Department of Pediatrics, Center for Microbial Pathogenesis, Duke University, Durham, NC, USA.
Virulence. 2011 May-Jun;2(3):222-32. doi: 10.4161/viru.2.3.16143. Epub 2011 May 1.
Uropathogenic Escherichia coli (UPEC) produces ~80% of community-acquired UTI, the second most common infection in humans. During UTI, UPEC has a complex life cycle, replicating and persisting in intracellular and extracellular niches. Host and environmental stresses may affect the integrity of the UPEC genome and threaten its viability. We determined how the host inflammatory response during UTI drives UPEC genome instability and evaluated the role of multiple factors of genome replication and repair for their roles in the maintenance of genome integrity and thus virulence during UTI. The urinary tract environment enhanced the mutation frequency of UPEC ~100-fold relative to in vitro levels. Abrogation of inflammation through a host TLR4-signaling defect significantly reduced the mutation frequency, demonstrating in the importance of the host response as a driver of UPEC genome instability. Inflammation induces the bacterial SOS response, leading to the hypothesis that the UPEC SOS-inducible translesion synthesis (TLS) DNA polymerases would be key factors in UPEC genome instability during UTI. However, while the TLS DNA polymerases enhanced in vitro, they did not increase in vivo mutagenesis. Although it is not a source of enhanced mutagenesis in vivo, the TLS DNA polymerase IV was critical for the survival of UPEC during UTI during an active inflammatory assault. Overall, this study provides the first evidence of a TLS DNA polymerase being critical for UPEC survival during urinary tract infection and points to independent mechanisms for genome instability and the maintenance of genome replication of UPEC under host inflammatory stress.
尿路致病性大肠杆菌（UPEC）导致了 80%的社区获得性尿路感染，这是人类第二大常见感染。在尿路感染期间，UPEC 经历了一个复杂的生命周期，在细胞内和细胞外小生境中复制和持续存在。宿主和环境压力可能会影响 UPEC 基因组的完整性，并威胁其生存能力。我们确定了宿主在尿路感染期间的炎症反应如何导致 UPEC 基因组不稳定性，并评估了多个基因组复制和修复因素在维持基因组完整性和因此在尿路感染期间维持毒力方面的作用。与体外水平相比，尿路环境将 UPEC 的突变频率提高了约 100 倍。通过宿主 TLR4 信号缺陷消除炎症大大降低了突变频率，这证明了宿主反应作为 UPEC 基因组不稳定性驱动因素的重要性。炎症会诱导细菌 SOS 反应，从而假设 UPEC SOS 诱导的跨损伤合成（TLS）DNA 聚合酶将是尿路感染期间 UPEC 基因组不稳定性的关键因素。然而，尽管 TLS DNA 聚合酶在体外增强，但它们并没有增加体内诱变。尽管它不是体内增强诱变的来源，但 TLS DNA 聚合酶 IV 在宿主炎症攻击期间对 UPEC 在尿路感染中的存活至关重要。总的来说，这项研究首次提供了证据表明，TLS DNA 聚合酶对于 UPEC 在尿路感染期间的存活至关重要，并指出了在宿主炎症应激下 UPEC 基因组不稳定性和基因组复制维持的独立机制。
