Stimulator of interferon genes (STING) plays a central role in innate immune responses to viral and intracellular bacterial infections, and cellular damage. STING is a cytosolic sensor of cyclic dinucleotides (CDNs) including those produced by pathogenic bacteria and those arising endogenously as products of the DNA sensor cGAS (e.g., 2′3′ cGAMP). The two most common alternative allelic variants of STING in humans are STING-R71H-G230A-R293Q (STING-HAQ) and STING-R232H that are found in 20.4% and 13.7–17.6% of the population, respectively. To determine the biologic consequences of these genotypic variations, we generated knock-in mice containing the murine equivalents of each variant and studied their responsiveness to CDNs. Homozygous STING-HAQ (R71H-I229A-R292Q) and STING-R231H mice were found to be unresponsive to all exogenous CDNs tested (ci-di-GMP, ci-di-AMP, 3′3′ cGAMP and Rp,Rp-CDA). Responses of homozygous STING-HAQ mice to endogenous 2′3′ cGAMP was also greatly impaired. However, homozygous STING-R231H mice are fully responsive to 2′3′ cGAMP. Analysis of heterozygous mice revealed reduced responsiveness to exogenous and endogenous CDNs in mice carrying a single copy of STING-HAQ, while STING-R231H heterozygous mice exhibit reduced responsiveness to exogenous but not endogenous CDNs. These findings confirm and extend previous reports by demonstrating differing impact of allelic variation of STING on the ability to sense and respond to exogenous vs. endogenous CDNs. Finally, the STING-R231H variant mouse represents a useful tool with which to examine the relative contributions of STING sensing of exogenous and endogenous CDNs in the context of bacterial infections and CDN-based cancer immunotherapeutics.

干扰素基因的刺激物（STING）在对病毒和细胞内细菌感染以及细胞损伤的固有免疫反应中起着核心作用。STING是环状二核苷酸（CDN）的胞质传感器，包括由致病细菌产生的环状二核苷酸和作为DNA传感器cGAS的内源性产生的环状二核苷酸（例如2'3'cGAMP）。在人类中，STING的两个最常见的替代等位基因变体是STING-R71H-G230A-R293Q（STING-HAQ）和STING-R232H，分别占总人口的20.4％和13.7–17.6％。为了确定这些基因型变异的生物学后果，我们生成了包含每种变异的鼠类等效物的敲入小鼠，并研究了它们对CDN的反应性。发现纯合子STING-HAQ（R71H-I229A-R292Q）和STING-R231H小鼠对所有测试的外源CDN（ci-di-GMP，ci-di-AMP，3'3'cGAMP和Rp，Rp-CDA没有反应） ）。纯合STING-HAQ小鼠对内源性2'3'cGAMP的反应也大大受损。然而，纯合的STING-R231H小鼠对2'3'cGAMP完全应答。杂合小鼠的分析显示，携带单拷贝STING-HAQ的小鼠对外源性和内源性CDN的反应性降低，而STING-R231H杂合性小鼠对外源性而非内源性CDN的反应性降低。这些发现证实了STING等位基因变异对感知和响应外源性CDN和内源性CDN的能力的不同影响，从而证实并扩展了以前的报道。最后，