Inhibition of JNK signaling in the Asian malaria vector Anopheles stephensi extends mosquito longevity and improves resistance to Plasmodium falciparum infection

Lattha Souvannaseng, Lewis Vibul Hun, Heather Baker, John M. Klyver, Bo Wang, Nazzy Pakpour, Jordan M. Bridgewater, Eleonora Napoli, Cecilia R Giulivi, Michael A. Riehle, Shirley Luckhart

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Malaria is a global health concern caused by infection with Plasmodium parasites. With rising insecticide and drug resistance, there is a critical need to develop novel control strategies, including strategies to block parasite sporogony in key mosquito vector species. MAPK signaling pathways regulated by extracellular signal-regulated kinases (ERKs) and the stress-activated protein kinases (SAPKs) c-Jun N-terminal kinases (JNKs) and p38 MAPKs are highly conserved across eukaryotes, including mosquito vectors of the human malaria parasite Plasmodium falciparum. Some of these pathways in mosquitoes have been investigated in detail, but the mechanisms of integration of parasite development and mosquito fitness by JNK signaling have not been elucidated. To this end, we engineered midgut-specific overexpression of MAPK phosphatase 4 (MKP4), which targets the SAPKs, and used two potent and specific JNK small molecule inhibitors (SMIs) to assess the effects of JNK signaling manipulations on Anopheles stephensi fecundity, lifespan, intermediary metabolism, and P. falciparum development. MKP4 overexpression and SMI treatment reduced the proportion of P. falciparum-infected mosquitoes and decreased oocyst loads relative to controls. SMI-treated mosquitoes exhibited no difference in lifespan compared to controls, whereas genetically manipulated mosquitoes exhibited extended longevity. Metabolomics analyses of SMI-treated mosquitoes revealed insights into putative resistance mechanisms and the physiology behind lifespan extension, suggesting for the first time that P. falciparum-induced JNK signaling reduces mosquito longevity and increases susceptibility to infection, in contrast to previously published reports, likely via a critical interplay between the invertebrate host and parasite for nutrients that play essential roles during sporogonic development.

Original languageEnglish (US)
Article numbere1007418
JournalPLoS Pathogens
Volume14
Issue number11
DOIs
StatePublished - Nov 1 2018

Fingerprint

Anopheles
JNK Mitogen-Activated Protein Kinases
Plasmodium falciparum
Culicidae
Malaria
Parasites
Dual Specificity Phosphatase 1
Heat-Shock Proteins
Protein Kinases
Insecticide Resistance
Metabolomics
Oocysts
Falciparum Malaria
Extracellular Signal-Regulated MAP Kinases
p38 Mitogen-Activated Protein Kinases
Invertebrates
Eukaryota
Drug Resistance
Fertility
Food

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Inhibition of JNK signaling in the Asian malaria vector Anopheles stephensi extends mosquito longevity and improves resistance to Plasmodium falciparum infection. / Souvannaseng, Lattha; Hun, Lewis Vibul; Baker, Heather; Klyver, John M.; Wang, Bo; Pakpour, Nazzy; Bridgewater, Jordan M.; Napoli, Eleonora; Giulivi, Cecilia R; Riehle, Michael A.; Luckhart, Shirley.

In: PLoS Pathogens, Vol. 14, No. 11, e1007418, 01.11.2018.

Research output: Contribution to journalArticle

Souvannaseng, Lattha ; Hun, Lewis Vibul ; Baker, Heather ; Klyver, John M. ; Wang, Bo ; Pakpour, Nazzy ; Bridgewater, Jordan M. ; Napoli, Eleonora ; Giulivi, Cecilia R ; Riehle, Michael A. ; Luckhart, Shirley. / Inhibition of JNK signaling in the Asian malaria vector Anopheles stephensi extends mosquito longevity and improves resistance to Plasmodium falciparum infection. In: PLoS Pathogens. 2018 ; Vol. 14, No. 11.
@article{77921a495e854af79962163bc8015a76,
title = "Inhibition of JNK signaling in the Asian malaria vector Anopheles stephensi extends mosquito longevity and improves resistance to Plasmodium falciparum infection",
abstract = "Malaria is a global health concern caused by infection with Plasmodium parasites. With rising insecticide and drug resistance, there is a critical need to develop novel control strategies, including strategies to block parasite sporogony in key mosquito vector species. MAPK signaling pathways regulated by extracellular signal-regulated kinases (ERKs) and the stress-activated protein kinases (SAPKs) c-Jun N-terminal kinases (JNKs) and p38 MAPKs are highly conserved across eukaryotes, including mosquito vectors of the human malaria parasite Plasmodium falciparum. Some of these pathways in mosquitoes have been investigated in detail, but the mechanisms of integration of parasite development and mosquito fitness by JNK signaling have not been elucidated. To this end, we engineered midgut-specific overexpression of MAPK phosphatase 4 (MKP4), which targets the SAPKs, and used two potent and specific JNK small molecule inhibitors (SMIs) to assess the effects of JNK signaling manipulations on Anopheles stephensi fecundity, lifespan, intermediary metabolism, and P. falciparum development. MKP4 overexpression and SMI treatment reduced the proportion of P. falciparum-infected mosquitoes and decreased oocyst loads relative to controls. SMI-treated mosquitoes exhibited no difference in lifespan compared to controls, whereas genetically manipulated mosquitoes exhibited extended longevity. Metabolomics analyses of SMI-treated mosquitoes revealed insights into putative resistance mechanisms and the physiology behind lifespan extension, suggesting for the first time that P. falciparum-induced JNK signaling reduces mosquito longevity and increases susceptibility to infection, in contrast to previously published reports, likely via a critical interplay between the invertebrate host and parasite for nutrients that play essential roles during sporogonic development.",
author = "Lattha Souvannaseng and Hun, {Lewis Vibul} and Heather Baker and Klyver, {John M.} and Bo Wang and Nazzy Pakpour and Bridgewater, {Jordan M.} and Eleonora Napoli and Giulivi, {Cecilia R} and Riehle, {Michael A.} and Shirley Luckhart",
year = "2018",
month = "11",
day = "1",
doi = "10.1371/journal.ppat.1007418",
language = "English (US)",
volume = "14",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "11",

