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Address: 2234B MERF
Phone: (319) 335-7597
Mentor: Jon C. Houtman, PhD
Undergraduate Institution: University of Iowa
Year Entered Into Program: 2013
Monolaurate (GML) is a naturally occurring fatty acid molecule and
antimicrobial agent. GML suppresses the
growth and virulence of numerous gram positive and gram negative bacteria,
fungi, and enveloped viruses. GML is on
the FDA’s Generally Recognized as Safe list (GRAS) and is incorporated in
various products such as deodorants, lotions, and cosmetics. It is also widely available as a homeopathic
supplement, and is extensively used as a food preservative and emulsifier.
Topical GML is being tested as a treatment and/or preventative measure for
Toxic Shock Syndrome, HIV transmission, and surgical site infections. Thus, GML is an effective antimicrobial that
comes in regular contact with the general public through its extensive
commercial and therapeutic uses.Interestingly,
GML suppresses mitogen induced lymphocyte proliferation and inositol
triphosphate production, suggesting that GML has immunomodulatory
functions. However, how GML treatment
affects the full T cell activation response from signaling events to effector
functions is not well understood. In
addition, the mechanism behind how GML mediates suppressed T cell activation is
completely unknown. My thesis project focuses on mechanistically
examining if GML affects the signaling, metabolism, and functional output of
human primary T cells. We found that GML
potently altered order and disorder dynamics in the plasma membrane that
resulted in reduced membrane localized clustering of the proteins LAT, PLC-γ,
and AKT, events integral for proper T cell receptor (TCR) signal propagation. Altered membrane signaling events induced
selective inhibition of TCR-induced phosphorylation of SLP-76, regulatory P85
subunit of PI3K, and AKT as well as abrogated calcium influx. In addition to
signaling defects, GML treated cells have profoundly altered metabolism
profiles characterized by suppressed oxidative phosphorylation and increased
glycolysis. Functionally, GML treatment
potently reduced TCR-induced production of the cytokines IL-2, IFN-γ, TNF-α,
and IL-10 and decreased cellular adhesion via defective actin polymerization.
Our data reveal that the widely used anti-microbial agent GML alters the lipid
dynamics of human T cells, leading to their defective signaling, metabolism,
Hassan IH, Zhang MS, Powers LS, Shao JQ, Baltrusaitis J, Rutkowski DT, Legge K, Monick MM. Influenza A viral replication is blocked by inhibition of the inositol-requiring enzyme 1 (IRE1) stress pathway. J Biol Chem. 2012 Feb 10;287(7):4679-89. doi: 10.1074/jbc.M111.284695. Epub 2011 Dec 22. PubMed PMID: 22194594; PubMed Central PMCID: PMC3281634.
Monick MM, Powers LS, Walters K, Lovan N, Zhang M, Gerke A, Hansdottir S, Hunninghake GW. Identification of an autophagy defect in smokers' alveolar macrophages. J Immunol. 2010 Nov 1;185(9):5425-35. doi: 10.4049/jimmunol.1001603. Epub 2010 Oct 4. PubMed PMID: 20921532; PubMed Central PMCID: PMC3057181.
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