Aedes aegypti sialokinin facilitates mosquito blood feeding and modulates host immunity and vascular biology

Martín-Martín, Inés; Valenzuela-León, Paola Carolina; Amo, Laura; Shrivastava, Gaurav; Iniguez, Eva; Aryan, Azadeh; Brooks, Steven; Kojin, Bianca Burini; Williams, Adeline E; Bolland, Silvia; Ackerman, Hans; Adelman, Zach N.; Calvo, Eric

doi:10.1016/j.celrep.2022.110648

Cited by 18 publications

(14 citation statements)

References 70 publications

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“…As tachykinins are known immunomodulatory proteins [34], we hypothesized that sialokinin would be immunomodulatory as well. Previous studies using the same sialokinin knockout mosquitoes as used in our study demonstrated that total leukocytes, neutrophils, and CD8+ T cells were decreased in footpads of mosquito bitten BALB/c mice [37]. These data further support our findings that sialokinin has an immunomodulatory effect and alters immune cell recruitment.…”

Section: Plos Neglected Tropical Diseasessupporting

confidence: 91%

“…Two sialokinin knockout Ae. aegypti (Liverpool) mosquito lines were created by using the CRISPR/Cas9 system and donated by the Adelman and Calvo laboratories [37]. The sialokinin d5 knockout line has a 5 base pair insertion, while the knockout line sialokinin d8 has an 8 base pair deletion.…”

Section: Mosquito Rearingmentioning

confidence: 99%

“…Both knockout lines were homozygous and contain frameshift mutations that resulted in premature stop codons. Sialokinin knockouts were verified via mass spectrometry and immunofluorescence for the presence of sialokinin in the saliva and salivary glands, respectively [37]. Our laboratory received sialokinin knockout mosquito lines as eggs and were reared in the same manner as wild-type mosquitoes.…”

Section: Mosquito Rearingmentioning

confidence: 99%

“…All of the mouse studies of mosquito saliva effects reported previously have used mice that differ from human immune systems: AG129 (which lack type I and type II IFN receptors), BALB/c mice (which are predisposed to T H 2 immune responses), C57BL/6 mice (which are predisposed to T H 1 immune responses), C3H/HeJ (which have a B cell deficiency), and C3H/ PRI-Flv r (which are resistant to flavivirus infection) [36,37,47,48,[51][52][53][54]. The humanized mouse model used in this study does not have the same limitations as previous models because these mice have been reconstituted with a human immune system, including innate immunity [55].…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

“…When injected into C3H/HeJ mice, sialokinin decreased production of T H 1 cytokines and increased production of T H 2 cytokines by mouse splenocytes [36]. Recent studies have also shown that sialokinin enhances arboviral infection by modulating endothelial barrier function and altering immune cell recruitment to the bite site [33,37]. However, these studies were performed in wild-type C57BL/6 and BALB/c mice and gave limited insight on human immune responses.…”

Section: Introductionmentioning

confidence: 99%

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Sialokinin in mosquito saliva shifts human immune responses towards intracellular pathogens

et al. 2023

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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.

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Section: Plos Neglected Tropical Diseasessupporting

confidence: 91%

Section: Mosquito Rearingmentioning

confidence: 99%

Section: Mosquito Rearingmentioning

confidence: 99%