Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Cell Host Microbe. 2019 Feb 13;25(2):336-343.e4. doi: 10.1016/j.chom.2019.01.001. Epub 2019 Jan 31.
Immune responses counteract infections but also cause collateral damage to hosts. Oligoadenylate synthetase 1 (OAS1) binds double-stranded RNA from invading viruses and produces 2'-5' linked oligoadenylate (2-5A) to activate ribonuclease L (RNase L), which cleaves RNA to inhibit virus replication. OAS1 can also undergo autoactivation by host RNAs, a potential trade-off to antiviral activity. We investigated functional variation in primate OAS1 as a model for how immune pathways evolve to mitigate costs and observed a surprising frequency of loss-of-function variation. In gorillas, we identified a polymorphism that severely decreases catalytic function, mirroring a common variant in humans that impairs 2-5A synthesis through alternative splicing. OAS1 loss-of-function variation is also common in monkeys, including complete loss of 2-5A synthesis in tamarins. The frequency of loss-of-function alleles suggests that costs associated with OAS1 activation can be so detrimental to host fitness that pathogen-protective effects are repeatedly forfeited.
免疫反应能抵抗感染，但也会对宿主造成附带损害。寡聚腺苷酸合成酶 1（OAS1）结合入侵病毒的双链 RNA，并产生 2'-5' 连接的寡腺苷酸（2-5A）以激活核糖核酸酶 L（RNase L），后者切割 RNA 以抑制病毒复制。OAS1 也可以通过宿主 RNA 进行自身激活，这是一种对抗病毒活性的潜在权衡。我们研究了灵长类动物 OAS1 的功能变异，以此作为研究免疫途径如何进化以减轻代价的模型，并观察到一种令人惊讶的失能变异频率。在大猩猩中，我们发现了一种严重降低催化功能的多态性，这与人类中一种常见的变体相似，该变体通过选择性剪接削弱 2-5A 的合成。OAS1 失能变异在猴子中也很常见，包括食蟹猴中 2-5A 合成的完全缺失。失能等位基因的频率表明，与 OAS1 激活相关的成本可能对宿主适应性造成如此大的损害，以至于病原体保护作用被反复放弃。
