Journal Article

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

Maloney, K. Nichole, Skaar, Eric P., Sheldon, Jessica R., Kunkle, Dillon E., Himmel, Lauren E., Monteith, Andrew J.

2022

Overview

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 contributing factor. Modulation of LCN2 expression or modifying the structure of LCN2 to expand upon its ability to sequester siderophores may thus represent feasible avenues for therapeutic development against this pathogen.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acinetobacter baumannii / Acinetobacter infections / Animal tissues / Antibiotics / Antiinfectives and antibacterials / Antimicrobial agents / Bacteremia / Bacteria / Biology and Life Sciences / Carrier proteins / COVID-19 / Disinfection & disinfectants / Drug development / Drug resistance / Gene expression / Genetic aspects / Global health / Health aspects / Health care / Health risks / Heavy metals / Homeostasis / Immune response / Immune system / Immunosuppressive agents / Infections / Innate immunity / Iron / Lipocalin / Medicine and Health Sciences / Metals / Multidrug resistance / Neutrophils / Nutrient availability / Opportunist infection / Pandemics / Pathogenesis / Pathogens / Physical Sciences / Pneumonia / Prevention / Public health / R&D / Research & development / Research and Analysis Methods / Sequestering / Siderophores / Ventilation / Ventilator-associated pneumonia / Virulence