The CYP4G15-SORD-like-associated pathway promotes ovarian ZIKV infection and egg-associated viral RNA detection in Aedes albopictus.

Zika virus (ZIKV) can persist in mosquito populations through both horizontal and vertical transmission, and successful ovarian infection is a prerequisite for transgenerational spread. However, the mosquito host factors that regulate ovarian permissiveness and vertical transmission remain poorly characterized. Here, we investigated the role of cytochrome P450 4G15 (CYP4G15) in ZIKV infection and vertical transmission in Aedes albopictus and identified an associated downstream pathway involving SORD-like, a predicted sorbitol dehydrogenase-like gene. Expression profiling revealed that CYP4G15 exhibits distinct tissue-, developmental-, blood-feeding-, and infection-responsive patterns, with transient induction in ovaries during the early phase of ZIKV infection. RNA interference-mediated silencing of CYP4G15, followed by transcriptomic analysis and RT-qPCR validation, identified SORD-like (LOC109415972) as a candidate CYP4G15-associated gene. SORD-like was highly expressed in the fat body, strongly induced after blood feeding, and responsive to ZIKV challenge in ovarian tissues. Functional assays showed that knockdown of SORD-like significantly reduced early ovarian infection rate and viral RNA accumulation, while also decreasing conditional progeny egg-pool positivity rate and minimum egg infection rate, indicating reduced ZIKV RNA detection in progeny egg pools. SORD-like silencing did not alter CYP4G15 transcript levels, whereas CYP4G15 overexpression was associated with increased SORD-like transcript abundance and functionally compensated for the ovarian viral RNA phenotype caused by SORD-like knockdown. Together, these findings support a functional association between CYP4G15, SORD-like, and ovarian ZIKV infection, but do not establish direct transcriptional regulation or a strict linear epistatic relationship. Our findings reveal a CYP4G15-SORD-like-associated metabolic-regulatory pathway that links mosquito physiology to arbovirus persistence. Given that CYP4G-related pathways are often associated with environmental adaptation and insecticide resistance-associated physiology, this pathway may represent an important point of intersection between vector fitness and viral transmission. It may therefore serve as a candidate target for reducing egg-associated ZIKV RNA detection and ZIKV maintenance in Aedes albopictus populations.