Using Dictyostelium to Develop Therapeutics for Acute Respiratory Distress Syndrome

Abstract

Acute respiratory distress syndrome (ARDS) involves damage to lungs causing an influx of neutrophils from the blood into the lung airspaces, and the neutrophils causing further damage, which attracts more neutrophils in a vicious cycle. There are ∼190,000 cases of ARDS per year in the US, and because of the lack of therapeutics, the mortality rate is ∼40%. Repelling neutrophils out of the lung airspaces, or simply preventing neutrophil entry, is a potential therapeutic. In this minireview, we discuss how our lab noticed that a protein called AprA secreted by growing Dictyostelium cells functions as a repellent for Dictyostelium cells, causing cells to move away from a source of AprA. We then found that AprA has structural similarity to a human secreted protein called dipeptidyl peptidase IV (DPPIV), and that DPPIV is a repellent for human neutrophils. In animal models of ARDS, inhalation of DPPIV or DPPIV mimetics blocks neutrophil influx into the lungs. To move DPPIV or DPPIV mimetics into the clinic, we need to know how this repulsion works to understand possible drug interactions and side effects. Combining biochemistry and genetics in Dictyostelium to elucidate the AprA signal transduction pathway, followed by drug studies in human neutrophils to determine similarities and differences between neutrophil and Dictyostelium chemorepulsion, will hopefully lead to the safe use of DPPIV or DPPIV mimetics in the clinic.

The Cellular and Developmental Roles of Cullins, Neddylation, and the COP9 Signalosome in Dictyostelium discoideum

“…Importantly, D. discoideum is genetically tractable and a variety of expression constructs have been generated to facilitate studies on protein localization and function ( Levi et al, 2000 ; Kuspa, 2006 ; Veltman et al, 2009 ; Faix et al, 2013 ; Müller-Taubenberger and Ishikawa-Ankerhold, 2013 ; Friedrich et al, 2015 ; Yamashita et al, 2021 ). For these and other reasons, it has also been used as a high-throughput biomedical model for studying variety of human diseases ( Huber, 2021 ; Kirolos et al, 2021 ; Mathavarajah et al, 2021 ; Pain et al, 2021 ).…”

Mfsd8 Modulates Growth and the Early Stages of Multicellular Development in Dictyostelium discoideum

“…The social amoeba D. discoideum is a eukaryotic microbe that is used as a biomedical model organism for studying a variety of human diseases, including the NCLs ( Huber, 2021 ; Kirolos et al, 2021 ; Mathavarajah et al, 2021 ; Pain et al, 2021 ). During the growth phase of the life cycle, haploid amoebae feed on nutrients and divide by mitosis ( Mathavarajah et al, 2017 ).…”

DataSheet1.docx

“…The social amoeba D. discoideum is a eukaryotic microbe that is used as a biomedical model organism for studying a variety of human diseases, including the NCLs (Huber, 2021;Kirolos et al, 2021;Mathavarajah et al, 2021;Pain et al, 2021). During the growth phase of the life cycle, haploid amoebae feed on nutrients and divide by mitosis (Mathavarajah et al, 2017).…”