Abstract

Innate recognition of invading intracellular pathogens is essential for regulating robust and rapid CD4+ T cell effector function, which is critical for host-mediated immunity. The intracellular apicomplexan parasite, Toxoplasma gondii, is capable of infecting almost any nucleated cell of warm-blooded animals, including humans, and establishing tissue cysts that persist throughout the lifetime of the host. Recognition of T. gondii by TLRs is essential for robust IL-12 and IFN-γ production, two major cytokines involved in host resistance to the parasite. In the murine model of infection, robust IL-12 and IFN-γ production have been largely attributed to T. gondii profilin recognition by the TLR11 and TLR12 heterodimer complex, resulting in Myd88-dependent IL-12 production. However, TLR11 or TLR12 deficiency failed to recapitulate the acute susceptibility to T. gondii infection seen in Myd88-/- mice. T. gondii triggers inflammasome activation in a caspase-1-dependent manner resulting in cytokine release; however, it remains undetermined if parasite-mediated inflammasome activation impacts IFN-γ production and host resistance to the parasite. Using mice which lack different inflammasome components, we observed that the inflammasome played a limited role in host resistance when TLR11 remained functional. Strikingly, in the absence of TLR11, caspase-1 and -11 played a significant role for robust CD4+ TH1-derived IFN-γ responses and host survival. Moreover, we demonstrated that in the absence of TLR11, production of the caspase-1-dependent cytokine IL-18 was sufficient and necessary for CD4+ T cell-derived IFN-γ responses. Mechanistically, we established that T. gondii-mediated activation of the inflammasome and IL-18 were critical to maintain robust CD4+ TH1 IFN-γ responses during parasite infection in the absence of TLR11.

Highlights

  • Toxoplasma gondii is an obligate intracellular apicomplexan parasite capable of infecting most nucleated cells of warm-blooded animals, including humans, resulting in persistent cysts residing within the skeletal muscle, cardiac tissue, and brain [1,2,3]

  • Parasite recognition by Toll-like receptors (TLRs) is critical for IL-12 production by dendritic cells (DCs), which is critical for a rapid and robust CD4+ T helper 1 (TH1) response leading to production of IFN-γ [7,8,9,10]

  • TLR11-independent mechanisms of T. gondii recognition required for establishing T cell immunity are largely unknown; several recent studies including our own have suggested that CCL2-mediated recruitment of monocytes and the inflammasome-dependent release of mature IL-1β and IL-18 represent the initial steps in driving a TLR11-independent protective immunity to the parasite [24,25,26,27,28]

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Summary

Introduction

Toxoplasma gondii is an obligate intracellular apicomplexan parasite capable of infecting most nucleated cells of warm-blooded animals, including humans, resulting in persistent cysts residing within the skeletal muscle, cardiac tissue, and brain [1,2,3]. A detailed understanding of the cellular and molecular mechanisms responsible for host resistance against T. gondii has been well-established in murine infection models [6]. Robust IL-12 production during mouse infection is largely attributed to direct recognition of T. gondii profilin by TLR11 which forms a heterodimer complex with TLR12 and leads to the activation of Myd88-dependent signaling pathways [16,17,18,19,20,21]. TLR11-independent mechanisms of T. gondii recognition required for establishing T cell immunity are largely unknown; several recent studies including our own have suggested that CCL2-mediated recruitment of monocytes and the inflammasome-dependent release of mature IL-1β and IL-18 represent the initial steps in driving a TLR11-independent protective immunity to the parasite [24,25,26,27,28]

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