Modeling Host–Vector–Pathogen Immuno-inflammatory Interactions in Malaria

Vodovotz, Yoram; Azhar, Nabil; Miskov-Zivanov, Natasa; Buliga, Marius; Zamora, Rubén; Ermentrout, Bard; Constantine, Gregory; Faeder, James R.; Pakpour, Nazzy; Luckhart, Shirley

doi:10.1007/978-1-4614-8008-2_14

Cited by 2 publications

(1 citation statement)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Anopheles gambiae [ 31 ] and Anopheles stephensi genomes each encode a single p38 MAPK, described herein, with associated pathway signaling proteins [ 31 ]. Based on collective observations from other species and the conservation of this pathway, we hypothesized that p38 MAPK signaling contributes to regulation of the response of Anopheles mosquitoes to midgut development of Plasmodium parasites [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

Anopheles stephensi p38 MAPK signaling regulates innate immunity and bioenergetics during Plasmodium falciparum infection

et al. 2015

Self Cite

View full text Add to dashboard Cite

BackgroundFruit flies and mammals protect themselves against infection by mounting immune and metabolic responses that must be balanced against the metabolic needs of the pathogens. In this context, p38 mitogen-activated protein kinase (MAPK)-dependent signaling is critical to regulating both innate immunity and metabolism during infection. Accordingly, we asked to what extent the Asian malaria mosquito Anopheles stephensi utilizes p38 MAPK signaling during infection with the human malaria parasite Plasmodium falciparum.MethodsA. stephensi p38 MAPK (AsP38 MAPK) was identified and patterns of signaling in vitro and in vivo (midgut) were analyzed using phospho-specific antibodies and small molecule inhibitors. Functional effects of AsP38 MAPK inhibition were assessed using P. falciparum infection, quantitative real-time PCR, assays for reactive oxygen species and survivorship under oxidative stress, proteomics, and biochemical analyses.ResultsThe genome of A. stephensi encodes a single p38 MAPK that is activated in the midgut in response to parasite infection. Inhibition of AsP38 MAPK signaling significantly reduced P. falciparum sporogonic development. This phenotype was associated with AsP38 MAPK regulation of mitochondrial physiology and stress responses in the midgut epithelium, a tissue critical for parasite development. Specifically, inhibition of AsP38 MAPK resulted in reduction in mosquito protein synthesis machinery, a shift in glucose metabolism, reduced mitochondrial metabolism, enhanced production of mitochondrial reactive oxygen species, induction of an array of anti-parasite effector genes, and decreased resistance to oxidative stress-mediated damage. Hence, P. falciparum-induced activation of AsP38 MAPK in the midgut facilitates parasite infection through a combination of reduced anti-parasite immune defenses and enhanced host protein synthesis and bioenergetics to minimize the impact of infection on the host and to maximize parasite survival, and ultimately, transmission.ConclusionsThese observations suggest that, as in mammals, innate immunity and mitochondrial responses are integrated in mosquitoes and that AsP38 MAPK-dependent signaling facilitates mosquito survival during parasite infection, a fact that may attest to the relatively longer evolutionary relationship of these parasites with their invertebrate compared to their vertebrate hosts. On a practical level, improved understanding of the balances and trade-offs between resistance and metabolism could be leveraged to generate fit, resistant mosquitoes for malaria control.Electronic supplementary materialThe online version of this article (doi:10.1186/s13071-015-1016-x) contains supplementary material, which is available to authorized users.

show abstract

Section: Introductionmentioning

confidence: 99%