UC Irvine

Toxoplasma gondii is a pathogen of global importance. Innate immunity is critical for control of acute infection. In vivo mouse models have shown that monocytes are rapidly recruited to sites of T. gondii infection and MCP-1 and CCR2 knock-out mice that fail to do so succumb to infection, underscoring the importance of monocytes in host defense. However, the role of human monocytes in immunity to T. gondii and their specific interactions with T. gondii are not well understood.

Human monocytes are actively infected by T. gondii and permissive to parasite replication. Infected human monocytes release interleukin-1beta (IL-1beta), a "master regulator" of inflammation that has been shown to be protective against T. gondii in vivo. However, the host and parasite factors regulating T. gondii-induced IL-1beta production in human monocytes were unknown. We found that T. gondii induces IL-1beta transcript, post-translational processing, and release from human monocytes. We demonstrate a role for host inflammasome components caspase-1 and ASC and the parasite protein GRA15 in the induction and release of IL-1beta. This work provides important mechanistic insight into the regulation of a key mediator of inflammation and is the first to identify a T. gondii factor that drives innate immune responses in human cells.

Recently, there has been increasing appreciation for the heterogeneity of circulating monocytes. Three phenotypically and functionally distinct subpopulations have been defined in humans based on CD14 and CD16 expression. However, the interactions of specific monocyte subsets with T. gondii and their functional outcomes have not been elucidated. We found that T. gondii preferentially invades classical (CD14+CD16-) and intermediate (CD14+CD16+) monocytes and that these subsets are more permissive to intracellular parasite survival. All monocyte subsets were capable of phagocytosing and degrading Mycalolide B-treated parasites. T. gondii infection induces IL-1beta in all three monocyte subsets, but the resident monocytes (CD14loCD16+) showed an enhanced IL-1beta response. These data suggest that resident monocytes are less permissive to infection and may play a critical role in parasite control.

Collectively, our work defines host and parasite pathways driving innate immunity and contributes to a better understanding of the role of human monocytes in parasite control.