Lei Liu

Infectious disease in aquaculture is shaped by interactions among pathogens, hosts and the surrounding environment. Temperature, salinity and other physicochemical conditions are established modifiers of several aquatic diseases, whereas environmental contaminants have been studied predominantly for their direct toxic effects. Whether contaminant exposure also alters subsequent infection has received much less integrated attention. We critically evaluate evidence linking environmental contaminants with viral, bacterial and parasitic infections in aquatic animals, while using established physicochemical stressors as a reference framework. Direct challenge studies show that pesticides, persistent organic contaminants, microplastics, mycotoxins and other pollutants can alter pathogen replication, infection severity or infection‐associated mortality in specific host–pathogen systems. Several studies report altered infection outcomes after sublethal exposure despite limited or absent mortality, growth impairment or overt cytotoxicity before pathogen challenge. Pathogen challenge can therefore reveal functional effects of contaminant exposure that may be missed by conventional apical toxicity endpoints. However, the relationship is not uniform. Null, non‐monotonic and occasionally protective effects have also been reported, and most direct evidence remains confined to laboratory studies in fish and shrimp. Evidence for transmission, commercial production systems, molluscs and parasitic diseases is comparatively scarce. Environmental contaminants should therefore be regarded as context‐dependent modifiers of infectious‐disease risk rather than universal causes of disease outbreaks. Where contaminant‐associated susceptibility is demonstrated, disease control may need to address both the relevant contaminant exposure and the pathogen. This evidence supports exploring dual‐function interventions that restore or mitigate contaminant‐induced host dysfunction while directly inhibiting the pathogen.

Spring viremia of carp virus (SVCV) poses a major threat to carp aquaculture due to the lack of effective antiviral strategies. This study investigates the antiviral potential of baicalin in epithelioma papulosum cyprini (EPC) cells and zebrafish. Baicalin exhibits antiviral activity during both pretreatment and post-infection treatment and shows direct virucidal activity during virus–compound co-incubation. Moreover, baicalin alleviated oxidative stress, preserved mitochondrial function, and reduced apoptosis in infected cells. Proteomic analyses revealed that baicalin suppressed SVCV replication by modulating the AMPK/mTOR signaling pathway, as evidenced by decreased AMPK phosphorylation, increased mTOR phosphorylation, and subsequent inhibition of autophagy. These findings demonstrate that baicalin significantly suppresses SVCV replication and is associated with modulation of the AMPK/mTOR-mediated autophagy pathway. These findings identify baicalin as a promising antiviral candidate against SVCV and provide a foundation for further evaluation in economically important aquaculture species.

Spring viremia of carp virus (SVCV), an aquatic rhabdovirus, causes lethal disease and major economic losses in carp aquaculture, yet no licensed antivirals are available. In this study, we identify the plant-derived diterpenoid quinone cryptotanshinone (CPT) as a potent inhibitor of SVCV that acts by inhibiting clathrin-mediated endocytosis (CME) and attenuating early mitochondrial apoptosis. CPT was well tolerated by epithelioma papulosum cyprinid cells (50% cytotoxic concentration [CC ₅₀ ] = 303.2 µM) and suppressed SVCV replication in a dose-dependent manner (50% inhibitory concentration [IC ₅₀ ] = 3.2 µM), reducing nucleoprotein (SVCV- N ) gene expression and infectious virion production by >99% at 16 μM. Time-of-addition/removal and virion pre-incubation assays revealed that CPT acts predominantly at early entry or early post-entry steps: CPT did not impair viral attachment but selectively blocked internalization, causing DiO-labeled SVCV particles to remain trapped at the plasma membrane. Mechanistically, CPT inhibited CME, as evidenced by reduced transferrin uptake and redistribution of clathrin heavy chain from the cytosol to the cell surface. CPT also preserved mitochondrial integrity by limiting Bcl-2-associated X protein translocation, cytochrome c release, and caspase-9/3 activation. In vivo , therapeutic bath treatment with 4 μM CPT significantly lowered viral loads, decreased cumulative mortality, and reduced horizontal transmission in juvenile common carp, whereas prophylactic oral CPT primed type I interferon and interferon-stimulated gene expression, and markedly improved survival after SVCV challenge. Together, these findings define CME-dependent internalization as a druggable entry checkpoint for an aquatic rhabdovirus and highlight CPT as a promising antiviral lead for integrated control of SVCV. IMPORTANCE: Viral diseases are a major bottleneck to sustainable aquaculture, yet most control strategies still depend on husbandry and culling rather than on mechanism-based antiviral therapy. For spring viremia of carp virus (SVCV), a notifiable rhabdovirus of global concern, it remains unclear whether host entry pathways in fish are realistically “druggable” and how small molecules can be integrated into practical farm interventions. Here, we use cryptotanshinone (CPT) as a chemical probe to demonstrate that clathrin-mediated endocytosis in fish cells can be selectively perturbed to block SVCV internalization, and that this strategy is compatible with immersion and oral delivery in juvenile carp. At the same time, CPT reshapes host responses by stabilizing mitochondrial function and sustaining antiviral signaling, thereby linking a defined entry pathway to cell-death control and innate immunity in vivo . These findings open a conceptual route toward host-targeted, entry-focused antivirals for aquatic rhabdoviruses and provide a translational framework for developing environmentally compatible antivirals in aquaculture.

