C-C motif chemokine receptor 2 (CCR2) is a major chemokine axis that recruits myeloid cells including monocytes and macrophages. Thus far, CCR2^-/- mice have not been found to be susceptible to infection with Mycobacterium tuberculosis (Mtb). Here, using a prototype W-Beijing family lineage 2 Mtb strain, HN878, we show that CCR2^-/- mice exhibit increased susceptibility to tuberculosis (TB). Following exposure to Mtb HN878, alveolar macrophages (AMs) are amongst the earliest cells infected. We show that AMs accumulate early in the airways following infection and express CCR2. During disease progression, CCR2-expressing AMs exit the airways and localize within the TB granulomas. RNA-sequencing of sorted airway and non-airway AMs from infected mice show distinct gene expression profiles, suggesting that upon exit from airways and localization within granulomas, AMs become classically activated. The absence of CCR2⁺ cells specifically at the time of AM egress from the airways resulted in enhanced susceptibility to Mtb infection. Furthermore, infection with an Mtb HN878 mutant lacking phenolic glycolipid (PGL) expression still resulted in increased susceptibility in CCR2^-/- mice. Together, these data show a novel role for CCR2 in protective immunity against clinically relevant Mtb infections.

中文翻译：

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CC 基序趋化因子受体 2 在高毒性结核分枝杆菌感染过程中的新作用。

CC 基序趋化因子受体 2 (CCR2) 是一个主要的趋化因子轴，可募集包括单核细胞和巨噬细胞在内的骨髓细胞。迄今为止，尚未发现CCR2 ^{-/-小鼠对结核分枝杆菌 (Mtb) 感染易感。}在这里，使用原型 W-Beijing 家族谱系 2 Mtb 菌株 HN878，我们显示 CCR2 ^-/-小鼠表现出对结核病 (TB) 的易感性增加。在接触 Mtb HN878 后，肺泡巨噬细胞 (AM) 是最早被感染的细胞之一。我们表明 AM 在感染后早期在气道中积聚并表达 CCR2。在疾病进展期间，表达 CCR2 的 AMs 离开气道并定位在 TB 肉芽肿内。来自受感染小鼠的分选气道和非气道 AM 的 RNA 测序显示出不同的基因表达谱，这表明在离开气道并在肉芽肿内定位后，AM 被经典激活。CCR2 ^+缺失特别是在 AM 从气道排出时的细胞导致对 Mtb 感染的易感性增强。此外，感染缺乏酚糖脂 (PGL) 表达的 Mtb HN878 突变体仍然导致 CCR2 ^-/-小鼠的易感性增加。总之，这些数据显示了 CCR2 在针对临床相关 Mtb 感染的保护性免疫中的新作用。