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

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.

Update on regulation and effector functions of Th17 cells.

T-helper cells that produce IL-17 are recognized as a significant subset within cell-mediated adaptive immunity. These cells are implicated in both the pathology of inflammatory disorders as well as the clearance of extracellular infections and the maintenance of the microbiota. However, the dynamic nature of this cell type has created controversy in understanding Th17 induction as well as Th17 phenotyping, since these cells may switch from Th17 to Treg or Th17 to Th1 cytokine profiles under certain conditions. This review highlights recent advances in Th17 cells in understanding their role in commensal regulation, sex difference in immune outcomes and the immunology of pregnancy, as well as inventive experimental models that have allowed for an increased understanding of Th17 regulation and induction.