Role of alveolar macrophage mitochondria and peroxisomes against aspergillus fumigatus

The National Institute of Allergy and Infectious Diseases awarded Trustees of Dartmouth College $100,228 on February 4, 2027, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the role of alveolar macrophage mitochondria and peroxisomes in antifungal immune responses against Aspergillus fumigatus infections.

The research addresses how mitochondria and peroxisomes regulate interferon type I and III production in alveolar macrophages exposed to the fungal opportunistic pathogen Aspergillus fumigatus, which causes high-morbidity infections in immunocompromised populations including individuals with AIDS, cancer patients, and those receiving immunosuppressants. The investigator will generate alveolar macrophage models with knocked-down organelles and regulated pathways, then employ in vitro and in vivo assays to characterize effects on the interferon response. In vitro work includes phagocytosis and killing assays, cytokine release quantified by ELISAs, and transcriptional profiles measured by QRT-PCR. In vivo studies will employ an adoptive transfer mouse model in which native alveolar macrophages are depleted and mutant macrophages transferred for implantation. The research will determine the significance of mitochondria and peroxisomes in antifungal phagocytosis, killing, and inflammatory response, and examine the role of MAVS, an adaptor protein localized to both organelles, in functional mitochondrial antifungal interferon response.

Work is performed in Hanover, New Hampshire with a period of performance through August 31, 2029. This is a Project Grant, an assistance type supporting biomedical research and research training in infectious diseases and related areas.

Abstract

Role of alveolar macrophage mitochondria and peroxisomes against aspergillus fumigatus infections with the fungal opportunistic pathogen aspergillus fumigatus (AF) are characterized by high morbidity and treatment resistance. These infections are of concern for immunocompromised populations such as individuals with aids, cancer patients, and those on immunosuppressants. The alveolar macrophage (am) interferon (IFN) type i and III response is required for early fungal spore clearance, but the regulation of these ifns is not well understood. Mitochondria and peroxisomes, membrane-bound organelles involved in lipid metabolism as well as the regulation of oxidative species, have recently been implicated as central regulators of immunity. My overall goal is to determine the role of mitochondria, peroxisomes and the organelle-specific- regulated pathways in the am antifungal IFN response. My central hypothesis is, therefore, that mitochondria and peroxisomes are essential for am-dependent IFN production and host resistance to AF. In aim 1, i will determine the significance of am mitochondria and peroxisomes in antifungal phagocytosis, killing, and the inflammatory response. In aim 2, i will determine the significance of mavs-an adaptor protein localized to both organelles-on functional mitochondria in the antifungal IFN response of am. Am models, in which the organelles and their regulated pathways have been knocked down, will be generated, and utilized in both in vitro and in vivo assays that will characterize their effect on the IFN response. In vitro assays will include phagocytosis and killing assays, cytokine release as quantified by elisas, and transcriptional profiles as quantified by QRT-PCR. I will study mitochondrial and peroxisomal deficiency using an adoptive transfer mouse model. Native am will be depleted, and mutant am will be transferred and allowed to implant. Afterwards, mice will be challenged with AF spores. Survival, inflammation, lung damage, and fungal growth will then be quantified. Understanding the role of mitochondria, peroxisomes and regulated pathways may identify therapeutic targets that can be manipulated in order to prevent AF infection progression and decrease the burden of infections on immunocompromised individuals.