Evaluation of cutaneous immune response in a controlled human in vivo model of mosquito bites

Abstract

Mosquito-borne viruses are a growing global threat. Initial viral inoculation occurs in the skin via the mosquito ‘bite’, eliciting immune responses that shape the establishment of infection and pathogenesis. Here we assess the cutaneous innate and adaptive immune responses to controlled Aedes aegypti feedings in humans living in Aedes-endemic areas. In this single-arm, cross-sectional interventional study (trial registration #NCT04350905), we enroll 30 healthy adult participants aged 18 to 45 years of age from Cambodia between October 2020 and January 2021. We perform 3-mm skin biopsies at baseline as well as 30 min, 4 h, and 48 h after a controlled feeding by uninfected Aedes aegypti mosquitos. The primary endpoints are measurement of changes in early and late innate responses in bitten vs unbitten skin by gene expression profiling, immunophenotyping, and cytokine profiling. The results reveal induction of neutrophil degranulation and recruitment of skin-resident dendritic cells and M2 macrophages. As the immune reaction progresses T cell priming and regulatory pathways are upregulated along with a shift to Th2-driven responses and CD8+ T cell activation. Stimulation of participants’ bitten skin cells with Aedes aegypti salivary gland extract results in reduced pro-inflammatory cytokine production. These results identify key immune genes, cell types, and pathways in the human response to mosquito bites and can be leveraged to inform and develop novel therapeutics and vector-targeted vaccine candidates to interfere with vector-mediated disease.

Aedes albopictusis not an arbovirus aficionado – Impacts of sylvatic flavivirus infection in vectors and hosts on mosquito engorgement on non-human primates

“…albopictus . Future experiments could pursue skin biopsies to investigate the immediate mobilization of these cytokines following a mosquito bite [58].…”

Neutrophil Extracellular Traps Formation: Effect of Leishmania major promastigotes and salivary gland homogenates of Phlebotomus papatasi in human neutrophil culture

“…On the other hand, the effect of arthropod's saliva on the accumulation of neutrophils was stated and interestingly the induction of neutrophil degranulation was proved after Aedes aegypti and Hyalomma anatolicum bites. Although it has not been proven for sand ies saliva but SGH may be capable of stimulating neutrophils towards degranulation rather than having the ability to induce NETosis, although it needs further investigations to be elucidated [55] [56].…”

Functional heterogeneity of human skin‐resident memory T cells in health and disease

“…119 Similarly, in Aedes aegypti bites, mosquito saliva suppressed proinflammatory responses, resulting in regulatory T cells and Th2 polarization in the skin. 120 In clearance of infection and in wound healing, tissue-resident T regs come into action: Directly following barrier breach, skinresident T regs initially promote inflammation at the keratinocyte layer. 121 In burn injury, skin T-cell populations shift from a resident phenotype to a circulating homing marker profile.…”

“…This results in increased transmission of Borrelia burgdorferi in transmission by tick vectors 119 . Similarly, in Aedes aegypti bites, mosquito saliva suppressed pro‐inflammatory responses, resulting in regulatory T cells and Th2 polarization in the skin 120 …”