Therapeutic Activity of Type 3 Streptococcus pneumoniae Capsule Degrading Enzyme Pn3Pase.
Therapeutic Activity of Type 3 Streptococcus pneumoniae Capsule Degrading Enzyme Pn3Pase.
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DOI：
10.1007/s11095-020-02960-3
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发表时间：
2020-11-02
影响因子：
3.7
通讯作者：
Avci FY
中科院分区：
文献类型：
--
作者：
Paschall AV;Middleton DR;Wantuch PL;Avci FY
肺炎链球菌（Spn）血清3型（Spn3）被认为是对常规疫苗和治疗方案具有耐药性的毒性最强的血清型之一。Pn3Pase是一种糖苷水解酶，我们之前已经证明它在降解3型Spn的荚膜多糖方面非常有效，使其对宿主免疫清除敏感。为了开始评估这种酶在未来临床研究中的价值和安全性，我们研究了高剂量Pn3Pase对宿主细胞和免疫系统的影响。我们在给药后评估了该酶在小鼠体内的催化活性，并进行了脓毒性感染模型，以确定事先给药是否会抑制spn3攻击小鼠的重复治疗。我们评估了给药后小鼠组织中的免疫群体，并在体外测试了Pn3Pase对其他哺乳动物细胞类型的毒性。体内反复给药并不妨碍酶在细菌攻击后促进细菌清除的功效，对酶产生的抗体反应微不足道。在高剂量Pn3Pase治疗后，免疫稳态得以维持，并且未观察到对哺乳动物细胞的细胞毒性作用。这些数据表明，Pn3Pase具有治疗Spn3的潜力。作为一种药物产品的进一步开发可以克服肺炎球菌感染的巨大障碍。
Streptococcus pneumoniae (Spn) serotype 3 (Spn3) is considered one of the most virulent serotypes with resistance to conventional vaccine and treatment regimens. Pn3Pase is a glycoside hydrolase that we have previously shown to be highly effective in degrading the capsular polysaccharide of type 3 Spn, sensitizing it to host immune clearance. To begin assessing the value and safety of this enzyme for future clinical studies, we investigated the effects of high doses of Pn3Pase on host cells and immune system. We assessed the enzyme’s catalytic activity following administration in mice, and performed septic infection models to determine if prior administration of the enzyme inhibited repeat treatments of Spn3-challenged mice. We assessed immune populations in mouse tissues following administration of the enzyme, and tested Pn3Pase toxicity on other mammalian cell types in vitro. Repeated administration of the enzyme in vivo does not prevent efficacy of the enzyme in promoting bacterial clearance following bacterial challenge, with insignificant antibody response generated against the enzyme. Immune homeostasis is maintained following high-dose treatment with Pn3Pase, and no cytotoxic effects were observed against mammalian cells. These data indicate that Pn3Pase has potential as a therapy against Spn3. Further development as a drug product could overcome a great hurdle of pneumococcal infections.
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影响因子：
3.7
作者：
Martens P;Worm SW;Lundgren B;Konradsen HB;Benfield T
通讯作者：
Benfield T
影响因子：
6.7
作者：
Azarian T;Mitchell PK;Georgieva M;Thompson CM;Ghouila A;Pollard AJ;von Gottberg A;du Plessis M;Antonio M;Kwambana-Adams BA;Clarke SC;Everett D;Cornick J;Sadowy E;Hryniewicz W;Skoczynska A;Moïsi JC;McGee L;Beall B;Metcalf BJ;Breiman RF;Ho PL;Reid R;O'Brien KL;Gladstone RA;Bentley SD;Hanage WP
通讯作者：
Hanage WP
影响因子：
3.1
作者：
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通讯作者：
YOTHER, J
影响因子：
11.8
作者：
Dagan, Ron;Patterson, Scott;Scott, Daniel A.
通讯作者：
Scott, Daniel A.
影响因子：
4.3
作者：
Middleton, Dustin R.;Zhang, Xing;Avci, Fikri Y.
通讯作者：
Avci, Fikri Y.