Pathogenic and protective lung lipid predictors of tuberculosis in Rhesus macaques 2308411

Abstract

Abstract Introduction Lipids are critical in pathogenesis and immunity. We hypothesize that Mycobacterium tuberculosis (M.tb) infection induces global lipid profile alterations in lung tissues to regulate host immunity. Methods To test the hypothesis, lipids from lung tissues of Bacillus Calmette-Guérin (BCG)-vaccinated (n = 4) and unvaccinated (n = 4) Rhesus macaques with M.tb infection and from uninfected controls (n = 4) were extracted with a modified Matyash method. Samples were profiled on a Vanquish HPLC-coupled Thermo Orbitrap IQ-X Tribrid mass spectrometer by heated electrospray ionization in positive and negative modes, with untargeted MS1/MS2 and data-dependent MS2/MS3 analyses. Mass profiles were annotated using the LipidSearch program. Results From over 1000 annotated lipid species of over 50 classes, the cholesterol esters and triacylglycerols, which are associated with lipid droplet and granuloma caseum formation, and the oxidized lipids that potentially contribute to ferroptosis, were detected more abundantly with active infection in unvaccinated animals. For ether-linked lipids with metabolic and immune regulatory functions as ligands for transcription factors and CD1 antigen-presentation molecules, plasmalogens and non-plasmalogens were enhanced, respectively, in vaccinated macaques exhibiting protection from subsequent M.tb challenge, and unvaccinated controls with active M.tb infection. Sphingosines and hexosylsphingosines were highly expressed in vaccine-protected animals but low in active infection, as sphingosines stimulate macrophage responses. Conclusion Our lipidomic platform displays superior sensitivity and accuracy in detecting essential lipid classes altered in lung tissues of Rhesus macaques with BCG vaccination and M.tb infections. The altered lipid classes, such as glycerolipids, phospholipids, sphingolipids, ether-lipids, and cholesterol, with various chain lengths and unsaturation, provide candidate lipids and metabolic pathways to induce protective anti-tuberculosis immunity. Funding Source N/A Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)