Sialokinin in mosquito saliva shifts human immune responses towards intracellular pathogens

Abstract

Mosquito saliva is a mix of numerous proteins that are injected into the skin while the mosquito searches for a blood meal. While mosquito saliva is known to be immunogenic, the salivary components driving these immune responses, as well as the types of immune responses that occur, are not well characterized. We investigated the effects of one potential immunomodulatory mosquito saliva protein, sialokinin, on the human immune response. We used flow cytometry to compare human immune cell populations between humanized mice bitten by sialokinin knockout mosquitoes or injected with sialokinin, and compared them to those bitten by wild-type mosquitoes, unbitten, or saline-injected control mice. Humanized mice received 4 mosquito bites or a single injection, were euthanized after 7 days, and skin, spleen, bone marrow, and blood were harvested for immune cell profiling. Our results show that bites from sialokinin knockout mosquitoes induced monocyte and macrophage populations in the skin, blood, bone marrow, and spleens, and primarily affected CD11c- cell populations. Other increased immune cells included plasmacytoid dendritic cells in the blood, natural killer cells in the skin and blood, and CD4+ T cells in all samples analyzed. Conversely, we observed that mice bitten with sialokinin knockout mosquitoes had decreased NKT cell populations in the skin, and fewer B cells in the blood, spleen, and bone marrow. Taken together, we demonstrated that sialokinin knockout saliva induces elements of a TH1 cellular immune response, suggesting that the sialokinin peptide is inducing a TH2 cellular immune response during wild-type mosquito biting. These findings are an important step towards understanding how mosquito saliva modulates the human immune system and which components of saliva may be critical for arboviral infection. By identifying immunomodulatory salivary proteins, such as sialokinin, we can develop vaccines against mosquito saliva components and direct efforts towards blocking arboviral infections.

Aedes aegypti salivary extracts exert immunomodulatory effects onmacrophages, dendritic cells, and T lymphocytes and increase Zikavirus production in vitro.

“…The modulation of the Th1/Th2 cytokine balance by mosquito saliva has been investigated (41,42). These studies suggest that mosquito saliva can in uence the cytokine milieu of APCs and impact the polarization of T-cell responses (41,42). Our study aligns with these ndings, demonstrating that Ae.…”

“…Our study aligns with these ndings, demonstrating that Ae. aegypti salivary glands can in uence the Th1/Th2 cytokine polarization in PBMCs during ZIKV infection (42). The changes in IL-4 and IFN-γ levels suggest mosquito saliva could contribute to the modulation of T cell responses, potentially affecting the outcome of viral infections.…”

“…aegypti salivary glands drive a shift towards Th2 polarization, as evidenced by the observed changes in this ratio. The modulation of the Th1/Th2 cytokine balance by mosquito saliva has been investigated (41,42). These studies suggest that mosquito saliva can in uence the cytokine milieu of APCs and impact the polarization of T-cell responses (41,42).…”

Aedes albopictus salivary adenosine deaminase is an immunomodulatory factor facilitating dengue virus replication

“…Therefore, a comprehensive understanding of the interaction between these cells, arbovirus, and mosquito saliva is important for developing strategies to combat mosquito-borne diseases. However, there are only a handful of studies investigating the interactions between certain salivary proteins and these cells 46 , particularly in Ae. albopictus .…”

The Dynamic Relationship between Dengue Virus and the Human Cutaneous Innate Immune Response

“…While the primary function of mosquito saliva is to facilitate bloodmeals, studies have revealed that it has immunomodulatory properties that inadvertently enhance infection of arboviruses in the skin. Sialokinin has been shown to influence cutaneous innate immunity by shifting from a T H 1-mediated, antiviral cellular response to a T H 2mediated humoral response [59]. While it is thought that this evolved in humans to induce tissue repair and prevent infection by opportunistic extracellular pathogens, it does create an ideal environment for viruses to infect.…”