Browsing by Author "Chalfant, Charles E."

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    Functional inhibition of acid sphingomyelinase disrupts infection by intracellular bacterial pathogens
    (Life Science Alliance, 2019-03-22) Cockburn, Chelsea L.; Green, Ryan S.; Damle, Sheela R.; Martin, Rebecca K.; Ghahrai, Naomi N.; Colonne, Punsiri M.; Fullerton, Marissa S.; Conrad, Daniel H.; Chalfant, Charles E.; Voth, Daniel E.; Rucks, Elizabeth A.; Gilk, Stacey D.; Carlyon, Jason A.; Department of Microbiology and Immunology, Indiana University School of Medicine
    Intracellular bacteria that live in host cell-derived vacuoles are significant causes of human disease. Parasitism of low-density lipoprotein (LDL) cholesterol is essential for many vacuole-adapted bacteria. Acid sphingomyelinase (ASM) influences LDL cholesterol egress from the lysosome. Using functional inhibitors of ASM (FIASMAs), we show that ASM activity is key for infection cycles of vacuole-adapted bacteria that target cholesterol trafficking-Anaplasma phagocytophilum, Coxiella burnetii, Chlamydia trachomatis, and Chlamydia pneumoniae. Vacuole maturation, replication, and infectious progeny generation by A. phagocytophilum, which exclusively hijacks LDL cholesterol, are halted and C. burnetii, for which lysosomal cholesterol accumulation is bactericidal, is killed by FIASMAs. Infection cycles of Chlamydiae, which hijack LDL cholesterol and other lipid sources, are suppressed but less so than A. phagocytophilum or C. burnetii A. phagocytophilum fails to productively infect ASM-/- or FIASMA-treated mice. These findings establish the importance of ASM for infection by intracellular bacteria and identify FIASMAs as potential host-directed therapies for diseases caused by pathogens that manipulate LDL cholesterol.
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    Lipid mediators and biomarkers associated with type 1 diabetes development
    (American Society for Clinical Investigation, 2020-08-20) Nelson, Alexander J.; Stephenson, Daniel J.; Bone, Robert N.; Cardona, Christopher L.; Park, Margaret A.; Tusing, Ying G.; Lei, Xiaoyong; Kokotos, George; Graves, Christina L.; Mathews, Clayton E.; Kramer, Joanna; Hessner, Martin J.; Chalfant, Charles E.; Ramanadham, Sasanka; Pediatrics, School of Medicine
    Type 1 diabetes (T1D) is a consequence of autoimmune β cell destruction, but the role of lipids in this process is unknown. We previously reported that activation of Ca2+-independent phospholipase A2β (iPLA2β) modulates polarization of macrophages (MΦ). Hydrolysis of the sn-2 substituent of glycerophospholipids by iPLA2β can lead to the generation of oxidized lipids (eicosanoids), pro- and antiinflammatory, which can initiate and amplify immune responses triggering β cell death. As MΦ are early triggers of immune responses in islets, we examined the impact of iPLA2β-derived lipids (iDLs) in spontaneous-T1D prone nonobese diabetic mice (NOD), in the context of MΦ production and plasma abundances of eicosanoids and sphingolipids. We find that (a) MΦNOD exhibit a proinflammatory lipid landscape during the prediabetic phase; (b) early inhibition or genetic reduction of iPLA2β reduces production of select proinflammatory lipids, promotes antiinflammatory MΦ phenotype, and reduces T1D incidence; (c) such lipid changes are reflected in NOD plasma during the prediabetic phase and at T1D onset; and (d) importantly, similar lipid signatures are evidenced in plasma of human subjects at high risk for developing T1D. These findings suggest that iDLs contribute to T1D onset and identify select lipids that could be targeted for therapeutics and, in conjunction with autoantibodies, serve as early biomarkers of pre-T1D.