灵长类动物中癌胚抗原相关细胞黏附分子（CEACAM）病原体诱饵受体的进化

Evolution of CEACAM pathogen decoy receptors in primates.

作者信息

Zimmermann Wolfgang, Kammerer Robert

机构信息

Tumor Immunology Laboratory, LIFE Center, Department of Urology, University Hospital, Ludwig-Maximilians University, Munich, Germany.

Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald, Germany.

出版信息

Eur J Clin Invest. 2024 Dec;54 Suppl 2(Suppl 2):e14356. doi: 10.1111/eci.14356.

DOI:10.1111/eci.14356

PMID:39674876

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11646289/

Abstract

BACKGROUND

CEACAM1 in leukocytes controls cell activation during inflammation. This and its expression in epithelial cells led to frequent independent appropriation of CEACAM1 as receptor by pathogens in humans and other species to gain host access and to downregulate its immune response. As a countermeasure, decoy receptors with CEACAM1-like pathogen-binding domains evolved. The granulocyte-specific human CEACAM3 endocytic receptor diverts CEACAM1-binding pathogens to neutrophils for internalization and destruction. The role of the glycosylphosphatidylinositol-anchored CEACAM5 and CEACAM6 which can also bind CEACAM1-targeting pathogens in humans is less clear.

METHODS

We analyzed the selection of CEACAMs to avoid pathogen binding and to maintain similarity between pathogen receptors and decoy receptors in 148 primate species.

RESULTS

Notably, functional CEACAM3 genes were not found in gibbons and New World monkeys. Interestingly, CEACAM6 in these primates exhibits similar high ratios of rates of nonsynonymous and synonymous substitution (dN/dS) in their pathogen-binding N domain exons as found for CEACAM1. High dN/dS ratios are indicative of selection for diversification typically seen in pathogen receptors. Human CEACAM6 is expressed on granulocytes and epithelial cells. Therefore, CEACAM6 could substitute for the missing endocytic receptor CEACAM3. In nearly all investigated primate groups also N exons of the epithelially expressed CEACAM5 exhibit selection for diversification. In African populations, five high-frequency polymorphisms are observed in the pathogen-binding region of CEACAM5 (I80V, V83A, I100T, I112V, I113T) with 3-4 polymorphisms combined in the same individual. These polymorphisms correspond to CEACAM1 pathogen-binding domain sequences.

CONCLUSION

The glycosylphosphatidylinositol-anchored CEACAM5 and CEACAM6 are under selection to maintain similarity to the pathogen receptor CEACAM1 in most primate species, indicating a function as decoy receptors.

摘要

背景

白细胞中的癌胚抗原相关细胞黏附分子1（CEACAM1）在炎症过程中控制细胞活化。这一点及其在上皮细胞中的表达导致人类和其他物种中的病原体频繁独立地将CEACAM1用作受体，以进入宿主并下调其免疫反应。作为一种应对措施，具有CEACAM1样病原体结合结构域的诱饵受体得以进化。粒细胞特异性的人类CEACAM3内吞受体将结合CEACAM1的病原体转移至中性粒细胞进行内化和破坏。糖基磷脂酰肌醇锚定的CEACAM5和CEACAM6在人类中也能结合靶向CEACAM1的病原体，但其作用尚不清楚。

方法

我们分析了148种灵长类动物中CEACAMs为避免病原体结合以及维持病原体受体和诱饵受体之间相似性的选择情况。

结果

值得注意的是，在长臂猿和新大陆猴中未发现功能性CEACAM3基因。有趣的是，这些灵长类动物中的CEACAM6在其病原体结合N结构域外显子中显示出与CEACAM1相似的非同义替换率和同义替换率（dN/dS）高比率。高dN/dS比率表明通常在病原体受体中出现的多样化选择。人类CEACAM6在粒细胞和上皮细胞上表达。因此，CEACAM6可以替代缺失的内吞受体CEACAM3。在几乎所有研究的灵长类动物群体中，上皮表达的CEACAM5的N外显子也表现出多样化选择。在非洲人群中，在CEACAM5的病原体结合区域观察到五个高频多态性（I80V、V83A、I100T、I112V、I113T），同一个体中组合有3 - 4个多态性。这些多态性对应于CEACAM1病原体结合结构域序列。