Biology subjects

Downey, J.

Publications and source records attributed to Downey, J..

3 recordsLinked to original sources

bioRxiv2024

β-Glucan Reprograms Neutrophils to Induce Disease Tolerance Against Influenza A Virus

ABSTRACTDisease tolerance is an evolutionarily conserved host defence strategy that preserves tissue integrity and physiology without affecting pathogen load. Unlike host resistance, the mechanisms underlying disease tolerance remain poorly understood. In the present study, we investigated whether an adjuvant ({beta}-glucan) can reprogram innate immunity to provide protection against Influenza A virus (IAV) infection. Here we observe that {beta}-glucan treatment reduced the morbidity and mortality against IAV infection, independent of host resistance (viral load). Increased survival of {beta}-glucan treated mice against IAV is associated with the accumulation of neutrophils via RoR{gamma}t+ T cells in the lung tissue. Using gain-and-loss-of-function approaches, we demonstrate that {beta}- glucan reprogrammed neutrophils are essential for promoting disease tolerance, limiting pulmonary tissue damage, and enhancing survival against IAV infection. {beta}-glucan treatment promotes granulopoiesis in a type 1 interferon-dependent manner that leads to the generation of a unique subset of neutrophils, which are less mature with higher mitochondrial mass utilizing mitochondrial oxidative (OXPHOS) metabolism. Collectively, our data indicate that {beta}-glucan reprograms hematopoietic stem cells (HSCs) to generate neutrophils with a novel "regulatory" function, which is required for promoting disease tolerance and maintaining lung tissue integrity against viral infection.

immunology↗

bioRxiv2021

Mitochondrial cyclophilin D promotes disease tolerance by licensing NK cell development and IL-22 production against influenza virus

Immunity to infectious disease involves a combination of host resistance, which eliminates the pathogen, and disease tolerance, which limits tissue damage. While the severity of most pulmonary viral infections, including influenza A virus (IAV), is linked to excessive inflammation, our mechanistic understanding of this observation remains largely unknown. Here we show that mitochondrial cyclophilin D (CypD) protects against IAV infection via disease tolerance. Mice deficient in CypD (CypD-/- mice) are significantly more susceptible to IAV infection despite comparable antiviral immunity. Instead, this susceptibility resulted from damage to the lung epithelial barrier caused by a significant reduction of IL-22 production by conventional NK cells in IAV-infected CypD-/- mice. Transcriptomic and functional data revealed that the compromised IL-22 production by NK cells resulted from dysregulated lymphopoiesis, stemming from increased cell death in NK cell progenitors, as well as the generation of immature NK cells that exhibited altered mitochondrial metabolism. Importantly, following IAV infection, administration of recombinant IL-22 abrogated pulmonary damage and enhanced survival of CypD-/- mice. Collectively, these results demonstrate a key role for CypD in NK cell-mediated disease tolerance.

immunology↗

bioRxiv2017

Biosynthesis of Isonitrile Lipopeptides by Conserved Non-ribosomal Peptide Synthetase Gene Clusters in Actinobacteria

A putative lipopeptide biosynthetic gene cluster is conserved in many species of Actinobacteria, including Mycobacterium tuberculosis and M. marinum, but the specific function of the encoding proteins has been elusive. Using both in vivo heterologous reconstitution and in intro biochemical analyses, we have revealed that the five encoding biosynthetic enzymes are capable of synthesizing a new family of isonitrile lipopeptides (INLPs) through a thio-template mechanism. The biosynthesis features the generation of isonitrile from a single precursor Gly promoted by a thioesterase and a non-heme iron(II)-dependent oxidase homologue, and the acylation of both amino groups of Lys by the same isonitrile acyl chain facilitated by a single condensation domain of a non-ribosomal peptide synthetase (NRPS). In addition, the deletion of INLP biosynthetic genes in M. marinum has decreased the intracellular metal concentration, suggesting the role of this biosynthetic gene cluster in metal transport.\n\nSignificance StatementMycobacterium tuberculosis is the leading causative agent of tuberculosis (TB), of which millions of deaths occur annually. A putative lipopeptide biosynthetic gene cluster has been shown to be essential for the survival of this pathogen in hosts, and homologous gene clusters have also been found in all pathogenic mycobacteria and other species of Actinobacteria. We have identified the function of these gene clusters in making a new family of isonitrile lipopeptides. The biosynthesis has several unique features, including an unprecedented mechanism for isonitrile synthesis. Our results have further suggested that these biosynthetic gene clusters play a role in metal transport, and thus have shed light on a new metal transport system that is crucial for virulence of pathogenic mycobacteria.

biochemistry↗