TY - JOUR
T1 - Cell-type deconvolution with immune pathways identifies gene networks of host defense and immunopathology in leprosy
AU - Inkeles, Megan S.
AU - Teles, Rosane M.B.
AU - Pouldar, Delila
AU - Andrade, Priscila R.
AU - Madigan, Cressida A.
AU - Lopez, David
AU - Ambrose, Mike
AU - Noursadeghi, Mahdad
AU - Sarno, Euzenir N.
AU - Rea, Thomas H.
AU - Ochoa, Maria T.
AU - Iruela-Arispe, M. Luisa
AU - Swindell, William R.
AU - Ottenhoff, Tom H.M.
AU - Geluk, Annemieke
AU - Bloom, Barry R.
AU - Pellegrini, Matteo
AU - Modlin, Robert L.
N1 - Funding Information:
This study was supported by the Order of Malta-Grants-for-Leprosy-Research, the Heiser Program for Research in Leprosy in The New York Community Trust (P13-000392), the NIH (AR063020, AI022553, AR040312, and AI04786), the Q.M. Gastmann-Wichers Foundation, and the Netherlands Leprosy Relief Foundation/Turing Foundation. MN is supported by the National Institute for Health Research Biomedical Research Centre at University College London Hospital.
Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.
PY - 2016/9/22
Y1 - 2016/9/22
N2 - Transcriptome profiles derived from the site of human disease have led to the identification of genes that contribute to pathogenesis, yet the complex mixture of cell types in these lesions has been an obstacle for defining specific mechanisms. Leprosy provides an outstanding model to study host defense and pathogenesis in a human infectious disease, given its clinical spectrum, which interrelates with the host immunologic and pathologic responses. Here, we investigated gene expression profiles derived from skin lesions for each clinical subtype of leprosy, analyzing gene coexpression modules by cell-type deconvolution. In lesions from tuberculoid leprosy patients, those with the self-limited form of the disease, dendritic cells were linked with MMP12 as part of a tissue remodeling network that contributes to granuloma formation. In lesions from lepromatous leprosy patients, those with disseminated disease, macrophages were linked with a gene network that programs phagocytosis. In erythema nodosum leprosum, neutrophil and endothelial cell gene networks were identified as part of the vasculitis that results in tissue injury. The present integrated computational approach provides a systems approach toward identifying cell-defined functional networks that contribute to host defense and immunopathology at the site of human infectious disease.
AB - Transcriptome profiles derived from the site of human disease have led to the identification of genes that contribute to pathogenesis, yet the complex mixture of cell types in these lesions has been an obstacle for defining specific mechanisms. Leprosy provides an outstanding model to study host defense and pathogenesis in a human infectious disease, given its clinical spectrum, which interrelates with the host immunologic and pathologic responses. Here, we investigated gene expression profiles derived from skin lesions for each clinical subtype of leprosy, analyzing gene coexpression modules by cell-type deconvolution. In lesions from tuberculoid leprosy patients, those with the self-limited form of the disease, dendritic cells were linked with MMP12 as part of a tissue remodeling network that contributes to granuloma formation. In lesions from lepromatous leprosy patients, those with disseminated disease, macrophages were linked with a gene network that programs phagocytosis. In erythema nodosum leprosum, neutrophil and endothelial cell gene networks were identified as part of the vasculitis that results in tissue injury. The present integrated computational approach provides a systems approach toward identifying cell-defined functional networks that contribute to host defense and immunopathology at the site of human infectious disease.
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U2 - 10.1172/jci.insight.88843
DO - 10.1172/jci.insight.88843
M3 - Article
C2 - 27699251
AN - SCOPUS:85055595634
SN - 2379-3708
VL - 1
JO - JCI Insight
JF - JCI Insight
IS - 15
M1 - e88843
ER -