<i>Burkholderia pseudomallei</i> interferes with host lipid metabolism via <i>NR1D2</i>-mediated <i>PNPLA2/ATGL</i> suppression to block autophagy-dependent inhibition of infection

Abstract

<b>Burkholderia pseudomallei</b>: which causes melioidosis with high mortality in humans, has become a global public health concern. Recently, infection-driven lipid droplet accumulation has been related to the progression of host-pathogen interactions, and its contribution to the pathogenesis of infectious disease has been investigated. Here, we demonstrated that <i>B. pseudomallei</i> infection actively induced a time-dependent increase in the number and size of lipid droplets in human lung epithelial cells and macrophages. We also found that lipid droplet accumulation following <i>B. pseudomallei</i> infection was associated with downregulation of <i>PNPLA2/ATGL</i> (patatin like phospholipase domain containing 2) and lipophagy inhibition. Functionally, lipid droplet accumulation, facilitated via <i>PNPLA2</i> downregulation, inhibited macroautophagic/autophagic flux and, thus, hindered autophagy-dependent inhibition of <i>B. pseudomallei</i> infection in lung epithelial cells. Mechanistically, we further revealed that nuclear receptor <i>NR1D2</i> might be involved in the suppression of <i>PNPLA2</i> after cell exposure to <i>B. pseudomallei</i>. Taken together, our findings unraveled an evolutionary strategy, by which <i>B. pseudomallei</i> interferes with the host lipid metabolism, to block autophagy-dependent suppression of infection. This study proposes potential targets for clinical therapy of melioidosis.<b>Abbreviations</b>: 3-MA: 3-methyladenine; ACTB: actin beta; ATG7: autophagy related 7; <i>B. pseudomallei: Burkholderia pseudomallei</i>; CFU: colony-forming unit; DG: diglyceride; FASN: fatty acid synthase; GFP: green fluorescent protein; LAMP1: lysosomal associated membrane protein 1; LC-MS/MS: liquid chromatography-tandem mass spectrometry; LD: lipid droplet; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MG: monoglyceride; MOI: multiplicity of infection; mRFP: monomeric red fluorescent protein; NR1D2: nuclear receptor subfamily 1 group D member 2; p.i., post-infection; PLIN2/ADRP: perilipin 2; PNPLA2/ATGL: patatin like phospholipase domain containing 2; Rapa: rapamycin; SQSTM1/p62: sequestosome 1; shRNA: short hairpin RNA; TEM: transmission electron microscopy; TG: triglyceride.