Human IGF1 extends lifespan and enhances resistance to Plasmodium falciparum infection in the malaria vector Anopheles stephensi

Abstract

SUMMARYThe highly conserved insulin/insulin-like growth factor (IGF) signaling (IIS) pathway regulates metabolism, development, lifespan and immunity across a wide range of organisms. Previous studies have shown that human insulin ingested in the blood meal can activate mosquito IIS, resulting in attenuated lifespan and increased malaria parasite infection. Because human IGF1 is present at higher concentrations in blood than insulin and is functionally linked with lifespan and immune processes, we predicted that human IGF1 ingested in a blood meal would affect lifespan and malaria parasite infection in the mosquito Anopheles stephensi. Here we demonstrate that physiological levels of ingested IGF1, like insulin, can persist intact in the blood-filled midgut for up to 30h and disseminate into the mosquito body, and that both peptides activate IIS in mosquito cells and midgut. At these same levels, ingested IGF1 alone extended average mosquito lifespan by 23% compared with controls and, more significantly, when ingested in infected blood meals, reduced the prevalence of Plasmodium falciparum-infected mosquitoes by >20% and parasite load by 35-50% compared with controls. Thus, the effects of ingested IGF1 on mosquito lifespan and immunity are opposite to those of ingested insulin. These results offer the first evidence that insect cells can functionally discriminate between mammalian insulin and IGF1. Further, in light of previous success in genetically targeting IIS to alter mosquito lifespan and malaria parasite transmission, this study indicates that a more complete understanding of the IIS-activating ligands in blood can be used to optimize transgenic strategies for malaria control.

Plasmodium falciparum suppresses the host immune response by inducing the synthesis of insulin-like peptides (ILPs) in the mosquito Anopheles stephensi

“…In the mosquito midgut, ingested Plasmodium gametocytes undergo a series of developmental changes in the context of robust immune responses that contribute to marked losses in parasite numbers (Clayton et al, 2014; Yassine et al, 2010). This process is regulated in part by insulin/insulin-like growth factor signaling (IIS) and mitogen-activated protein kinase (MAPK) pathways (Corby-Harris et al, 2010; Drexler et al, 2013; Drexler et al, 2014; Hauck et al, 2013; Horton et al, 2010; Luckhart et al, 2013; Pakpour et al, 2012; Surachetpong et al, 2009; Surachetpong et al, 2010). …”

Human IGF1 Regulates Midgut Oxidative Stress and Epithelial Homeostasis to Balance Lifespan and Plasmodium falciparum resistance in Anopheles stephensi

“…In particular, human insulin induces phosphorylation of FOXO in the A. stephensi midgut [13] as does low IGF1 [17], whereas high IGF1 has no effect on FOXO [17]. Low IGF1 induces phosphorylation of p70S6K, a protein that is not activated by insulin, and both low and high IGF1 repress phosphorylation of ERK [17], a protein that is activated by insulin in the A. stephensi midgut [12], [13].…”

Effects of ingested vertebrate-derived factors on insect immune responses

“…IIS protein orthologs can be found in a broad range of insect species including the true bug R. prolixus, tsetse flies, sand flies, mosquitoes, and the human body louse Pediculus humanus humanus [26–32]. In addition to conservation of IIS architecture, mammalian insulin and invertebrate insulin-like peptides (ILPs) share a conserved structure that facilitates the binding of mammalian insulin to insect ILP receptors [33].…”

“…Although human insulin and insulin-like growth factor-1 (IGF-1) are structurally similar, they vary considerably in their effects in both humans and blood feeding insects [32]. Unlike insulin, ingested human IGF-1 increases resistance of A. stephensi to P. falciparum through the induction of midgut mitochondrial ROS and nitric oxide (NO) [32, 41•].…”

“…Unlike insulin, ingested human IGF-1 increases resistance of A. stephensi to P. falciparum through the induction of midgut mitochondrial ROS and nitric oxide (NO) [32, 41•]. In humans, IGF binding proteins (IGFBPs) regulate the bioavailability of IGF-1 and can also independently activate the IGF receptor [42].…”