A requirement forpurine biosynthesis during lung infection is exacerbated by host zinc deficiency.

Abstract

is a leading cause of hospital-acquired infections, including ventilator-associated pneumonia. Dietary zinc deficiency is a major risk factor for pneumonia, and hospitalized patients at risk forinfection have increased rates of zinc deficiency. We previously showed that dietary zinc deficiency enhancedpneumonia pathogenesis via an IL-13-dependent mechanism in mice. Here, we identifiedgenes required for proliferation in the lungs of zinc-deficient mice using a genome-wide transposon sequencing (Tn-seq) screen. In zinc-deficient mice, Tn insertions in 614genes led to significant differences in fitness in the lungs at 24 h. Most of these genes were also required in zinc-sufficient control mice. Mutants with disruptions in genes in the purine biosynthetic pathway, such as, and acinetobactin iron siderophore pathways were more strongly selected during lung infection in zinc-deficient mice compared to zinc-sufficient mice by Tn-seq. A reconstructedmutant was defective compared to wild type during lung infection in zinc-sufficient mice, with the defect further exacerbated in zinc-deficient mice. Thus,purine biosynthesis is required to infect the lung, and its requirement is exacerbated in a zinc-deficient host.IMPORTANCEDietary zinc deficiency is a major risk factor for infection worldwide. In the United States, hospitalized patients are at increased risk of zinc deficiency andpneumonia. In this study,purine biosynthesis was required for lung infection of mice, independent of dietary zinc. Therefore, bacterial purine biosynthesis is an attractive drug target for treating lung infections in patients with variable dietary zinc statuses, such as in hospitalized patients.