Research ArticleEMERGING INFECTIONS

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

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Science Translational Medicine  22 Jan 2020:
Vol. 12, Issue 527, eaax2421
DOI: 10.1126/scitranslmed.aax2421

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Taking the bite out of vector-borne infections

Arthropods are the most abundant animals on Earth and can transmit a variety of diseases such as dengue or West Nile virus to humans. To broadly combat these infections, Bryden et al. investigated whether the immune reaction at the site of mosquito bites could be manipulated to restrict viral dissemination. They observed that local TLR7 activation shortly after infection dampened replication of a model alphavirus in mice. This held true for clinically relevant arboviruses and also in human skin explants. The viral restriction was due to activation of skin macrophages and heightened type I interferon production. Topical TLR7 activation after mosquito bites could be a broad-acting approach to abrogate arboviruses.

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.

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