Department of Entomology, University of Arizona, Tucson, AZ, USA.
Departrment of Entomology, Plant Pathology and Nematology, University of Idaho, Moscow, ID, USA.
Insect Biochem Mol Biol. 2022 Oct;149:103834. doi: 10.1016/j.ibmb.2022.103834. Epub 2022 Sep 7.
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.
泛酸（Pan）是蚊子载体和疟原虫都需要的必需营养素。我们之前的研究表明，增加泛酸激酶（PanK）活性和辅酶 A（CoA）生物合成可显著降低疟蚊按蚊中的寄生虫感染率和强度。在这项研究中，我们证明了按蚊中的 Pan 储存是一种有限的资源，并且通过 PanK 的小分子调节剂或转基因蚊子来操纵 PanK 水平或活性，会导致 Pan 转化为 CoA，总体上减少 Pan 水平，对蚊子的适应性几乎没有影响。由于 PTEN 过表达导致胰岛素信号下调或由于 MAPK 磷酸酶 4（MKP4）过表达导致 c-Jun N 末端激酶（JNK）信号下调的转基因按蚊品系表现出增强的 PanK 水平和相对于非转基因对照的 Pan 显著减少，PTEN 品系还表现出显著增加的 CoA 水平。由于小分子 PanK 调节剂 PZ-2891 的提供，PTEN 品系的 CoA 水平增加，而化合物 7 降低了 CoA 水平，证实了对蚊子 PanK 的化学操纵。我们在优化的实验室条件下评估了这些小分子对按蚊寿命、繁殖和新陈代谢的影响。在整个蚊子寿命期间通过血餐提供 PZ-2891 和化合物 7 对按蚊的生存没有影响。此外，PZ-2891 的供应对前两个生殖周期的产卵没有影响。最后，在优化的饲养条件下，用小分子进行 PanK 操作与按蚊中营养物质储存的最小影响有关。结合我们之前的研究数据表明 PanK 激活与按蚊对恶性疟原虫感染的抗性显著增加有关，本研究表明蚊子 Pan 耗竭作为一种可行的新型策略来控制按蚊寄生虫感染的可能性，没有适应度成本。
