Veterans Administration Western New York Healthcare System, Buffalo, NY, USA; Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA; Department of Microbiology and Immunology, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA; The Witebsky Center for Microbial Pathogenesis, University at Buffalo, State University of New York, Buffalo, NY, USA.
Veterans Administration Western New York Healthcare System, Buffalo, NY, USA; Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA.
EBioMedicine. 2024 Sep;107:105302. doi: 10.1016/j.ebiom.2024.105302. Epub 2024 Aug 22.
Quantitating the contribution of phenotype-responsible elements in hypervirulent Klebsiella pneumoniae is needed.
Isogenic mutants of four hypervirulent clinical isolates that produced K1 (ST23), K2 (ST86), K20 (ST1544), or K54 (ST29) capsules (mean 2.2 log LD (range 1.5-2.9)) were created to measure the effects on LD in a murine model of the hypervirulence-associated plasmid (pVir), iucA, rmpA, rmpA2 (truncated), irp2, and clbBC.
Curing pVir had the greatest increase in survival (mean LD to 7.6 (range 7.0-9.0, p ≤ 0.0001), a dosage comparable to classical K. pneumoniae. Results also showed increased mean LDs for ΔrmpA (5.9, p ≤ 0.0001), ΔiucA (3.6, p ≤ 0.0001), Δirp2 (3.4), ΔrmpAΔiucA (6.3, p ≤ 0.0001), and ΔpVirΔirp2 (8.7, p ≤ 0.0001). Notably ΔpVir had an additional mean LD increase of 1.3 compared to the pVir-encoded ΔrmpAΔiucA (p ≤ 0.01), suggesting presence of additional pVir-virulence genes. Truncated RmpA2 did not contribute to virulence. Odd ratios in the absence of pVir/yersiniabactin, pVir, RmpA/aerobactin, RmpA, aerobactin, yersiniabactin, and colibactin demonstrated a 250-fold, 67-fold, 20-fold, 16.7-fold, 9.6-fold, and 1.7-fold decrease in lethality respectively.
These data can guide countermeasure development.
This work was supported by NIH R21 AI123558-01 and 1R21AI141826-01A1 (Dr. Russo) and the Department of Veterans Affairs VA Merit Review (I01 BX004677-01) (Dr. Russo). This study was also partially funded by the U.S. Defense Health Program (DHP) Operations and Maintenance.
需要定量分析高毒力肺炎克雷伯菌中表型相关元件的贡献。
构建了四个产生 K1（ST23）、K2（ST86）、K20（ST1544）或 K54（ST29）荚膜（平均 2.2 对数致死剂量（范围 1.5-2.9））的高毒力临床分离株的同源突变体，以测量 hypervirulence-associated 质粒（pVir）、iucA、rmpA、rmpA2（截断）、irp2 和 clbBC 在小鼠模型中的致死剂量的影响。
pVir 缺失后存活率显著增加（平均 LD 增加至 7.6（范围 7.0-9.0，p≤0.0001），与经典肺炎克雷伯菌相当。结果还显示 rmpA（5.9，p≤0.0001）、iucA（3.6，p≤0.0001）、irp2（3.4）、rmpAΔiucA（6.3，p≤0.0001）和 pVirΔirp2（8.7，p≤0.0001）的平均 LD 也增加。值得注意的是，与 pVir 编码的 rmpAΔiucA 相比，pVir 缺失的平均 LD 增加了 1.3（p≤0.01），这表明存在其他 pVir 毒力基因。截断的 RmpA2 对毒力没有贡献。在没有 pVir/耶尔森菌素、pVir、RmpA/铁载体、RmpA、铁载体、耶尔森菌素和 colibactin 的情况下，Odd 比值分别降低了 250 倍、67 倍、20 倍、16.7 倍、9.6 倍和 1.7 倍。
这些数据可以指导对策的制定。
本工作得到 NIH R21 AI123558-01 和 1R21 AI141826-01A1（Russo 博士）和美国退伍军人事务部 VA 优秀审查（I01 BX004677-01）（Russo 博士）的资助。本研究还部分得到美国国防健康计划（DHP）运营和维护的资助。
