Department of Microbiology and Medical Zoology, University of Puerto Rico, Medical Sciences Campusgrid.267034.4, San Juan, Puerto Rico.
Caribbean Primate Research Center University of Puerto Rico, Medical Sciences Campusgrid.267034.4, Toa Baja, Puerto Rico.
Microbiol Spectr. 2021 Dec 22;9(3):e0191021. doi: 10.1128/Spectrum.01910-21.
Due to their phylogenetic proximity to humans, nonhuman primates (NHPs) are considered an adequate choice for a basic and preclinical model of sepsis. Gram-negative bacteria are the primary causative of sepsis. During infection, bacteria continuously release the potent toxin lipopolysaccharide (LPS) into the bloodstream, which triggers an uncontrolled systemic inflammatory response leading to death. Our previous research has demonstrated and using a mouse model of septic shock that Fh15, a recombinant variant of the Fasciola hepatica fatty acid binding protein, acts as an antagonist of Toll-like receptor 4 (TLR4) suppressing the LPS-induced proinflammatory cytokine storm. The present communication is a proof-of concept study aimed to demonstrate that a low-dose of Fh15 suppresses the cytokine storm and other inflammatory markers during the early phase of sepsis induced in rhesus macaques by intravenous (i.v.) infusion with lethal doses of live Escherichia coli. Fh15 was administered as an isotonic infusion 30 min prior to the bacterial infusion. Among the novel findings reported in this communication, Fh15 (i) significantly prevented bacteremia, suppressed LPS levels in plasma, and the production of C-reactive protein and procalcitonin, which are key signatures of inflammation and bacterial infection, respectively; (ii) reduced the production of proinflammatory cytokines; and (iii) increased innate immune cell populations in blood, which suggests a role in promoting a prolonged steady state in rhesus macaques even in the presence of inflammatory stimuli. This report is the first to demonstrate that a -derived molecule possesses potential as an anti-inflammatory drug against sepsis in an NHP model. Sepsis caused by Gram-negative bacteria affects 1.7 million adults annually in the United States and is one of the most important causes of death at intensive care units. Although the effective use of antibiotics has resulted in improved prognosis of sepsis, the pathological and deathly effects have been attributed to the persistent inflammatory cascade. There is a present need to develop anti-inflammatory agents that can suppress or neutralize the inflammatory responses and prevent the lethal consequences of sepsis. We demonstrated here that a small molecule of 14.5 kDa can suppress the bacteremia, endotoxemia, and many other inflammatory markers in an acute Gram-negative sepsis rhesus macaque model. These results reinforce the notion that Fh15 constitutes an excellent candidate for drug development against sepsis.
由于与人类的系统发育关系密切，非人类灵长类动物（NHPs）被认为是脓毒症基础和临床前模型的合适选择。革兰氏阴性菌是脓毒症的主要病原体。在感染过程中，细菌会不断将强效毒素脂多糖（LPS）释放到血液中，引发失控的全身炎症反应，导致死亡。我们之前的研究已经表明，[原文作者]使用脓毒性休克的小鼠模型，肝片吸虫脂肪酸结合蛋白的重组变体 Fh15 作为 Toll 样受体 4（TLR4）的拮抗剂，抑制 LPS 诱导的促炎细胞因子风暴。本通讯是一项概念验证研究，旨在证明低剂量的 Fh15 可抑制恒河猴静脉内（i.v.）输注致死剂量活大肠杆菌诱导的脓毒症早期阶段的细胞因子风暴和其他炎症标志物。Fh15 在细菌输注前 30 分钟作为等渗输注给予。在本通讯中报告的新发现中，Fh15（i）显著预防菌血症，抑制血浆中的 LPS 水平以及 C 反应蛋白和降钙素原的产生，这分别是炎症和细菌感染的关键特征；（ii）减少促炎细胞因子的产生；和（iii）增加血液中的固有免疫细胞群，这表明它在促进恒河猴的持久稳定状态方面发挥作用，即使存在炎症刺激也是如此。本报告首次证明，源自[原文作者]的分子具有作为抗脓毒症的抗炎药物在非人类灵长类动物模型中的潜力。由革兰氏阴性菌引起的脓毒症每年影响美国 170 万成年人，是重症监护病房死亡的最重要原因之一。尽管有效使用抗生素可改善脓毒症的预后，但病理和致命影响归因于持续的炎症级联反应。目前需要开发能够抑制或中和炎症反应并防止脓毒症致命后果的抗炎药物。我们在这里证明，一种 14.5 kDa 的小分子可以抑制急性革兰氏阴性脓毒症恒河猴模型中的菌血症、内毒素血症和许多其他炎症标志物。这些结果强化了这样一种观点，即 Fh15 是开发针对脓毒症的药物的极好候选物。
