In Vivo Evolution of a Klebsiella pneumoniae Capsule Defect With wcaJ Mutation Promotes Complement-Mediated Opsonophagocytosis During Recurrent Infection

Author:

Bain William12ORCID,Ahn Brian3,Peñaloza Hernán F1,McElheny Christi L4,Tolman Nathanial1,van der Geest Rick1,Gonzalez-Ferrer Shekina1,Chen Nathalie4,An Xiaojing1,Hosuru Ria1,Tabary Mohammadreza1,Papke Erin1,Kohli Naina1,Farooq Nauman5,Bachman William4,Olonisakin Tolani F1,Xiong Zeyu1,Griffith Marissa P4,Sullivan Mara6,Franks Jonathan6,Mustapha Mustapha M4,Iovleva Alina4,Suber Tomeka1,Shanks Robert Q7ORCID,Ferreira Viviana P8ORCID,Stolz Donna B6ORCID,Van Tyne Daria4ORCID,Doi Yohei4ORCID,Lee Janet S19ORCID

Affiliation:

1. Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh

2. Veterans Affairs Pittsburgh Healthcare System , Pittsburgh, Pennsylvania

3. Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus School of Medicine , Denver

4. Division of Infectious Diseases, Department of Medicine

5. Department of Critical Care Medicine

6. Center for Biologic Imaging, Department of Cell Biology

7. Department of Ophthalmology, University of Pittsburgh , Pennsylvania

8. Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences , Ohio

9. Division of Pulmonary and Critical Care Medicine, Washington University in St Louis , Missouri

Abstract

Abstract Background Klebsiella pneumoniae carbapenemase–producing K pneumoniae (KPC-Kp) bloodstream infections are associated with high mortality. We studied clinical bloodstream KPC-Kp isolates to investigate mechanisms of resistance to complement, a key host defense against bloodstream infection. Methods We tested growth of KPC-Kp isolates in human serum. In serial isolates from a single patient, we performed whole genome sequencing and tested for complement resistance and binding by mixing study, direct enzyme-linked immunosorbent assay, flow cytometry, and electron microscopy. We utilized an isogenic deletion mutant in phagocytosis assays and an acute lung infection model. Results We found serum resistance in 16 of 59 (27%) KPC-Kp clinical bloodstream isolates. In 5 genetically related bloodstream isolates from a single patient, we noted a loss-of-function mutation in the capsule biosynthesis gene, wcaJ. Disruption of wcaJ was associated with decreased polysaccharide capsule, resistance to complement-mediated killing, and surprisingly, increased binding of complement proteins. Furthermore, an isogenic wcaJ deletion mutant exhibited increased opsonophagocytosis in vitro and impaired in vivo control in the lung after airspace macrophage depletion in mice. Conclusions Loss of function in wcaJ led to increased complement resistance, complement binding, and opsonophagocytosis, which may promote KPC-Kp persistence by enabling coexistence of increased bloodstream fitness and reduced tissue virulence.

Funder

National Institutes of Health

Department of Veterans Affairs

Publisher

Oxford University Press (OUP)

Subject

Infectious Diseases,Immunology and Allergy

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