title: Human IGF1 regulates midgut oxidative stress and epithelial homeostasis to balance lifespan and Plasmodium falciparum resistance in Anopheles stephensi.
abstract: 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.
authors: Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
authors: Anna L
authors: AL
authors: Drexler
authors: Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
authors: Jose E
authors: JE
authors: Pietri
authors: Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
authors: Nazzy
authors: N
authors: Pakpour
authors: Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
authors: Eric
authors: E
authors: Hauck
authors: Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
authors: Bo
authors: B
authors: Wang
authors: Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
authors: Elizabeth K K
authors: EK
authors: Glennon
authors: Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
authors: Martha
authors: M
authors: Georgis
authors: Department of Entomology, University of Arizona, Tucson, Arizona, United States of America.
authors: Michael A
authors: MA
authors: Riehle
authors: Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, United States of America.
authors: Shirley
authors: S
authors: Luckhart
mesh_terms: D000818:Animals; D000852:Anopheles / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000469:parasitology; D003140:Communicable Disease Control; D005260:Female; D006706:Homeostasis / Q000187:drug effects; D059165:Hormesis; D006790:Host-Parasite Interactions / Q000187:drug effects*; D006801:Humans; D019476:Insect Proteins / Q000378:metabolism; D007303:Insect Vectors / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism / Q000469:parasitology; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008136:Longevity / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016778:Malaria, Falciparum / Q000517:prevention & control / Q000635:transmission; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D010963:Plasmodium falciparum / Q000302:isolation & purification / Q000472:pathogenicity*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: C583557:IGF1 protein, human; D019476:Insect Proteins; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I