Ingested Human Insulin Inhibits the Mosquito NF-κB-Dependent Immune Response to Plasmodium falciparum

Pakpour, Nazzy; Corby‐Harris, Vanessa; Green, Gabriel P.; Smithers, Hannah; Cheung, Kong Wai; Riehle, Michael A.; Luckhart, Shirley

doi:10.1128/iai.00024-12

Cited by 66 publications

(91 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, the set point of ERK signaling in the gut may alter the permissivity to viral infection. In contrast, studies of Plasmodium falciparum in mosquitoes demonstrate that ingested human insulin increases the susceptibility of Anopheles stephensi by promoting replication of Plasmodium via the down-regulation of NF-κB signaling (51,52). Furthermore, ERK pathway activation by another mammalian blood product, TGF-β, in Anopheles mosquitoes has been found to down-regulate ROS production and also promote parasite growth (30).…”

Section: Discussionmentioning

confidence: 98%

ERK signaling couples nutrient status to antiviral defense in the insect gut

Hopkins

Sabin

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

127

View full text Add to dashboard Cite

A unique facet of arthropod-borne virus (arbovirus) infection is that the pathogens are orally acquired by an insect vector during the taking of a blood meal, which directly links nutrient acquisition and pathogen challenge. We show that the nutrient responsive ERK pathway is both induced by and restricts disparate arboviruses in Drosophila intestines, providing insight into the molecular determinants of the antiviral "midgut barrier." Wild-type flies are refractory to oral infection by arboviruses, including Sindbis virus and vesicular stomatitis virus, but this innate restriction can be overcome chemically by oral administration of an ERK pathway inhibitor or genetically via the specific loss of ERK in Drosophila intestinal epithelial cells. In addition, we found that vertebrate insulin, which activates ERK in the mosquito gut during a blood meal, restricts viral infection in Drosophila cells and against viral invasion of the insect gut epithelium. We find that ERK's antiviral signaling activity is likely conserved in Aedes mosquitoes, because genetic or pharmacologic manipulation of the ERK pathway affects viral infection of mosquito cells. These studies demonstrate that ERK signaling has a broadly antiviral role in insects and suggest that insects take advantage of cross-species signals in the meal to trigger antiviral immunity.innate immunity | enterocytes

show abstract

Section: Discussionmentioning

confidence: 98%

ERK signaling couples nutrient status to antiviral defense in the insect gut

Hopkins

Sabin

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

127

View full text Add to dashboard Cite

show abstract

“…Human insulin reduces lifespan and enhances parasite infection by suppressing A. stephensi immune processes (Kang et al, 2008;Surachetpong et al, 2009;Pakpour et al, 2012). In contrast, ingested human IGF1 can dose-dependently extend lifespan and enhance antiparasite immune responses in A. stephensi.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of midgut IIS can shorten mosquito lifespan and enhance susceptibility to P. falciparum infection in A. stephensi (Kang et al, 2008;Surachetpong et al, 2009). In particular, Pakpour et al (Pakpour et al, 2012) showed that insulin-induced susceptibility is due to the sustained activation of the phosphatidylinositol 3-kinase (PI3K)/Akt branch of the A. stephensi IIS, which in turn inhibits NF-κB-regulated immune gene expression. Furthermore, overexpression of Akt, a key IIS nexus protein, in the midgut of A. stephensi shortened lifespan and inhibited malaria parasite infection (Corby-Harris et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Drexler

Nuss

Hauck

et al. 2013

Journal of Experimental Biology

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…In particular, human insulin and transforming growth factor beta in ingested blood can signal in the mosquito midgut to alter parasite infection. 16,17 Given that ABA has been detected in human blood in the nanomolar range, we hypothesized that mosquitoes could respond to ingested ABA. 7,18 Further, ABA regulation of granulocyte synthesis of RNOS-compounds that are essential to the mosquito immune response to Plasmodium infection-suggested that ABA could regulate analogous mosquito responses to developing parasites.…”

Section: Introductionmentioning

confidence: 99%

Supplementation with Abscisic Acid Reduces Malaria Disease Severity and Parasite Transmission

Glennon¹,

Adams²,

Hicks³

et al. 2016

The American Society of Tropical Medicine and Hygiene

Self Cite

View full text Add to dashboard Cite

Abstract. Nearly half of the world's population is at risk for malaria. Increasing drug resistance has intensified the need for novel therapeutics, including treatments with intrinsic transmission-blocking properties. In this study, we demonstrate that the isoprenoid abscisic acid (ABA) modulates signaling in the mammalian host to reduce parasitemia and the formation of transmissible gametocytes and in the mosquito host to reduce parasite infection. Oral ABA supplementation in a mouse model of malaria was well tolerated and led to reduced pathology and enhanced gene expression in the liver and spleen consistent with infection recovery. Oral ABA supplementation also increased mouse plasma ABA to levels that can signal in the mosquito midgut upon blood ingestion. Accordingly, we showed that supplementation of a Plasmodium falciparum-infected blood meal with ABA increased expression of mosquito nitric oxide synthase and reduced infection prevalence in a nitric oxide-dependent manner. Identification of the mechanisms whereby ABA reduces parasite growth in mammals and mosquitoes could shed light on the balance of immunity and metabolism across eukaryotes and provide a strong foundation for clinical translation.

show abstract

Ingested Human Insulin Inhibits the Mosquito NF-κB-Dependent Immune Response to Plasmodium falciparum

Cited by 66 publications

References 52 publications

ERK signaling couples nutrient status to antiviral defense in the insect gut

ERK signaling couples nutrient status to antiviral defense in the insect gut

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

Supplementation with Abscisic Acid Reduces Malaria Disease Severity and Parasite Transmission

Contact Info

Product

Resources

About