103 strain and complete protection against a noncytotoxic PAO1 strain. In contrast, vaccination with the PH-deficient OMVs or PH antigen alone failed to offer effective protection against the same challenge. Immune analysis showed that the rOMV-PH vaccination induced potent humoral and Th1/Th17 responses compared to the PH vaccination. The rOMV-PH vaccination rapidly cleared P. aeruginosa burdens with coordinated production of proinflammatory cytokines in mice. Moreover, antigen-specific CD4+ and CD8+ T cells and their producing cytokines (tumor necrosis factor alpha and interleukin-17A), rather than antibodies, were essential for protection against pneumonic P. aeruginosa infection. Our studies demonstrated that the recombinant Y. pseudotuberculosis OMVs delivering heterologous P. aeruginosa antigens could be a new promising vaccine candidate for preventing the spread of drug-resistant P. aeruginosa. IMPORTANCE Hospital- and community-acquired infections with Pseudomonas aeruginosa cause a high rate of morbidity and mortality in patients who have underlying medical conditions. The spread of multidrug-resistant P. aeruginosa strains is becoming a great challenge for treatment using antibiotics. Thus, a vaccine as one of the alternative strategies is urgently required to prevent P. aeruginosa infection.