Apoptosis-Associated Speck–like Protein Containing a Caspase Recruitment Domain Inflammasomes Mediate IL-1β Response and Host Resistance to Trypanosoma cruzi Infection

Abstract

The innate immune response to Trypanosoma cruzi infection comprises several pattern recognition receptors (PRRs), including TLR-2, -4, -7, and -9, as well as the cytosolic receptor Nod1. However, there are additional PRRs that account for the host immune responses to T. cruzi. In this context, the nucleotide-binding oligomerization domain–like receptors (NLRs) that activate the inflammasomes are candidate receptors that deserve renewed investigation. Following pathogen infection, NLRs form large molecular platforms, termed inflammasomes, which activate caspase-1 and induce the production of active IL-1β and IL-18. In this study, we evaluated the involvement of inflammasomes in T. cruzi infection and demonstrated that apoptosis-associated speck–like protein containing a caspase recruitment domain (ASC) inflammasomes, including NLR family, pyrin domain–containing 3 (NLRP3), but not NLR family, caspase recruitment domain–containing 4 or NLR family, pyrin domain–containing 6, are required for triggering the activation of caspase-1 and the secretion of IL-1β. The mechanism by which T. cruzi mediates the activation of the ASC/NLRP3 pathway involves K+ efflux, lysosomal acidification, reactive oxygen species generation, and lysosomal damage. We also demonstrate that despite normal IFN-γ production in the heart, ASC−/− and caspase-1−/− infected mice exhibit a higher incidence of mortality, cardiac parasitism, and heart inflammation. These data suggest that ASC inflammasomes are critical determinants of host resistance to infection with T. cruzi.

Caspase-1/ASC Inflammasome-Mediated Activation of IL-1β–ROS–NF-κB Pathway for Control of Trypanosoma cruzi Replication and Survival Is Dispensable in NLRP3−/− Macrophages

“…In agreement with the literature, we also observed ROS-dependent IL-1β activation mediated by caspase-1/ASC inflammasome in mφs exposed to T. cruzi (Figs.1–4). The exogenous addition of ATP resulted in a higher level of IL-1β activation in infected mφs at 3 h pi, as also noted by others [28]. The lack of an effect of exogenous ATP on the extent of IL-1β activation in infected mφs at 18 h pi may mean that other signals were generated.…”

“…NOD1 [26], and NLRP3 [27], [28]). Genetically modified mice deficient in MYD88 (interacts with TLR-2, -4, -6), TLR-4, NOD1, and ASC exhibited an increased susceptibility to T. cruzi , thus pointing to these PRRs as critical determinants of host resistance to T. cruzi infection [24], [26], [28], [29]. In this manuscript, we have utilized cultured and primary mφs and employed inhibitory approaches to investigate the mechanisms of caspase-1/ASC inflammasome activation and their role in the context of T. cruzi infection.…”

“…6). ASC -/- and caspase-1 -/- mice have been doCumented to exhibit a higher incidence of mortality, cardiac parasitism and heart inflammation, meaning that ASC/caspase-1 inflammasomes are critical determinants of host resistance to infection with T. cruzi [28]. Like ASC -/- mice and in vitro cultured ASC -/- mφs, NOD1 -/- mice and BM-derived derived mφs from NOD1 -/- mice also showed an impaired induction of NF-κB-dependent products and failed to restrict T. cruzi infection [26].…”

Inhibition of Cyclooxygenase-1 and Cyclooxygenase-2 Impairs Trypanosoma cruzi Entry into Cardiac Cells and Promotes Differential Modulation of the Inflammatory Response

“…In fact, IL-1␤ is critical for the restriction of Leishmania amazonensis infection (44), and recently it was demonstrated that T. cruzi-infected macrophages treated with IL-1␤ released fewer trypomastigotes than untreated macrophages and that IL-1␤ triggered NO release by infected macrophages in a dose-dependent manner (45).…”

Experimental Chagas disease in Balb/c mice previously vaccinated with T. rangeli. II. The innate immune response shows immunological memory: Reality or fiction?

“…Another cytokine that contributes to the inflammatory response in animals resistant to the infection is IL-1␤. In this work, the levels of this cytokine in V-I were always greater than in I group, which could be associated with the induction of inflammasomes, a synthesis of reactive mediators of oxygen, the acidification of lysosome and the activation of caspases according to the observations of Silva et al (2013). Levels of IL-10 were determined to evaluate their possible role in regulating the early response to T. cruzi infection.…”