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Human IGF1 regulates midgut oxidative stress and epithelial homeostasis to balance lifespan and Plasmodium falciparum resistance in Anopheles stephensi.
Drexler, Anna L; Pietri, Jose E; Pakpour, Nazzy; Hauck, Eric; Wang, Bo; Glennon, Elizabeth K K; Georgis, Martha; Riehle, Michael A; Luckhart, Shirley.
Afiliação
  • Drexler AL; Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
  • Pietri JE; Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
  • Pakpour N; Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
  • Hauck E; Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
  • Wang B; Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
  • Glennon EK; Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
  • Georgis M; Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
  • Riehle MA; Department of Entomology, University of Arizona, Tucson, Arizona, United States of America.
  • Luckhart S; Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
PLoS Pathog ; 10(6): e1004231, 2014 Jun.
Article em En | MEDLINE | ID: mdl-24968248
Insulin and insulin-like growth factor signaling (IIS) regulates cell death, repair, autophagy, and renewal in response to stress, damage, and pathogen challenge. Therefore, IIS is fundamental to lifespan and disease resistance. Previously, we showed that insulin-like growth factor 1 (IGF1) within a physiologically relevant range (0.013-0.13 µM) in human blood reduced development of the human parasite Plasmodium falciparum in the Indian malaria mosquito Anopheles stephensi. Low IGF1 (0.013 µM) induced FOXO and p70S6K activation in the midgut and extended mosquito lifespan, whereas high IGF1 (0.13 µM) did not. In this study the physiological effects of low and high IGF1 were examined in detail to infer mechanisms for their dichotomous effects on mosquito resistance and lifespan. Following ingestion, low IGF1 induced phosphorylation of midgut c-Jun-N-terminal kinase (JNK), a critical regulator of epithelial homeostasis, but high IGF1 did not. Low and high IGF1 induced midgut mitochondrial reactive oxygen species (ROS) synthesis and nitric oxide (NO) synthase gene expression, responses which were necessary and sufficient to mediate IGF1 inhibition of P. falciparum development. However, increased ROS and apoptosis-associated caspase-3 activity returned to baseline levels following low IGF1 treatment, but were sustained with high IGF1 treatment and accompanied by aberrant expression of biomarkers for mitophagy, stem cell division and proliferation. Low IGF1-induced ROS are likely moderated by JNK-induced epithelial cytoprotection as well as p70S6K-mediated growth and inhibition of apoptosis over the lifetime of A. stephensi to facilitate midgut homeostasis and enhanced survivorship. Hence, mitochondrial integrity and homeostasis in the midgut, a key signaling center for IIS, can be targeted to coordinately optimize mosquito fitness and anti-pathogen resistance for improved control strategies for malaria and other vector-borne diseases.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2014 Tipo de documento: Article