{Reference Type}: Journal Article
{Title}: In Vivo Evolution of a Klebsiella pneumoniae Capsule Defect With wcaJ Mutation Promotes Complement-Mediated Opsonophagocytosis During Recurrent Infection.
{Author}: Bain W;Ahn B;PeƱaloza HF;McElheny CL;Tolman N;van der Geest R;Gonzalez-Ferrer S;Chen N;An X;Hosuru R;Tabary M;Papke E;Kohli N;Farooq N;Bachman W;Olonisakin TF;Xiong Z;Griffith MP;Sullivan M;Franks J;Mustapha MM;Iovleva A;Suber T;Shanks RQ;Ferreira VP;Stolz DB;Van Tyne D;Doi Y;Lee JS;
{Journal}: J Infect Dis
{Volume}: 230
{Issue}: 1
{Year}: 2024 Jul 25
{Factor}: 7.759
{DOI}: 10.1093/infdis/jiae003
{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.