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Journal of Clinical Immunology and Allergy
ISSN: 2471-304X
16 th EuroSciCon Conference on
Immunology
M a r c h 1 1 - 1 2 , 2 0 1 9
Am s t e r d a m , N e t h e r l a n d s
Immunology 2019
Phospoinositide-3-kinases (PI3Ks) are important evolutionarily conserved
lipid kinases, regulating organismal pathways essential for cell growth,
division, proliferation, and are often deregulated in cancer and inflammation.
Colorectal and gastric cancers are reported to have high rates of activating
mutations in the ubiquitously expressed gene encoding PI3Kα. PI3Ks
regulate PRR-driven innate immune responses however how PI3Kα couples
to intestinal epithelial cell (IEC) functions and gut homeostasis is not well
understood. Intestinal epithelium is the largest and fastest regenerative tissue
with protective barrier-type function. Disruption of the intestinal barrier due to
genetic and/or environmental factors results in inflammatory bowel disease
(IBD). NOD2 is the first identified susceptibility gene in IBD, and regulates
innate immune responses to bacteria-derived dipeptides. In IECs, NOD1/2
was reported to regulate intestinal stem cell renewal and contribute to wound
healing response. Since PRR signalling plays an important role in IEC division
and self-renewal under stress conditions, upon injury and infection, we
investigated whether IEC-intrinsic PI3Kα regulates NOD1/2 signalling and is
involved in responses to gut protective responses, following gut injury. Herein
by genetic and pharmacological targeting in vivo and in vitro, we showed that
PI3Kα couples to NOD1/2 pathways, activated by bacterial dipeptides and
induces mTOR signalling, analogous to nutrient sensing of eukaryotic amino
acids. Strikingly, conditional inactivation of PI3Kα in adult mice result in lethality
shortly following DSS-induced injury, while not showing gross differences in
inflammation. Our findings demonstrate PI3Kα is an essential in intestinal
integrity, function and IEC-intrinsic PI3Kα coupling to NOD1/2 mediated mTOR
signalling adds a new layer to the complexity to the symbiotic host microbiome
interactions even under stressful conditions.
Biography
LauraMedrano Gonzalez has completed her degree in Genetics
from Universitat Autonoma de Barcelona. During her four year
degree, she was awarded with an international studentship to
work in Professor Andy Waters’ research group at the Institute
of Infection, Immunity and Inflammation, University of Glasgow.
Afterherexperiencestudyingaproteincomplexrelatedtosexual
development ofmalaria’s parasite, shewas accepted at Imperial
College London to pursue her research career with an MSc in
Immunology. During her Master’s-project, she joined Professor
Peter Openshaw’s laboratory in order to perform independent
research, experimental setup and analysis focusing on B-cell
responses against RSV. She joined Dr Ezra Aksoy's pioneering
research groupworking inmucosal immunity and inflammation
at the William Harvey Research Institute. She is currently a PhD
candidate investigating the isoform-selective roles of PI3Ks
and innate immune receptor signalling in the intestinal epithelial
cells (IECs) and has presented her research data in several
international conferences.
Class I PI3K isoform regulates NOD1/2 mediated bacterial
amino acid sensing pathway and control gut homeostasis under
inflammatory conditions
Laura Medrano Gonzalez and Ezra Aksoy
Queen Mary University of London, UK
Laura Medrano Gonzalez et al., J Clin Immunol Allergy 2019, Volume:5
DOI: 10.21767/2471-304X-C1-008