Lipocalin-2 is an essential component of the innate immune response to Acinetobacter baumannii infection

Acinetobacter baumannii is an opportunistic pathogen and an emerging global health threat. Within healthcare settings, major presentations of A . baumannii include bloodstream infections and ventilator-associated pneumonia. The increased prevalence of ventilated patients during the COVID-19 pandemic has led to a rise in secondary bacterial pneumonia caused by multidrug resistant (MDR) A . baumannii . Additionally, due to its MDR status and the lack of antimicrobial drugs in the development pipeline, the World Health Organization has designated carbapenem-resistant A . baumannii to be its priority critical pathogen for the development of novel therapeutics. To better inform the design of new treatment options, a comprehensive understanding of how the host contains A . baumannii infection is required. Here, we investigate the innate immune response to A . baumannii by assessing the impact of infection on host gene expression using NanoString technology. The transcriptional profile observed in the A . baumannii infected host is characteristic of Gram-negative bacteremia and reveals expression patterns consistent with the induction of nutritional immunity, a process by which the host exploits the availability of essential nutrient metals to curtail bacterial proliferation. The gene encoding for lipocalin-2 ( Lcn2 ), a siderophore sequestering protein, was the most highly upregulated during A . baumannii bacteremia, of the targets assessed, and corresponds to robust LCN2 expression in tissues. Lcn2 -/- mice exhibited distinct organ-specific gene expression changes including increased transcription of genes involved in metal sequestration, such as S100A8 and S100A9 , suggesting a potential compensatory mechanism to perturbed metal homeostasis. In vitro , LCN2 inhibits the iron-dependent growth of A . baumannii and induces iron-regulated gene expression. To elucidate the role of LCN2 in infection, WT and Lcn2 -/- mice were infected with A . baumannii using both bacteremia and pneumonia models. LCN2 was not required to control bacterial growth during bacteremia but was protective against mortality. In contrast, during pneumonia Lcn2 -/- mice had increased bacterial burdens in all organs evaluated, suggesting that LCN2 plays an important role in inhibiting the survival and dissemination of A . baumannii . The control of A . baumannii infection by LCN2 is likely multifactorial, and our results suggest that impairment of iron acquisition by the pathogen is a contribu