Manipulation of pantothenate kinase in Anopheles stephensi suppresses pantothenate levels with minimal impacts on mosquito fitness. (October 2022)

• Record Type: Journal Article
• Authors: Thakre, Neha; Simão Gurge, Raquel M.; Isoe, Jun; Kivi, Heather; Strickland, Jessica; Delacruz, Lillian R.; Rodriguez, Anna M.; Haney, Reagan; Sadeghi, Rohollah; Joy, Teresa; Chen, Minhao; Luckhart, Shirley; Riehle, Michael A.
• Is Part Of: Insect biochemistry and molecular biology. Volume 149(2022)
• Publication Date: 2022-10
• Subjects: Pantothenate kinase -- PanK -- Mosquito -- Coenzyme a -- Acetyl-CoA -- Lifespan -- Reproduction -- Fecundity -- Insulin -- PTEN -- MKP4; Insect biochemistry -- Periodicals; Insects -- Physiology -- Periodicals; Insects -- Molecular aspects -- Periodicals; Biochemistry -- Periodicals; Insectes -- Biochimie -- Périodiques; Insectes -- Composition -- Périodiques; Insectes -- Physiologie -- Périodiques; Insectes -- Aspect moléculaire -- Périodiques; Biochimie -- Périodiques; Biochemistry; Insect biochemistry; Insects -- Molecular aspects; Insects -- Physiology; Periodicals; 572.8157
• DOI: 10.1016/j.ibmb.2022.103834
• Languages: English
• ISSNs: 0965-1748

Abstract

Abstract: Pantothenate (Pan) is an essential nutrient required by both the mosquito vector and malaria parasite. We previously demonstrated that increasing pantothenate kinase (PanK) activity and co-enzyme A (CoA) biosynthesis led to significantly decreased parasite infection prevalence and intensity in the malaria mosquito Anopheles stephensi . In this study, we demonstrate that Pan stores in A. stephensi are a limited resource and that manipulation of PanK levels or activity, via small molecule modulators of PanK or transgenic mosquitoes, leads to the conversion of Pan to CoA and an overall reduction in Pan levels with minimal to no effects on mosquito fitness. Transgenic A. stephensi lines with repressed insulin signaling due to PTEN overexpression or repressed c-Jun N-terminal kinase (JNK) signaling due to MAPK phosphatase 4 (MKP4) overexpression exhibited enhanced PanK levels and significant reductions in Pan relative to non-transgenic controls, with the PTEN line also exhibiting significantly increased CoA levels. Provisioning of the PTEN line with the small molecule PanK modulator PZ-2891 increased CoA levels while provisioning Compound 7 decreased CoA levels, affirming chemical manipulation of mosquito PanK. We assessed effects of these small molecules on A. stephensi lifespan, reproduction and metabolism under optimized laboratory conditions. PZ-2891 and Compound 7 had no impact on A. stephensi survival when delivered via bloodmeal throughout mosquito lifespan. Further, PZ-2891 provisioning had no impact on egg production over the first two reproductive cycles. Finally, PanK manipulation with small molecules was associated with minimal impacts on nutritional stores in A. stephensi mosquitoes under optimized rearing conditions. Together with our previous data demonstrating that PanK activation was associated with significantly increased A. stephensi resistance to Plasmodium falciparum infection, the studies herein demonstrate a lack of fitness costs of mosquito Pan depletion as a basis for a feasible, novel strategy to control parasite infection of anopheline mosquitoes. Graphical abstract: Image 1 Highlights: Increased PanK activity reduces pantothenate stores in the A. stephensi midgut and whole body. Increased PanK levels in MKP4 and PTEN transgenic A. stephensi lead to increased CoA levels. Increased CoA biosynthesis and reduced pantothenate stores do not affect A. stephensi fitness.