- ABSTRACT.
- INTRODUCTION
- MATERIALS AND METHODS
- Ethics statement.
- mf preparations.
- In vitro exposure of monocytes to live mf.
- RNA preparation and real-time reverse transcription polymerase chain reaction.
- Electron microscopy.
- Determination of IDO enzymatic activity.
- Flow cytometry staining.
- Flow cytometric analysis.
- Stimulation of monocytes for immunoblotting and autophagy.
- Immunoblot analysis.
- Statistical analysis.
- RESULTS
- DISCUSSION
- ACKNOWLEDGMENTS
- References
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Brugia malayi Microfilariae Induce Autophagy through an Interferon-γ Dependent Mechanism in Human Monocytes
ABSTRACT.
Monocyte dysfunction in helminth infection is one of the mechanisms proposed to explain the diminished parasite antigen-specific T cell responses seen with patent filarial infection. In fact, monocytes from filariae-infected individuals demonstrate internalized filarial antigens and, as a consequence, express inhibitory surface molecules and have diminished cytokine production. To investigate the mechanisms underlying monocyte dysfunction in filarial infections, purified human monocytes were exposed to live microfilariae (mf) of Brugia malayi, and the mRNA and protein expression of important inhibitory and/or autophagy-related molecules were assessed. Our data indicate that mf-induced autophagy in human monocytes shown by the formation of autophagic vesicles, by the upregulation in the mRNA expression of autophagy-related genes BCN1, LC3B, ATG5, ATG7 (P < 0.05), and by increase in the levels of LC3B protein. Furthermore, this mf-induced autophagy increased the levels of monocyte CD206 expression. In addition, mf significantly induced the frequency of interferon (IFN)-γ+ human monocytes and at the same time induced the mRNA expression of indoleamine 2,3-dioxygenase (IDO) through an IFN-γ-dependent mechanism; significantly enhanced tryptophan degradation (an indicator of IDO activity; P < 0.005). Interestingly, this autophagy induction by mf in monocytes was IFN-γ-dependent but IDO-independent as was reversed by anti-IFN-γ but not by an IDO inhibitor. Our data collectively suggest that mf of Brugia malayi regulate the function of monocytes by induction of IDO and IFN-γ, induce autophagy through an IFN-γ-dependent mechanism, and increase M2 phenotype through induction of autophagy; all acting in concert to drive monocyte dysfunction.
Author Notes
Authors’ addresses: Prakash Babu Narasimhan, Department of Clinical Immunology, SSB, JIPMER, Puducherry, India, E-mail: nprakbab@gmail.com. Sameha Tariq, Leor Akabas, and Thomas B. Nutman, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, E-mails: sameha-tarig@gmail.com, leor.akabas@gmail.com, and tnutman@niaid.nih.gov. Roshanak Tolouei Semani, Precigen, Inc., Germantown, MD, E-mail: rsemnani@precigen.com. David W. Dorward, Microscopy Unit, Research Technologies Branch. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratories, Bethesda, MD, E-mail: ddorward@outlook.com.