Cross-Talk Between Nitric Oxide and Transforming Growth Factor- &amp;#946;1 in Malaria

Developmental & Comparative Immunology

Riehle

2007

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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...

“…Like the insulin signaling pathway, the TGF-β signaling pathway regulates the NO-dependent immune response in An. stephensi [49,74].…”

Section: Insulin Signaling and Its Impact On Malaria Transmissionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Developmental & Comparative Immunology

Riehle

2007

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“…A key target in mammalian cells of TGF-β1 regulation during inflammation is inducible nitric oxide synthase (iNOS; (Vodovotz, 1997 andVodovotz et al, 2004). In this context, the primary role of TGF-β1 (at doses as low as 100 pg/ml) is to decrease iNOS induction (Vodovotz et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Low levels of mammalian TGF-β1 are protective against malaria parasite infection, a paradox clarified in the mosquito host

Experimental Parasitology

Lieber

Singh

et al. 2008

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Nitric oxide (NO), derived from catalysis of inducible NO synthase (iNOS), limits malaria parasite growth in mammals. Transforming growth factor (TGF)-β1 suppresses iNOS in cells in vitro as well as in vivo in mice, but paradoxically severe malaria in humans is associated with low levels of TGF-β1. We hypothesized that this paradox is a universal feature of infection and occurs in the mosquito Anopheles stephensi, an invertebrate host for Plasmodium that also regulates parasite development with inducible NO synthase (AsNOS). We show that exogenous human TGF-β1 dose-dependently regulates mosquito AsNOS expression and that parasite killing by low dose TGF-β1 depends on AsNOS catalysis. Furthermore, induction of AsNOS expression by TGF-β1 is regulated by NO synthesis. These results suggest that TGF-β1 plays similar roles during parasite infection in mammals and mosquitoes and that this role is linked to the effects of TGF-β1 on inducible NO synthesis. .

“…Orthologous proteins from the TGF-β signaling pathway have been identified in a diversity of blood feeding insects [49], raising the possibility that ingested human TGF-β1 activates endogenous TGF-β1 signaling pathways in other insect vectors as well. One of the most potent effects of TGF-β1 is the regulation of NO production, which is used by both mammals and mosquitoes to kill Plasmodium parasites [50]. In mosquitoes, low levels of human TGF-β1 (≤ 200 pg/ml) ingested in an infectious blood meal induce a moderate increase in nitric oxide synthase (NOS) activity that inhibits malaria parasite development.…”

Section: Tgf-β1mentioning

confidence: 99%

Effects of ingested vertebrate-derived factors on insect immune responses

Pakpour

Riehle

Current Opinion in Insect Science

2014

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During the process of blood feeding insect vectors are exposed to an array of vertebrate-derived blood factors ranging from byproducts of blood meal digestion to naturally occurring products in the blood including growth hormones, cytokines and factors derived from blood-borne pathogens themselves. In this review, we examine the ability of these ingested vertebrate blood factors to alter the innate pathogen defenses of insect vectors. The ability of these factors to modify the immune responses of insect vectors offers new intriguing targets for blocking or reducing transmission of human disease-causing pathogens.