}

TY - JOUR

T1 - Inhibition of JNK signaling in the Asian malaria vector Anopheles stephensi extends mosquito longevity and improves resistance to Plasmodium falciparum infection

AU - Souvannaseng, Lattha

AU - Hun, Lewis Vibul

AU - Baker, Heather

AU - Klyver, John M.

AU - Wang, Bo

AU - Pakpour, Nazzy

AU - Bridgewater, Jordan M.

AU - Napoli, Eleonora

AU - Giulivi, Cecilia R

AU - Riehle, Michael A.

AU - Luckhart, Shirley

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Malaria is a global health concern caused by infection with Plasmodium parasites. With rising insecticide and drug resistance, there is a critical need to develop novel control strategies, including strategies to block parasite sporogony in key mosquito vector species. MAPK signaling pathways regulated by extracellular signal-regulated kinases (ERKs) and the stress-activated protein kinases (SAPKs) c-Jun N-terminal kinases (JNKs) and p38 MAPKs are highly conserved across eukaryotes, including mosquito vectors of the human malaria parasite Plasmodium falciparum. Some of these pathways in mosquitoes have been investigated in detail, but the mechanisms of integration of parasite development and mosquito fitness by JNK signaling have not been elucidated. To this end, we engineered midgut-specific overexpression of MAPK phosphatase 4 (MKP4), which targets the SAPKs, and used two potent and specific JNK small molecule inhibitors (SMIs) to assess the effects of JNK signaling manipulations on Anopheles stephensi fecundity, lifespan, intermediary metabolism, and P. falciparum development. MKP4 overexpression and SMI treatment reduced the proportion of P. falciparum-infected mosquitoes and decreased oocyst loads relative to controls. SMI-treated mosquitoes exhibited no difference in lifespan compared to controls, whereas genetically manipulated mosquitoes exhibited extended longevity. Metabolomics analyses of SMI-treated mosquitoes revealed insights into putative resistance mechanisms and the physiology behind lifespan extension, suggesting for the first time that P. falciparum-induced JNK signaling reduces mosquito longevity and increases susceptibility to infection, in contrast to previously published reports, likely via a critical interplay between the invertebrate host and parasite for nutrients that play essential roles during sporogonic development.

AB - Malaria is a global health concern caused by infection with Plasmodium parasites. With rising insecticide and drug resistance, there is a critical need to develop novel control strategies, including strategies to block parasite sporogony in key mosquito vector species. MAPK signaling pathways regulated by extracellular signal-regulated kinases (ERKs) and the stress-activated protein kinases (SAPKs) c-Jun N-terminal kinases (JNKs) and p38 MAPKs are highly conserved across eukaryotes, including mosquito vectors of the human malaria parasite Plasmodium falciparum. Some of these pathways in mosquitoes have been investigated in detail, but the mechanisms of integration of parasite development and mosquito fitness by JNK signaling have not been elucidated. To this end, we engineered midgut-specific overexpression of MAPK phosphatase 4 (MKP4), which targets the SAPKs, and used two potent and specific JNK small molecule inhibitors (SMIs) to assess the effects of JNK signaling manipulations on Anopheles stephensi fecundity, lifespan, intermediary metabolism, and P. falciparum development. MKP4 overexpression and SMI treatment reduced the proportion of P. falciparum-infected mosquitoes and decreased oocyst loads relative to controls. SMI-treated mosquitoes exhibited no difference in lifespan compared to controls, whereas genetically manipulated mosquitoes exhibited extended longevity. Metabolomics analyses of SMI-treated mosquitoes revealed insights into putative resistance mechanisms and the physiology behind lifespan extension, suggesting for the first time that P. falciparum-induced JNK signaling reduces mosquito longevity and increases susceptibility to infection, in contrast to previously published reports, likely via a critical interplay between the invertebrate host and parasite for nutrients that play essential roles during sporogonic development.

UR - http://www.scopus.com/inward/record.url?scp=85057528949&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057528949&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1007418

DO - 10.1371/journal.ppat.1007418

M3 - Article

VL - 14

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 11

M1 - e1007418

ER -