Laboratorio de Fisiología de los Procesos Inflamatorios, Instituto de Medicina Experimental (IMEX)- Consejo Nacional de investigaciones Científicas y Tecnológicas (CONICET)/Academia Nacional de Medicina de Buenos Aires, Buenos Aires, Argentina.
Instituto de Agrobiotecnología y Biología Molecular (IABIMO), Instituto Nacional de Tecnología Agropecuaria (INTA), Consejo Nacional de investigaciones Científicas y Tecnológicas (CONICET), Buenos Aires, Argentina.
Front Immunol. 2019 Apr 26;10:929. doi: 10.3389/fimmu.2019.00929. eCollection 2019.
The epidemic clone of (Kpn), sequence type 258 (ST258), carbapenamase producer (KPC), commonly infects hospitalized patients that are left with scarce therapeutic option since carbapenems are last resort antibiotics for life-threatening bacterial infections. To improve prevention and treatment, we should better understand the biology of Kpn KPC ST258 infections. Our hypothesis was that Kpn KPC ST258 evade the first line of defense of innate immunity, the polymorphonuclear neutrophil (PMN), by decreasing its functional response. Therefore, our aim was to evaluate how the ST258 Kpn clone affects PMN responses, focusing on the respiratory burst, compared to another opportunistic pathogen, (Eco). We found that Kpn KPC ST258 was unable to trigger bactericidal responses as reactive oxygen species (ROS) generation and NETosis, compared to the high induction observed with Eco, but both bacterial strains were similarly phagocytized and cause increases in cell size and CD11b expression. The absence of ROS induction was also observed with other Kpn ST258 strains negative for KPC. These results reflect certain selectivity in terms of the functions that are triggered in PMN by Kpn, which seems to evade specifically those responses critical for bacterial survival. In this sense, bactericidal mechanisms evasion was associated with a higher survival of Kpn KPC ST258 compared to Eco. To investigate the mechanisms and molecules involved in ROS inhibition, we used bacterial extracts (BE) and found that BE were able to inhibit ROS generation triggered by the well-known ROS inducer, fMLP. A sequence of experiments led us to elucidate that the polysaccharide part of LPS was responsible for this inhibition, whereas lipid A mediated the other responses that were not affected by bacteria, such as cell size increase and CD11b up-regulation. In conclusion, we unraveled a mechanism of immune evasion of Kpn KPC ST258, which may contribute to design more effective strategies for the treatment of these multi-resistant bacterial infections.
（Kpn）的流行克隆株，序列型 258（ST258），产碳青霉烯酶（KPC），通常感染住院患者，由于碳青霉烯类药物是危及生命的细菌感染的最后一道防线，因此这些患者的治疗选择非常有限。为了改善预防和治疗，我们应该更好地了解 Kpn KPC ST258 感染的生物学特性。我们的假设是，Kpn KPC ST258 通过降低其功能反应来逃避先天免疫的第一道防线，多形核中性粒细胞（PMN）。因此，我们的目的是评估 ST258 Kpn 克隆如何影响 PMN 反应，特别是与另一种机会性病原体（Eco）相比，呼吸爆发。我们发现，与高诱导的 Eco 相比，Kpn KPC ST258 无法触发杀菌反应，如活性氧物质（ROS）生成和 NETosis，但两种细菌菌株都被类似地吞噬，并导致细胞大小和 CD11b 表达增加。与其他产 KPC 的 Kpn ST258 菌株一样，也观察到 ROS 诱导的缺失。这些结果反映了 Kpn 在 PMN 中触发的某些功能的选择性，这似乎专门逃避了那些对细菌生存至关重要的反应。在这种意义上，杀菌机制的逃避与 Kpn KPC ST258 与 Eco 相比更高的生存能力相关。为了研究涉及 ROS 抑制的机制和分子，我们使用细菌提取物（BE），并发现 BE 能够抑制由众所周知的 ROS 诱导剂 fMLP 触发的 ROS 生成。一系列实验使我们能够阐明 LPS 的多糖部分负责这种抑制，而脂多糖 A 介导了不受细菌影响的其他反应，如细胞大小增加和 CD11b 上调。总之，我们揭示了 Kpn KPC ST258 的免疫逃避机制，这可能有助于设计更有效的治疗这些多耐药菌感染的策略。
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