Deciphering the relative importance of genetic elements in hypervirulent Klebsiella pneumoniae to guide countermeasure developmentResearch in context
Thomas A. Russo,
Ulrike Carlino-MacDonald,
Zachary J. Drayer,
Connor J. Davies,
Cassandra L. Alvarado,
Alan Hutson,
Ting L. Luo,
Melissa J. Martin,
Patrick T. McGann,
Francois Lebreton
Affiliations
Thomas A. Russo
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; Corresponding author. The Veterans Administration Western New York Healthcare System, 3495 Bailey Ave, Buffalo, NY 14215, USA.
Ulrike Carlino-MacDonald
Veterans Administration Western New York Healthcare System, Buffalo, NY, USA; Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA
Zachary J. Drayer
Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA
Connor J. Davies
Veterans Administration Western New York Healthcare System, Buffalo, NY, USA; Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA
Cassandra L. Alvarado
Veterans Administration Western New York Healthcare System, Buffalo, NY, USA; Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA
Alan Hutson
Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
Ting L. Luo
Multidrug-Resistant Organism Repository and Surveillance Network (MRSN), Walter Reed Army Institute of Research, Silver Spring, MD, USA
Melissa J. Martin
Multidrug-Resistant Organism Repository and Surveillance Network (MRSN), Walter Reed Army Institute of Research, Silver Spring, MD, USA
Patrick T. McGann
Multidrug-Resistant Organism Repository and Surveillance Network (MRSN), Walter Reed Army Institute of Research, Silver Spring, MD, USA
Francois Lebreton
Multidrug-Resistant Organism Repository and Surveillance Network (MRSN), Walter Reed Army Institute of Research, Silver Spring, MD, USA
Summary: Background: Quantitating the contribution of phenotype-responsible elements in hypervirulent Klebsiella pneumoniae is needed. Methods: Isogenic mutants of four hypervirulent clinical isolates that produced K1 (ST23), K2 (ST86), K20 (ST1544), or K54 (ST29) capsules (mean 2.2 log10 LD50 (range 1.5–2.9)) were created to measure the effects on LD50 in a murine model of the hypervirulence-associated plasmid (pVir), iucA, prmpA, prmpA2 (truncated), irp2, and clbBC. Findings: Curing pVir had the greatest increase in survival (mean LD50 to 7.6 (range 7.0–9.0, p ≤ 0.0001), a dosage comparable to classical K. pneumoniae. Results also showed increased mean LD50s for ΔprmpA (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 LD50 increase of 1.3 compared to the pVir-encoded ΔprmpAΔiucA (p ≤ 0.01), suggesting presence of additional pVir-virulence genes. Truncated pRmpA2 did not contribute to virulence. Odd ratios in the absence of pVir/yersiniabactin, pVir, pRmpA/aerobactin, pRmpA, 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. Interpretation: These data can guide countermeasure development. Funding: 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.
