School of Medicine, University of Colorado, Aurora CO 80045, USA.
Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins CO 80523, USA.
J Med Microbiol. 2024 Apr;73(4). doi: 10.1099/jmm.0.001821.
is the leading cause of acute medical implant infections, representing a significant modern medical concern. The success of as a pathogen in these cases resides in its arsenal of virulence factors, resistance to multiple antimicrobials, mechanisms of immune modulation, and ability to rapidly form biofilms associated with implant surfaces. device-associated, biofilm-mediated infections are often persistent and notoriously difficult to treat, skewing innate immune responses to promote chronic reoccurring infections. While relatively little is known of the role neutrophils play in response to acute biofilm infections, these effector cells must be efficiently recruited to sites of infection via directed chemotaxis. Here we investigate the effects of modulating CXC chemokine receptor 2 (CXCR2) activity, predominantly expressed on neutrophils, during implant-associated infection. We hypothesize that modulation of CXCR2 expression and/or signalling activities during infection, and thus neutrophil recruitment, extravasation and antimicrobial activity, will affect infection control and bacterial burdens in a mouse model of implant-associated infection. This investigation aims to elucidate the impact of altered CXCR2 activity during biofilm-mediated infection that may help develop a framework for an effective novel strategy to prevent morbidity and mortality associated with implant infections. To examine the role of CXCR2 during implant infection, we employed a mouse model of indwelling subcutaneous catheter infection using a community-associated methicillin-resistant (MRSA) strain. To assess the role of CXCR2 induction or inhibition during infection, treatment groups received daily intraperitoneal doses of either Lipocalin-2 (Lcn2) or AZD5069, respectively. At the end of the study, catheters and surrounding soft tissues were analysed for bacterial burdens and dissemination, and transcription within the implant-associated tissues was quantified. Mice treated with Lcn2 developed higher bacterial burdens within the soft tissue surrounding the implant site, which was associated with increased expression. AZD5069 treatment also resulted in increased implant- and tissues-associated bacterial titres, as well as enhanced expression. Our results demonstrate that CXCR2 plays an essential role in regulating the severity of implant-associated infections. Interestingly, however, perturbation of CXCR2 expression or signalling both resulted in enhanced transcription and elevated implant-associated bacterial burdens. Thus, CXCR2 appears finely tuned to efficiently recruit effector cells and mediate control of biofilm-mediated infection.
是急性医疗植入物感染的主要原因，是现代医学的一个重大关注点。作为病原体，它在这些病例中的成功在于其毒力因子库、对多种抗菌药物的耐药性、免疫调节机制以及与植入物表面相关的生物膜快速形成的能力。与设备相关的、由生物膜介导的感染通常持续存在，并且治疗起来非常困难，导致先天免疫反应偏向于慢性反复感染。虽然人们对中性粒细胞在急性生物膜感染中的作用知之甚少，但这些效应细胞必须通过定向趋化作用有效地募集到感染部位。在这里，我们研究了调节 CXC 趋化因子受体 2 (CXCR2) 活性在对生物膜感染的反应中的作用，该受体主要在中性粒细胞上表达。我们假设，在感染过程中调节 CXCR2 的表达和/或信号转导活性，从而影响中性粒细胞的募集、渗出和抗菌活性，将影响植入物相关感染的感染控制和细菌负荷。这项研究旨在阐明改变 CXCR2 活性在生物膜介导的感染中的影响，这可能有助于为预防与植入物感染相关的发病率和死亡率制定有效的新策略。为了研究 CXCR2 在植入物感染中的作用，我们使用一种社区相关的耐甲氧西林金黄色葡萄球菌（MRSA）菌株建立了皮下留置导管感染的小鼠模型。为了评估感染过程中 CXCR2 诱导或抑制的作用，治疗组分别接受了每日腹腔内剂量的脂联素 2 (Lcn2) 或 AZD5069。在研究结束时，分析了导管和周围软组织中的细菌负荷和传播情况，并定量了植入物相关组织中的转录。用 Lcn2 治疗的小鼠在植入部位周围的软组织中形成更高的细菌负荷，这与增加有关。AZD5069 治疗也导致植入物和组织相关细菌滴度增加，并增强了表达。我们的结果表明，CXCR2 在调节金黄色葡萄球菌植入物相关感染的严重程度方面起着至关重要的作用。然而，有趣的是，CXCR2 的表达或信号转导的扰动都导致了增强的转录和升高的植入物相关细菌负荷。因此，CXCR2 似乎被精细地调节以有效地募集效应细胞并介导对生物膜介导的感染的控制。
