The redox-sensing gene Nrf2 affects intestinal homeostasis, insecticide resistance, and Zika virus susceptibility in the mosquito Aedes aegypti

Abstract

Production and degradation of reactive oxygen species (ROS) are extensively regulated to ensure proper cellular responses to various environmental stimuli and stresses. Moreover, physiologically generated ROS function as secondary messengers that can influence tissue homeostasis. The cap'n'collar transcription factor known as nuclear factor erythroid-derived factor 2 (Nrf2) coordinates an evolutionarily conserved transcriptional activation pathway that mediates antioxidant and detoxification responses in many animal species, including insects and mammals. Here, we show that Nrf2-mediated signaling affects embryo survival, midgut homeostasis, and redox biology in , a mosquito species vector of dengue, Zika, and other disease-causing viruses. We observed that AeNrf2 silencing increases ROS levels and stimulates intestinal stem cell proliferation. Because ROS production is a major aspect of innate immunity in mosquito gut, we found that a decrease in Nrf2 signaling results in reduced microbiota growth and Zika virus infection. Moreover, we provide evidence that AeNrf2 signaling also controls transcriptional adaptation of to insecticide challenge. Therefore, we conclude that Nrf2-mediated response regulates assorted gene clusters in that determine cellular and midgut redox balance, affecting overall xenobiotic resistance and vectorial adaptation of the mosquito.

On the use of inhibitors of 4-hydroxyphenylpyruvate dioxygenase as a vector-selective insecticide in the control of mosquitoes

“…A combination of different mechanisms, such as metabolic resistance, mutation of the target proteins and penetration factors (cuticular resistance) contribute to the resistance of insects to contact insecticides. Here we searched for cross-resistance using populations known to be resistant to organophosphates and pyrethroids, where both metabolic resistance (increased expression of detoxifying enzymes) and target-site mutations ( kdr ) are at play [24,25,27–30]. No evidence for cross-resistance to NTBC appeared using oral administration (Figure 4, Table 3), but when using the topical application assays a moderate (3.9 to 5.5 fold) but significant (p<0.001) increase in the LD50 was observed in Santarem, Nova Iguaçu and Oiapoque populations (Figure 5, Table 3).…”

“…aegypti Rockefeller strain (also maintained at FIOCRUZ-RJ), which is commonly used as a standard for insecticide susceptibility assays, was used here as a reference strain, in order to allow better comparison with literature data [26]. RR50 (Resistance rate 50: LD50 of strain or population studied/LD50 of Rockefeller strain) for deltamethrin was: Santarém population = 30.4, Nova Iguaçu population = 25.4, Oiapoque population = 143.9 [27–30]. In the case of Rock-kdr, a knockdown time assay with deltamethrin revealed that the time necessary to knockdown 95% of the Rock-kdr lineage was 6.7x longer than the time found for the Rockefeller susceptible strain [25].…”

Redox state affects fecundity and insecticide susceptibility in Anopheles gambiae

“…The Nrf2 signaling mediates a defense mechanism against oxidative stress 47 . Recently, Nrf2-mediated signaling was shown to play roles in redox biology in Aedes aegypti , affecting embryo survival, midgut redox homeostasis, xenobiotic metabolism and vectoral adaptation 48 . In our study, 6AN significantly and PQ marginally upregulated the transcription of Nrf2 (Fig.…”

Perspectives on mechanistic implications of ROS inducers for targeting viral infections

“…Hence, the administration of antioxidants like Vitamin C, which has been proved to be preventive against viral pneumonia, can serve as an ideal prevention strategy against viral infections; however, ROS induction can be superlative in disease therapy ( Hemilä and Louhiala, 2013 ; Kim et al, 2013 ). Further, there are several host redox and other associated genes which are modulated during a viral infection enabling the viral propagation and pathogenesis as depicted in Table 1 (( Ahmed and Rahman, 2006 ; Bender and Hildt, 2019 ; Bottino-Rojas et al, 2018 ; Checconi et al, 2020 ; Chen et al, 2020a ; Cuadrado et al, 2020 ; Jacoby and Choi, 1994 ; Lee, 2018a ; Simenauer et al, 2019 ; Zhang et al, 2020 ).…”

“… S. No. Redox and other associated genes activated during RNA viral infections Reference 1 Superoxide dismutase 3 (SOD3) ( Ahmed and Rahman, 2006 ) 2 Activating transcription factor 4 (ATF4) 3 Metallothionein 2A (M2TA) 4 Nuclear factor erythroid 2-related factor 2 (NRF-2) ( Bottino-Rojas et al, 2018 ; McCord et al, 2020) 5 Heme oxygenase (HMOX1) ( Cuadrado et al, 2020 ; Singh et al, 2018 ) 6 Sulfiredoxin-1 (SRXN-1) ( Simenauer et al, 2019 ) 7 NADPH quinone dehydrogenase 1 (NQO1) 8 Glutamate cysteine ligase catalytic and regulatory subunits (GCLC and GCLM) ( Lee, 2018a ) 9 Glutathione S-transferase (GST) 10 Uridine diphosphate glucuronosyltransferase (UDPGT) 11 Catalase (CAT) 12 Glucose 6 phosphate dehydrogenase (G6PD) 13 Glutathione peroxidase-1 (GPx) 14 Glutathione disulfide reductase (GSR) Checconi et al (2020) 15 Copper/zinc superoxide dismutase (Cu/ZnSOD) ( Jacoby and Choi, 1994 ) 16 Manganese superoxide dismutase (MnSOD) 17 Indole- amine dioxygenase (IDO) 18 Mel...…”