Citation

Neutrophils are a major player in host immunity to infection; however, the mechanisms by which human neutrophils respond to the intracellular protozoan parasiteToxoplasma gondiiare still poorly understood. In the current study, we found that, whereas primary human monocytes produced interleukin-1beta (IL-1) in response toT. gondiiinfection, human neutrophils from the same blood donors did not. Moreover,T. gondiiinhibited lipopolysaccharide (LPS)-induced IL-1 synthesis in human peripheral blood neutrophils. IL-1 suppression required active parasite invasion, since heat-killed or mycalolide B-treated parasites did not inhibit IL-1 release. By investigating the mechanisms involved in this process, we found thatT. gondiiinfection of neutrophils treated with LPS resulted in reduced transcript levels ofIL-1andNLRP3and reduced protein levels of pro-IL-1, mature IL-1, and the inflammasome sensor NLRP3. InT. gondii-infected neutrophils stimulated with LPS, the levels of MyD88, TRAF6, IKK, IKK, and phosphorylated IKK/ were not affected. However, LPS-induced IB degradation and p65 phosphorylation were reduced inT. gondii-infected neutrophils, and degradation of IB was reversed by treatment with the proteasome inhibitor MG-132. Finally, we observed thatT. gondiiinhibited the cleavage and activity of caspase-1 in human neutrophils. These results indicate thatT. gondiisuppression of IL-1 involves a two-pronged strategy wherebyT. gondiiinhibits both NF-B signaling and activation of the NLRP3 inflammasome. These findings represent a novel mechanism ofT. gondiievasion of human neutrophil-mediated host defense by targeting the production of IL-1.IMPORTANCEToxoplasma gondiiis an obligate intracellular parasite that infects approximately one-third of humans worldwide and can invade virtually any nucleated cell in the human body. Although it is well documented that neutrophils infiltrate the site of acuteT. gondiiinfection, there is limited understanding of how human neutrophils respond toT. gondiiNeutrophils control infectious pathogens by a variety of mechanisms, including the release of the cytokine IL-1, a major driver of inflammation during infection. This study reveals thatT. gondiiis able to inhibit IL-1 production in human neutrophils by impairing the activation of the NF-B signaling pathway and by inhibiting the inflammasome, the protein complex responsible for IL-1 maturation. This two-pronged strategy of targeting the IL-1 pathway may facilitate the survival and spread ofT. gondiiduring acute infection. Copyright 2018 Lima et al.