The insulin signaling cascade from nematodes to mammals: Insights into innate immunity of Anopheles mosquitoes to malaria parasite infection

Abstract

As revealed over the past twenty years, the insulin signaling cascade plays a central role in regulating immune and oxidative stress responses that affect the life spans of mammals and two model invertebrates, the nematode Caenorhabitis elegans and the fruit fly Drosophila melanogaster. In mosquitoes, insulin signaling regulates key steps in egg maturation and immunity and likely affects aging, although the latter has yet to be examined in detail. Reproduction, immunity and aging critically influence the capacity of mosquitoes to effectively transmit malaria parasites. Current work has demonstrated that molecules from the invading parasite and the blood meal elicit functional responses in female mosquitoes that are regulated through the insulin signaling pathway or by crosstalk with interacting pathways. Defining the details of these regulatory interactions presents significant challenges for future research, but will increase our understanding of mosquito/malaria parasite transmission and of the conservation of insulin signaling as a key regulatory nexus in animal biology. Keywordsinsulin; Anopheles; Plasmodium; mosquito; malaria; aging; oxidative stress; innate immunity; nitric oxide; transforming growth factor; β In all well-studied metazoans, metabolism, growth, and longevity are coordinately regulated via a nexus that involves signaling cascades activated by insulin and insulin-like growth factors (IGF). Although these pathways differ in downstream physiological effects and some of their signaling proteins, the proteins themselves and their scaffolding interactions are largely conserved among model organisms ( Fig. 1), particularly in the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the mouse Mus musculus. This review will examine our current understanding of how the insulin and IGF signaling cascades (ISC) regulate immunity in these diverse model organisms. In addition, we will explore how recent Correspondence to: Shirley Luckhart. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errorsmaybe discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Key targets of daf-16 regulation include genes for mitochondrial manganese superoxide dismutase (MnSOD) and glutathione S-transferase, which are closely linked to aging in C. elegans and other organisms, and genes for numerous C-type lectins, which play critical roles in cell adhesion and pathogen recognition [5]. Downregulation of these gene targets in daf-16 mutants would be predicted to enhance oxidative stress, which has been linked directly to aging in C. elegans [6,7], and decrease pathogen recognition [8]. Conversely, rescue of downregulated MnSOD...

Insulin regulates aging and oxidative stress in Anopheles stephensi

“…Our results with insulin are consistent with the prediction from numerous studies on lifespan extension in model organisms that enhanced insulin signaling would lead to a shortened lifespan (reviewed in Giannakou and Partridge, 2007;Luckhart and Riehle, 2007). For example, mutations in daf-16, which mimic exclusion of this transcription factor from the nucleus during insulin signaling, shorten lifespan in C. elegans (Ogg et al, 1997).…”

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

“…The most vulnerable point of the malaria parasite life cycle is the transition from the human blood stream to the mosquito midgut. During this transition, hormones, growth factors and cytokines in infected blood can regulate aspects of mosquito physiology and lifespan that directly affect parasite development (Kang et al, 2008;Luckhart et al, 2003;Luckhart and Riehle, 2007;Pakpour et al, 2012;Surachetpong et al, 2009;Surachetpong et al, 2011).…”

Deletion of Drosophila insulin-like peptides causes growth defects and metabolic abnormalities

“…In addition, while insulins are canonical activators of Receptor Tyrosine Kinase (RTK) activity, some ligands in C. elegans may act as antagonists of IIS [reviewed in (20)]. For mosquitoes, eight ILPs have been identified (21) and functional studies indicate roles for different ILPs in egg laying, diapause, immunity, and metabolism (22)(23)(24). The ILPS are thought to be secreted proteins (25,26), as are mammalian insulin and IGFs (2).…”