Abstract
Innate immune cells quickly infiltrate the site of pathogen entry and not only stave off infection but also initiate antigen presentation and promote adaptive immunity. The recruitment of innate leukocytes has been well studied in the context of extracellular bacterial and fungal infection but less during viral infections. We have recently shown that the understudied cytokine Interleukin (IL)-17D can mediate neutrophil, natural killer (NK) cell and monocyte infiltration in sterile inflammation and cancer. Herein, we show that early immune cell accumulation at the peritoneal site of infection by mouse cytomegalovirus (MCMV) is mediated by IL-17D. Mice deficient in IL-17D or the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an inducer of IL-17D, featured an early decreased number of innate immune cells at the point of viral entry and were more susceptible to MCMV infection. Interestingly, we were able to artificially induce innate leukocyte infiltration by applying the Nrf2 activator tert-butylhydroquinone (tBHQ), which rendered mice less susceptible to MCMV infection. Our results implicate the Nrf2/IL-17D axis as a sensor of viral infection and suggest therapeutic benefit in boosting this pathway to promote innate antiviral responses.
Highlights
Cytomegaloviruses (CMVs) are herpesviruses that can cause fatal disease in their respective hosts
We previously showed that mice lacking IL-17D are mildly more susceptible to mouse cytomegalovirus (MCMV) infection[15], as measured by weight loss
Glycoprotein B of cDNA converted from total mRNA (Fig. 1b left, expressed as fold change compared to WT mice); 2) qPCR of the viral gene Immediate early 1 (IE1) performed on total cellular DNA with viral copy number calculated from a standard curve as read-out (Fig. 1b, middle, expressed as fold change compared to WT mice) and 3) viral plaque assays (Fig. 1b right, expressed as absolute plaque forming units/mg organ)
Summary
Cytomegaloviruses (CMVs) are herpesviruses that can cause fatal disease in their respective hosts. It is established that infiltration of leukocytes to local sites of pathogen entry involves cytokine and chemokine production by resident or early-recruited cells. CCL2 has been established as a central mediator for recruiting macrophages and NK cells to MCMV-infected sites[14]. GB gene expression is expressed as fold change relative to expression in MCMV-infected WT mice for each organ. The amount of viral copies is expressed as fold change compared to MCMV-infected WT mice for each organ. (a,b), left) Representative of three independent experiments with n = 5 or 6 mice per group. (b), right) Representative of two independent experiments with n = 4 or 5 mice per group. (d,e) Representative of three independent experiments with n = 5 mice in each group. Activating Nrf[2] with the agonist tert-butylhydroquinone (tBHQ) induced IL-17D in vitro and in vivo and led to NK cell-mediated tumor rejection in vivo[15]
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