TY - JOUR
T1 - Engineered Aedes aegypti JAK/STAT Pathway-Mediated Immunity to Dengue Virus
AU - Jupatanakul, Natapong
AU - Sim, Shuzhen
AU - Angleró-Rodríguez, Yesseinia I.
AU - Souza-Neto, Jayme
AU - Das, Suchismita
AU - Poti, Kristin E.
AU - Rossi, Shannan L.
AU - Bergren, Nicholas
AU - Vasilakis, Nikos
AU - Dimopoulos, George
N1 - Funding Information:
SS was supported by a fellowship from the Agency for Science, Technology and Research, Singapore. NJ was supported by a fellowship from the Royal Thai Government. The work was supported by grants from the NIH, NIAID: AI101431 (to GD), R21AI090188 (to GD), 1R24AI120942 (to NV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We are grateful to Anna P. Durbin (Johns Hopkins School of Public Health) for providing technical support and materials (DENV strains, C6/36 and Vero cell lines, and 4G2 antibody). We thank the insectary personnel at the Johns Hopkins Malaria Research Institute for assistance with mosquito rearing and the Microarray Core Facilities at the Johns Hopkins School of Public Health and School of Medicine for help with array scanning. We thank Dr. Deborah McClellan for editorial assistance.
PY - 2017/1/12
Y1 - 2017/1/12
N2 - We have developed genetically modified Ae. aegypti mosquitoes that activate the conserved antiviral JAK/STAT pathway in the fat body tissue, by overexpressing either the receptor Dome or the Janus kinase Hop by the blood feeding-induced vitellogenin (Vg) promoter. Transgene expression inhibits infection with several dengue virus (DENV) serotypes in the midgut as well as systemically and in the salivary glands. The impact of the transgenes Dome and Hop on mosquito longevity was minimal, but it resulted in a compromised fecundity when compared to wild-type mosquitoes. Overexpression of Dome and Hop resulted in profound transcriptome regulation in the fat body tissue as well as the midgut tissue, pinpointing several expression signatures that reflect mechanisms of DENV restriction. Our transcriptome studies and reverse genetic analyses suggested that enrichment of DENV restriction factor and depletion of DENV host factor transcripts likely accounts for the DENV inhibition, and they allowed us to identify novel factors that modulate infection. Interestingly, the fat body-specific activation of the JAK/STAT pathway did not result in any enhanced resistance to Zika virus (ZIKV) or chikungunya virus (CHIKV) infection, thereby indicating a possible specialization of the pathway’s antiviral role.
AB - We have developed genetically modified Ae. aegypti mosquitoes that activate the conserved antiviral JAK/STAT pathway in the fat body tissue, by overexpressing either the receptor Dome or the Janus kinase Hop by the blood feeding-induced vitellogenin (Vg) promoter. Transgene expression inhibits infection with several dengue virus (DENV) serotypes in the midgut as well as systemically and in the salivary glands. The impact of the transgenes Dome and Hop on mosquito longevity was minimal, but it resulted in a compromised fecundity when compared to wild-type mosquitoes. Overexpression of Dome and Hop resulted in profound transcriptome regulation in the fat body tissue as well as the midgut tissue, pinpointing several expression signatures that reflect mechanisms of DENV restriction. Our transcriptome studies and reverse genetic analyses suggested that enrichment of DENV restriction factor and depletion of DENV host factor transcripts likely accounts for the DENV inhibition, and they allowed us to identify novel factors that modulate infection. Interestingly, the fat body-specific activation of the JAK/STAT pathway did not result in any enhanced resistance to Zika virus (ZIKV) or chikungunya virus (CHIKV) infection, thereby indicating a possible specialization of the pathway’s antiviral role.
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U2 - 10.1371/journal.pntd.0005187
DO - 10.1371/journal.pntd.0005187
M3 - Article
C2 - 28081143
AN - SCOPUS:85012918899
VL - 11
JO - PLoS Neglected Tropical Diseases
JF - PLoS Neglected Tropical Diseases
SN - 1935-2727
IS - 1
M1 - e0005187
ER -