Pan-viral protection against arboviruses by activating skin macrophages at the inoculation site

Abstract

Arthropod-borne viruses (arboviruses) are important human pathogens for which there are no specific antiviral medicines. The abundance of genetically distinct arbovirus species, coupled with the unpredictable nature of their outbreaks, has made the development of virus-specific treatments challenging. Instead, we have defined and targeted a key aspect of the host innate immune response to virus at the arthropod bite that is common to all arbovirus infections, potentially circumventing the need for virus-specific therapies. Using mouse models and human skin explants, we identify innate immune responses by dermal macrophages in the skin as a key determinant of disease severity. Post-exposure treatment of the inoculation site by a topical TLR7 agonist suppressed both the local and subsequent systemic course of infection with a variety of arboviruses from the Alphavirus, Flavivirus, and Orthobunyavirus genera. Clinical outcome was improved in mice after infection with a model alphavirus. In the absence of treatment, antiviral interferon expression to virus in the skin was restricted to dermal dendritic cells. In contrast, stimulating the more populous skin-resident macrophages with a TLR7 agonist elicited protective responses in key cellular targets of virus that otherwise proficiently replicated virus. By defining and targeting a key aspect of the innate immune response to virus at the mosquito bite site, we have identified a putative new strategy for limiting disease after infection with a variety of genetically distinct arboviruses.

A novel antiviral formulation inhibits a range of enveloped viruses

“…Treatment modalities that incorporate ViroSAL to target skin arbovirus infection should be explored further as e.g. treatment of the mosquito bite inoculation site with an immunomodulator has recently been shown to be an effective strategy in suppressing arbovirus infection (Bryden et al, 2020). Moreover, ViroSAL also neutralized measles virus and SARS-CoV-1 pseudovirus infection.…”

“…qPCR primers for SFV amplified a section of E1 and primers for ZIKV amplified a section of the env gene. For SFV and ZIKV, qPCR assays measured the sum value of both genome and subgenomic RNA (Bryden et al, 2020). Each result represents the median of three or four technical replicates of one biological replicate.…”

“…Arboviruses are transmitted to their mammalian hosts via the bite of an insect vector. Given that ViroSAL has optimal activity at a slightly acidic pH, such as that seen on skin and mucosal surfaces, we investigated the effects of ViroSAL treatment on mouse skin following viral inoculation at the site of Aedes aegypti bites, according to previously published protocols (Bryden et al, 2020). Arbovirus replication in the skin at mosquito bites is a key stage of infection during virus replicates rapidly before disseminating to the blood and other tissues (Pingen et al, 2016).…”

“…Arbovirus replication in the skin at mosquito bites is a key stage of infection during virus replicates rapidly before disseminating to the blood and other tissues (Pingen et al, 2016). Previous work has suggested therapeutic targeting this site may be efficacious in reducing severity of infection (Bryden et al, 2020). Here, ZIKV was chosen, as it is a medically important emerging arbovirus, whereas SFV was used as a model virus that replicates efficiently in immunocompetent mice.…”

A novel antiviral formulation inhibits a range of enveloped viruses

“…qPCR primers for SFV amplified a section of E1 and primers for ZIKV amplified a section of the env gene. For SFV and ZIKV, qPCR assays measured the sum value of both genome and subgenomic RNA [27]. Each result represents the median of three or four technical replicates of one biological replicate.…”