d-enantiomers of CATH-2 enhance the response of macrophages against Streptococcus suis serotype 2,Journal of Advanced Research

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d-enantiomers of CATH-2 enhance the response of macrophages against Streptococcus suis serotype 2
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2021-05-26 , DOI: 10.1016/j.jare.2021.05.009
Roel M van Harten ₁ , Johanna L M Tjeerdsma-van Bokhoven ₁ , Astrid de Greeff ₂ , Melanie D Balhuizen ₁ , Albert van Dijk ₁ , Edwin J A Veldhuizen ₁ , Henk P Haagsman ₁ , Maaike R Scheenstra ₁

Affiliation

Introduction

Due to the increase of antibiotic resistant bacterial strains, there is an urgent need for development of alternatives to antibiotics. Cathelicidins can be such an alternative to antibiotics having both a direct antimicrobial capacity as well as an immunomodulatory function. Previously, the full d-enantiomer of chicken cathelicidin-2 (d-CATH-2) has shown to prophylactically protect chickens against infection 7 days post hatch when administered in ovo three days before hatch.

Objectives

To further evaluate d-CATH-2 in mammals as a candidate for an alternative to antibiotics.

In this study, the prophylactic capacity of d-CATH-2 and two truncated derivatives, d-C(1–21) and d-C(4–21), was determined in mammalian cells.

Methods

Antibacterial assays; immune cell differentiation and modulation; cytotoxicity, isothermal titration calorimetry; in vivo prophylactic capacity of peptides in an S. suis infection model.

Results

d-CATH-2 and its derivatives were shown to have a strong direct antibacterial capacity against four different S. suis serotype 2 strains (P1/7, S735, D282, and OV625) in bacterial medium and even stronger in cell culture medium. In addition, d-CATH-2 and its derivatives ameliorated the efficiency of mouse bone marrow-derived macrophages (BMDM) and skewed mouse bone marrow-derived dendritic cells (BMDC) towards cells with a more macrophage-like phenotype. The peptides directly bind lipoteichoic acid (LTA) and inhibit LTA-induced activation of macrophages. In addition, S. suis killed by the peptide was unable to further activate mouse macrophages, which indicates that S. suis was eliminated by the previously reported silent killing mechanism. Administration of d-C(1–21) at 24 h or 7 days before infection resulted in a small prophylactic protection with reduced disease severity and reduced mortality of the treated mice.

Conclusion

d-enantiomers of CATH-2 show promise as anti-infectives against pathogenic S. suis for application in mammals.

中文翻译：

CATH-2的d-对映异构体增强巨噬细胞对猪链球菌血清型2的反应

介绍

由于抗生素耐药菌株的增加，迫切需要开发抗生素的替代品。Cathelicidins 可以作为抗生素的替代品，既具有直接抗菌能力又具有免疫调节功能。以前，鸡cathelicidin-2 ( d -CATH-2)的全d-对映异构体已显示在孵化前三天在蛋内给药时可预防性保护鸡在孵化后7天免受感染。

目标

进一步评估哺乳动物中的d -CATH-2 作为抗生素替代品的候选者。

在这项研究中，d -CATH-2 和两种截短的衍生物d -C(1-21) 和d -C(4-21) 的预防能力在哺乳动物细胞中进行了测定。

方法

抗菌检测；免疫细胞分化和调节；细胞毒性，等温滴定量热法；猪链球菌感染模型中肽的体内预防能力。

结果

d -CATH-2 及其衍生物在细菌培养基中对四种不同的猪链球菌血清型 2 菌株（P1/7、S735、D282 和 OV625）具有很强的直接抗菌能力，在细胞培养基中甚至更强。此外，d -CATH-2 及其衍生物改善了小鼠骨髓来源的巨噬细胞 (BMDM) 的效率，并使小鼠骨髓来源的树突状细胞 (BMDC) 偏向具有更多类似巨噬细胞表型的细胞。这些肽直接结合脂磷壁酸 (LTA) 并抑制 LTA 诱导的巨噬细胞活化。此外，被该肽杀死的猪链球菌无法进一步激活小鼠巨噬细胞，这表明猪链球菌被先前报道的沉默杀死机制消除。在感染前 24 小时或 7 天给予d -C(1-21) 导致小的预防性保护，降低了疾病的严重程度并降低了治疗小鼠的死亡率。