PMID- 27297394 OWN - NLM STAT- MEDLINE DCOM- 20170512 LR - 20220317 IS - 1098-5522 (Electronic) IS - 0019-9567 (Print) IS - 0019-9567 (Linking) VI - 84 IP - 9 DP - 2016 Sep TI - Microfilariae of Brugia malayi Inhibit the mTOR Pathway and Induce Autophagy in Human Dendritic Cells. PG - 2463-72 LID - 10.1128/IAI.00174-16 [doi] AB - Immune modulation is a hallmark of patent filarial infection, including suppression of antigen-presenting cell function and downmodulation of filarial antigen-specific T cell responses. The mammalian target of rapamycin (mTOR) signaling pathway has been implicated in immune regulation, not only by suppressing T cell responses but also by regulating autophagy (through mTOR sensing amino acid availability). Global proteomic analysis (liquid chromatography-tandem mass spectrometry) of microfilaria (mf)-exposed monocyte-derived dendritic cells (DC) indicated that multiple components of the mTOR signaling pathway, including mTOR, eIF4A, and eIF4E, are downregulated by mf, suggesting that mf target this pathway for immune modulation in DC. Utilizing Western blot analysis, we demonstrate that similar to rapamycin (a known mTOR inhibitor), mf downregulate the phosphorylation of mTOR and its regulatory proteins, p70S6K1 and 4E-BP1, a process essential for DC protein synthesis. As active mTOR signaling regulates autophagy, we examined whether mf exposure alters autophagy-associated processes. mf-induced autophagy was reflected in marked upregulation of phosphorylated Beclin 1, known to play an important role in both autophagosome formation and autolysosome fusion, in induction of LC3II, a marker of autophagosome formation, and in induced degradation of p62, a ubiquitin-binding protein that aggregates protein in autophagosomes and is degraded upon autophagy that was reduced significantly by mf exposure and by rapamycin. Together, these results suggest that Brugia malayi mf employ mechanisms of metabolic modulation in DC to influence the regulation of the host immune response by downregulating mTOR signaling, resulting in increased autophagy. Whether this is a result of the parasite-secreted rapamycin homolog is currently under study. CI - Copyright (c) 2016, American Society for Microbiology. All Rights Reserved. FAU - Narasimhan, Prakash Babu AU - Narasimhan PB AD - Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Bennuru, Sasisekhar AU - Bennuru S AD - Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Meng, Zhaojing AU - Meng Z AD - Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA. FAU - Cotton, Rachel N AU - Cotton RN AD - Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Elliott, Kathleen R AU - Elliott KR AD - Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Ganesan, Sundar AU - Ganesan S AD - Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - McDonald-Fleming, Renee AU - McDonald-Fleming R AD - Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Veenstra, Timothy D AU - Veenstra TD AD - Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA. FAU - Nutman, Thomas B AU - Nutman TB AD - Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. FAU - Tolouei Semnani, Roshanak AU - Tolouei Semnani R AD - Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA rsemnani@niaid.nih.gov. LA - eng PT - Journal Article DEP - 20160819 PL - United States TA - Infect Immun JT - Infection and immunity JID - 0246127 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Apoptosis Regulatory Proteins) RN - 0 (Beclin-1) RN - 0 (Cell Cycle Proteins) RN - 0 (EIF4EBP1 protein, human) RN - 0 (Eukaryotic Initiation Factor-4E) RN - 0 (Phosphoproteins) RN - 0 (Ubiquitin) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.7.- (Eukaryotic Initiation Factor-4A) SB - IM MH - Adaptor Proteins, Signal Transducing/metabolism MH - Animals MH - Apoptosis Regulatory Proteins/metabolism MH - Autophagosomes/metabolism/parasitology MH - Autophagy/*physiology MH - Beclin-1/metabolism MH - Brugia malayi/*parasitology MH - Cell Cycle Proteins MH - Dendritic Cells/metabolism/*parasitology MH - Down-Regulation/physiology MH - Eukaryotic Initiation Factor-4A/metabolism MH - Eukaryotic Initiation Factor-4E/metabolism MH - Humans MH - Lysosomes/metabolism/parasitology MH - Microfilariae/*physiology MH - Monocytes/metabolism/parasitology MH - Phosphoproteins/metabolism MH - Phosphorylation/physiology MH - Proteomics/methods MH - Ribosomal Protein S6 Kinases, 70-kDa/metabolism MH - Signal Transduction/physiology MH - TOR Serine-Threonine Kinases/*metabolism MH - Ubiquitin/metabolism MH - Up-Regulation/physiology PMC - PMC4995918 EDAT- 2016/06/15 06:00 MHDA- 2017/05/13 06:00 PMCR- 2017/02/19 CRDT- 2016/06/15 06:00 PHST- 2016/02/25 00:00 [received] PHST- 2016/09/08 00:00 [accepted] PHST- 2016/06/15 06:00 [entrez] PHST- 2016/06/15 06:00 [pubmed] PHST- 2017/05/13 06:00 [medline] PHST- 2017/02/19 00:00 [pmc-release] AID - IAI.00174-16 [pii] AID - 00174-16 [pii] AID - 10.1128/IAI.00174-16 [doi] PST - epublish SO - Infect Immun. 2016 Aug 19;84(9):2463-72. doi: 10.1128/IAI.00174-16. Print 2016 Sep.