Pharmaceutical Sciences Faculty Publications

Document Type

Article

Publication Date

9-1-2016

Journal Title

Infection and immunity

ISSN

1098-5522

Volume

84

Issue

9

First Page

2463

Last Page

2472

DOI

10.1128/IAI.00174-16

PubMed ID

27297394

PubMed Central® ID

PMC4995918

Abstract

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.

Keywords

Adaptor Proteins, Signal Transducing, Animals, Apoptosis Regulatory Proteins, Autophagosomes, Autophagy, Beclin-1, Brugia malayi, Dendritic Cells, Down-Regulation, Eukaryotic Initiation Factor-4A, Eukaryotic Initiation Factor-4E, Humans, Lysosomes, Microfilariae, Monocytes, Phosphoproteins, Phosphorylation, Proteomics, Ribosomal Protein S6 Kinases, 70-kDa, Signal Transduction, TOR Serine-Threonine Kinases, Ubiquitin, Up-Regulation

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