Human cutaneous responses to arthropod-mediated viral transmission

SUMMARY Arthropod-borne viruses (ABV), such as Zika virus (ZIKV), Dengue virus (DENV) and tick-borne viruses (TBV) are responsible for major health and economic concerns worldwide. ABV are transmitted to humans through the bites of infected arthropods, mainly mosquitoes and ticks. Upon mosquito bite, mosquito saliva triggers specific cutaneous immune responses that foster effective ABV transmission and systemic dissemination. However, our understanding of how mosquito feeding remodels skin responses to favor ABV transmission has been significantly hindered by the lack of animal models that accurately mimic human cutaneous responses to natural ABV transmission, impeding the development of antiviral countermeasures against ABV. While routinely used in infectious disease and immunology research because of their cost-effectiveness and amenability to genetic manipulations, mice harbor significant immunological and cutaneous differences from humans that hamper their use in uncovering mechanisms of ABV transmission. Indeed, the human and mouse immune systems display critical functional differences, and the human and mouse skins are structurally distinct. Mice reconstituted with a human immune system (HIS mice) have been shown to be permissive to ABV infection and mount human-like immune responses to these viruses. However, these models have remained poorly permissive to ABV infection due to the limited crosstalk between the mouse epithelium/stromal and human hematopoietic compartments in the skin, their low human myeloid engraftment, and the absence of functional lymph node structure. In this proposal, we aim to address these limitations and develop a novel mouse model of ABV transmission co-engrafted with a functional human immune system (HIS) and autogenic human skin organoids (HSO). We hypothesize that this model, referred to as SKIN mouse, recapitulates key cutaneous events defining effective mosquito-mediated ABV transmission to humans. In Aim 1, we will define the ability of SKIN mice to recapitulate human cutaneous responses to mosquito feeding, using human volunteer data as a benchmark. In Aim 2, we will demonstrate that SKIN mice support effective ZIKV transmission in a mosquito-feeding-dependent manner, and we will map the specific human cutaneous responses associated with this process. This project will generate unique insights into how mosquito feeding remodels human cutaneous responses to ABV to favor effective viral transmission and systemic dissemination. Our work will also provide an instrumental platform to the biomedical research community to dissect key cutaneous processes defining the transmission and pathogenesis of many arthropod-borne diseases relevant to the NIH's mission, from arboviral diseases to arthropod-mediated bacterial diseases (e.g., Lyme disease) and autoimmune disorders. By opening such avenues, this project will prove instrumental for the development and/or evaluation of preventive clinical strategies against these diseases.