An Interferon-Related Signature in the Transcriptional Core Response of Human Macrophages to Mycobacterium tuberculosis Infection

The W-Beijing family of Mycobacterium tuberculosis (Mtb) strains is known for its high-prevalence and -virulence, as well as for its genetic diversity, as recently reported by our laboratories and others. However, little is known about how the immune system responds to these strains. To explore this issue, here we used reverse engineering and genome-wide expression profiling of human macrophage-like THP-1 cells infected by different Mtb strains of the W-Beijing family, as well as by the reference laboratory strain H37Rv. Detailed data mining revealed that host cell transcriptome responses to H37Rv and to different strains of the W-Beijing family are similar and overwhelmingly induced during Mtb infections, collectively typifying a robust gene expression signature (“THP1r2Mtb-induced signature”). Analysis of the putative transcription factor binding sites in promoter regions of genes in this signature identified several key regulators, namely STATs, IRF-1, IRF-7, and Oct-1, commonly involved in interferon-related immune responses. The THP1r2Mtb-induced signature appeared to be highly relevant to the interferon-inducible signature recently reported in active pulmonary tuberculosis patients, as revealed by cross-signature and cross-module comparisons. Further analysis of the publicly available transcriptome data from human patients showed that the signature appears to be relevant to active pulmonary tuberculosis patients and their clinical therapy, and be tuberculosis specific. Thus, our results provide an additional layer of information at the transcriptome level on mechanisms involved in host macrophage response to Mtb, which may also implicate the robustness of the cellular defense system that can effectively fight against genetic heterogeneity in this pathogen.

结核分枝杆菌（Mycobacterium tuberculosis, Mtb）W-Beijing家族菌株以高流行率、高毒力及遗传多样性而闻名，这一结论已由本实验室及其他研究团队近期报道。然而，目前对于宿主免疫系统如何应答这类菌株仍知之甚少。为探究这一科学问题，本研究针对感染不同W-Beijing家族Mtb菌株以及实验室参考菌株H37Rv的人类巨噬细胞样THP-1细胞，开展了反向工程与全基因组表达谱分析。

细致的数据挖掘结果显示，宿主细胞对H37Rv以及不同W-Beijing家族菌株的转录组应答模式高度相似，且在Mtb感染过程中被显著诱导，共同构成一套稳健的基因表达特征（“THP1r2Mtb诱导特征”）。对该特征相关基因启动子区域的推定转录因子结合位点进行分析后，我们鉴定出STAT家族、IRF-1、IRF-7及Oct-1等数个关键调控因子，这些因子均广泛参与干扰素相关免疫应答过程。

通过跨特征与跨模块比较分析发现，这套THP1r2Mtb诱导特征与近期报道的活动性肺结核患者体内干扰素诱导特征高度相关。进一步对公开可用的人类患者转录组数据进行分析后证实，该特征与活动性肺结核患者及其临床治疗高度相关，且具备结核病特异性。

综上，本研究从转录组层面为宿主巨噬细胞应答Mtb的相关机制提供了额外的信息维度，同时也提示细胞防御系统能够有效对抗该病原体的遗传异质性，彰显了其稳健性。