Environmental pollutants are increasingly recognized as disease modifiers, reshaping host homeostasis and shifting host-pathogen dynamics toward higher infection risk in aquatic ecosystems. Here, we show that the widely used strobilurin fungicide trifloxystrobin (TFS) persistently erodes antiviral competence in fish and increases susceptibility to spring viremia of carp virus (SVCV) by driving dynamin-related protein 1 (Drp1)-mediated excessive mitophagy and sustained mitochondrial dysfunction. Using epithelioma papulosum cyprini (EPC) cells and zebrafish as complementary models, we find that environmentally plausible TFS exposures (2.5–25 μg/L) elevate SVCV permissiveness; notably, this phenotype resolves incompletely after chemical withdrawal. Transcriptomics revealed a dose-concordant shift toward stress/innate immune signaling and mitophagy programs, alongside broad repression of proliferative and DNA-repair pathways. Consistently, TFS induces persistent mitochondrial membrane depolarization, promotes fragmentation and ultrastructural deterioration, and increases mitochondria–lysosome coupling. Mechanistically, TFS elevates Drp1 abundance and Ser616 phosphorylation, promotes Drp1 recruitment to mitochondria, and sustains microtubule-associated protein 1 light chain 3B (LC3B)/lysosomal-associated membrane protein 2 (LAMP2) engagement, accompanied by persistent induction of core autophagy regulators ( gabarap , atg5 , wipi1 , and ambra1 ) across extended recovery windows. In vivo , prolonged TFS exposure similarly yields durable enhancement of SVCV susceptibility even after long recovery periods, indicating incomplete restoration of host resistance. Together, these findings link a major agricultural fungicide to persistent Drp1-driven mitophagy overactivation and identify long-term antiviral resistance as an ecologically relevant endpoint for pesticide risk assessment and aquatic disease forecasting. IMPORTANCE: Viral diseases pose a significant challenge to sustainable aquaculture, and effective antiviral interventions remain limited. In this study, we reveal that trifloxystrobin, a widely used fungicide, induces mitochondrial dysfunction and Drp1-mediated excessive mitophagy, leading to long-term suppression of antiviral immune responses in fish. Importantly, this work identifies mitochondrial dynamics as a key determinant of viral susceptibility and demonstrates how environmental pollutants can reshape host-pathogen interactions. By linking mitophagy and Drp1 activation to increased spring viremia of carp virus susceptibility, our findings provide a novel perspective on how pollutants may exacerbate viral infections in aquaculture species. This work underscores the urgent need for ecosystem-based antiviral strategies and offers a mechanistic framework for assessing ecological risks posed by common agricultural chemicals, thereby informing environmental and disease management in aquaculture.

Spring viremia of carp virus (SVCV) is a significant pathogen that has notably hindered the advancement of cyprinid aquaculture in recent years. Infections caused by SVCV are often associated with substantial economic losses due to the absence of effective treatment options. Previous reports indicated that N-(4-methyl-2-oxo-2H-chromen-7-yl) benzenesulfonamide (N6) exhibits inhibitory effects on SVCV proliferation. This study aims to comprehensively evaluate the anti-SVCV effects of N6 using healthy young carp as the experimental model. The research investigates the antiviral activity of this compound in vivo, the immune response of interferon (IFN)-related genes, its impact on the horizontal transmission of SVCV, and histopathological changes. The results indicate that N6 significantly inhibits SVCV infectivity and apoptosis in EPC cells in vitro. Furthermore, while N6 reduced horizontal transmission of SVCV in a static cohabitation challenge model, the N6-treated SVCV-infected group showed a nearly 3-fold decrease in viral load compared to the control group, it did not completely prevent transmission at established antiviral dosages. Histopathological analysis of the affected fish revealed that N6 effectively mitigated tissue damage induced by SVCV. Additionally, the up-regulation of six IFN-related genes suggests that N6 may indirectly activate IFNs to facilitate the clearance of SVCV in the kidney and spleen, as demonstrated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). These findings provide a foundation for further investigations into the mechanisms by which N6 acts against SVCV and may aid in the development of novel anti-SVCV therapeutics.