Inhibition of an Aquatic Rhabdovirus Demonstrates Promise of a Broad-Spectrum Antiviral for Use in Aquaculture

Abstract

Many enveloped viruses cause devastating disease in aquaculture, resulting in significant economic impact. LJ001 is a broad-spectrum antiviral compound that inhibits enveloped virus infections by specifically targeting phospholipids in the lipid bilayer via the production of singlet oxygen ( 1 O 2 ). This stabilizes positive curvature and decreases membrane fluidity, which inhibits virus-cell membrane fusion during viral entry. Based on data from previous mammalian studies and the requirement of light for the activation of LJ001, we hypothesized that LJ001 may be useful as a preventative and/or therapeutic agent for infections by enveloped viruses in aquaculture. Here, we report that LJ001 was more stable with a prolonged inhibitory half-life at relevant aquaculture temperatures (15°C), than in mammalian studies at 37°C. When LJ001 was preincubated with our model virus, infectious hematopoietic necrosis virus (IHNV), infectivity was significantly inhibited in vitro (using the epithelioma papulosum cyprini [EPC] fish cell line) and in vivo (using rainbow trout fry) in a dose-dependent and time-dependent manner. While horizontal transmission of IHNV in a static cohabitation challenge model was reduced by LJ001, transmission was not completely blocked at established antiviral doses. Therefore, LJ001 may be best suited as a therapeutic for aquaculture settings that include viral infections with lower virus-shedding rates than IHNV or where higher viral titers are required to initiate infection of naive fish. Importantly, our data also suggest that LJ001-inactivated IHNV elicited an innate immune response in the rainbow trout host, making LJ001 potentially useful for future vaccination approaches.IMPORTANCE Viral diseases in aquaculture are challenging because there are few preventative measures and/or treatments. Broad-spectrum antivirals are highly sought after and studied because they target common components of viruses. In our studies, we used LJ001, a broad-spectrum antiviral compound that specifically inhibits enveloped viruses. We used the fish rhabdovirus infectious hematopoietic necrosis virus (IHNV) as a model to study aquatic enveloped virus diseases and their inhibition. We demonstrated inhibition of IHNV by LJ001 both in cell culture as well as in live fish. Additionally, we showed that LJ001 inhibited the transmission of IHNV from infected fish to healthy fish, which lays the groundwork for using LJ001 as a possible therapeutic for aquatic viruses. Our results also suggest that virus inactivated by LJ001 induces an immune response, showing potential for future preventative (e.g., vaccine) applications.

Small Molecule Inhibitors of White Spot Syndrome Virus: Promise in Shrimp Seedling Culture

“…To address the negative effects of C2 and C7 during the WSSV infection cycle, the virus was pre-incubated with the compounds for 1–4 h prior to infection of larvae ( Figure 4 ).The results showed a suppressed WSSV infection ( Figure 4 B) and increased the survival rate by up to 40% ( Figure 4 C,D). Based on the findings of previous studies [ 17 , 33 , 40 ], we consider that C2 and C7 may have a direct influence on the infectivity of WSSV virion particles, rather than on the host’s receptor protein, to block virus infection in the early stage. This therefore provides insight into the properties of coumarin products required for anti-WSSV therapeutic inhibitors and for vaccine development.…”

Method for serial passage of infectious hematopoietic necrosis virus (IHNV) in rainbow trout

“…Although previous groups have investigated IHNV transmission during cohabitation, our method differed in several important ways. Perhaps the most notable difference is that previous studies have used a design in which large groups of fish are cohabitated for long periods of time (Amend 1975, Mulcahy et al 1983, Traxler et al 1993, Ogut & Reno 2004b, Balmer et al 2017. Given the acute nature of IHNV transmission, nu merous rounds of transmission back and forth be tween donor and recipient fish likely occurred in these previous studies, making it impossible to determine the original source of transmission.…”

Hydroxycoumarin efficiently inhibits spring viraemia of carp virus infection <i>in vitro</i> and <i>in vivo</i>

“…Natural SVCV infection stimulates a robust early innate response, followed by a long-term specific immune response that is dependent on water temperature, virus dose, virus strain, and other host/virus factors ( Balmer et al, 2017 ; Wang et al, 2017 ; Wei et al, 2016 ). As the first line of defense against pathogens, the response of the innate immune system to SVCV infection is mainly mediated by interferons (IFNs) and IFN-induced proteins during the middle and late period of infection ( Adamek et al, 2012 ; Forlenza et al, 2008 ).…”