Evasion of Human Neutrophil-Mediated Host Defense during Toxoplasma gondii Infection

Neutrophils are a major player in host immunity to infection; however, the mechanisms by which human neutrophils respond to the intracellular protozoan parasite Toxoplasma gondii are still poorly understood. In the current study, we found that, whereas primary human monocytes produced interleukin-1beta (IL-1 beta) in response to T. gondii infection, human neutrophils from the same blood donors did not. Moreover, T. gondii inhibited lipopolysaccharide (LPS)-induced IL-1 beta synthesis in human peripheral blood neutrophils. IL-1 beta suppression required active parasite invasion, since heat-killed or mycalolide B-treated parasites did not inhibit IL-1 beta release. By investigating the mechanisms involved in this process, we found that T. gondii infection of neutrophils treated with LPS resulted in reduced transcript levels of IL-1 beta and NLRP3 and reduced protein levels of pro-IL-1 beta, mature IL-1 beta, and the inflammasome sensor NLRP3. In T. gondii-infected neutrophils stimulated with LPS, the levels of MyD88, TRAF6, IKK alpha, IKK beta, and phosphorylated IKK alpha/beta were not affected. However, LPS-induced I kappa B alpha degradation and p65 phosphorylation were reduced in T. gondii-infected neutrophils, and degradation of I kappa B alpha was reversed by treatment with the proteasome inhibitor MG-132. Finally, we observed that T. gondii inhibited the cleavage and activity of caspase-1 in human neutrophils. These results indicate that T. gondii suppression of IL-1 beta involves a two-pronged strategy whereby T. gondii inhibits both NF-kappa B signaling and activation of the NLRP3 inflammasome. These findings represent a novel mechanism of T. gondii evasion of human neutrophil-mediated host defense by targeting the production of IL-1 beta. IMPORTANCE Toxoplasma gondii is 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 acute T. gondii infection, there is limited understanding of how human neutrophils respond to T. gondii. Neutrophils control infectious pathogens by a variety of mechanisms, including the release of the cytokine IL-1 beta, a major driver of inflammation during infection. This study reveals that T. gondii is able to inhibit IL-1 beta production in human neutrophils by impairing the activation of the NF-kappa B signaling pathway and by inhibiting the inflammasome, the protein complex responsible for IL-1 beta maturation. This two-pronged strategy of targeting the IL-1 beta pathway may facilitate the survival and spread of T. gondii during acute infection.