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

• Published in: mBio 2018-02, Vol.9 (1)
• Main Authors: Lima, Tatiane S, Gov, Lanny, Lodoen, Melissa B
• Format: Article
• Language: English
• Subjects: Cells, Cultured; Healthy Volunteers; Humans; Immune Evasion; Immunologic Factors - metabolism; Interleukin-1beta - metabolism; Monocytes - immunology; Neutrophils - immunology; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Toxoplasma - immunology; Toxoplasmosis - immunology
• ISSN: 2161-2129; 2150-7511
• DOI: 10.1128/mBio.02027-17

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