Variations in blood microbiome and LPS concentration inform disease susceptibility differences in primates

Differential exposure to microorganisms over time has contributed to the evolution of primate immune system and its resident microbiota. Since blood is an important immune compartment containing high density of professional immune cells, its microbiome may help explain the divergence of human immune responses from non-human primates (NHPs). The NHP blood microbiota, however, remains uncharacterized and its relationship to blood immune functions are unknown. Here, we aim to characterize primate blood microbiome, its association with inter-species differences in immune phenotypes such as lipopolysaccharide (LPS) sensitivity and infectious disease manifestations. We compare blood microbiome, LPS levels and transcriptomes in four major primate groups [apes, African & Asian monkeys, South American monkeys, strepsirrhines] to assess the role of their variations on observed immune susceptibility differences in primates. Our results show a connection between blood LPS concentrations and known species-specific susceptibilities and stark differences in blood bacterial composition and expression of genes that are important in primate immunity. As expected by their higher LPS susceptibility, humans had the lowest LPS concentrations compared with NHPs. Genes important in LPS responses, e.g. IRAK1, IRF7, Map Kinases and TGF-beta were at least two times more highly expressed in humans compared to macaque, a more resistant species. Our data further provides evidence that many blood microbes are probably mainly sourced from the gut and continuously and selectively leak in to the circulation. Overall, our results provide evidence of a link between the evolution of primate immunity and blood microbiota, possibly affecting disease susceptibility differences.

长期以来微生物暴露的差异推动了灵长类免疫系统及其常驻微生物群的演化。血液作为一类重要的免疫区室，含有高密度的专职免疫细胞，其微生物组或可解释人类免疫反应与非人灵长类（non-human primates, NHPs）的分化。然而，非人灵长类的血液微生物组尚未得到系统表征，且其与血液免疫功能的关联仍属未知。本研究旨在解析灵长类血液微生物组，及其与免疫表型种间差异的关联，如脂多糖（lipopolysaccharide, LPS）敏感性与传染病表型。我们对四大类灵长类动物[类人猿、非洲与亚洲猴、南美洲猴、原猴亚目动物]的血液微生物组、LPS水平及转录组进行比较分析，以评估其变异在灵长类已观测到的免疫易感性差异中所起的作用。研究结果显示，血液LPS浓度与已知的物种特异性易感性存在关联，且血液细菌组成以及灵长类免疫相关基因的表达均存在显著差异。正如预期，由于人类LPS敏感性更高，其血液LPS浓度相较于所有非人灵长类最低。与LPS应答相关的关键基因（如IRAK1、IRF7、丝裂原活化蛋白激酶（Map Kinases）及转化生长因子β（TGF-beta））在人类中的表达量至少是抗性更强的物种猕猴的两倍。本研究数据还进一步证实，多数血液微生物可能主要源自肠道，并持续选择性地渗漏进入血液循环系统。总体而言，本研究结果为灵长类免疫演化与血液微生物组之间存在关联提供了证据，该关联或可影响不同物种间的疾病易感性差异。