Host immunology and rational immunotherapy for carbapenem-resistant Klebsiella pneumoniae infection

Abstract

Infections due to carbapenem-resistant Klebsiella pneumoniae have emerged as a global threat due to its widespread antimicrobial resistance. Transplant recipients and patients with hematologic malignancies have high mortality rate, suggesting host factors in susceptibility. We developed a model of pulmonary infection using ST258 strain C4, KPC-2 clone, which are predominant K. pneumoniae carbapenemase-producing (KPC-producing) bacteria, and demonstrated that Rag2-/- Il2rg-/- mice - but not WT C57BL/6 or Rag2-/- mice - were susceptible to this opportunistic infection. Using single cell RNA sequencing in infected Rag2-/- mice, we identified distinct clusters of Ifng+ NK cells and Il17a+, Il22+, and inducible T cell costimulatory molecule-positive (ICOS+) group 3 innate lymphoid cells (ILCs) that were critical for host resistance. As solid organ transplantation is a risk factor, we generated a more clinically relevant model using FK506 in WT C57BL/6 mice. We further demonstrated that immunotherapy with recombinant IL-22 treatment ameliorated the ST258 pulmonary infection in both FK506-treated WT mice and Rag2-/- Il2rg-/- mice via hepatic IL-22ra1 signaling. These data support the development of host-directed immunotherapy as an adjunct treatment to new antibiotics.