NLRP3 Controls Trypanosoma cruzi Infection through a Caspase-1-Dependent IL-1R-Independent NO Production

Abstract

Trypanosoma cruzi (T. cruzi) is an intracellular protozoan parasite and the etiological agent of Chagas disease, a chronic infectious illness that affects millions of people worldwide. Although the role of TLR and Nod1 in the control of T. cruzi infection is well-established, the involvement of inflammasomes remains to be elucidated. Herein, we demonstrate for the first time that T. cruzi infection induces IL-1β production in an NLRP3- and caspase-1-dependent manner. Cathepsin B appears to be required for NLRP3 activation in response to infection with T. cruzi, as pharmacological inhibition of cathepsin B abrogates IL-1β secretion. NLRP3−/− and caspase1−/− mice exhibited high numbers of T. cruzi parasites, with a magnitude of peak parasitemia comparable to MyD88−/− and iNOS−/− mice (which are susceptible models for T. cruzi infection), indicating the involvement of NLRP3 inflammasome in the control of the acute phase of T. cruzi infection. Although the inflammatory cytokines IL-6 and IFN-γ were found in spleen cells from NLRP3−/− and caspase1−/− mice infected with T. cruzi, these mice exhibited severe defects in nitric oxide (NO) production and an impairment in macrophage-mediated parasite killing. Interestingly, neutralization of IL-1β and IL-18, and IL-1R genetic deficiency demonstrate that these cytokines have a minor effect on NO secretion and the capacity of macrophages to control T. cruzi infection. In contrast, inhibition of caspase-1 with z-YVAD-fmk abrogated NO production by WT and MyD88−/− macrophages and rendered them as susceptible to T. cruzi infection as NLRP3−/− and caspase-1−/− macrophages. Taken together, our results demonstrate a role for the NLRP3 inflammasome in the control of T. cruzi infection and identify NLRP3-mediated, caspase-1-dependent and IL-1R-independent NO production as a novel effector mechanism for these innate receptors.

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

“…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].…”

Proteomic analysis reveals different composition of extracellular vesicles released by two Trypanosoma cruzi strains associated with their distinct interaction with host cells

“…For example, we observed that Toll-like receptors have been shown to modulate invasion by the EVs, which contain GPI-anchors (unpublished results). The growth of the intracellular parasites could be also affected by the different escape mechanisms from the parasitophorous vacuole [65,66], or the specific induction of inflammasomes in the macrophage lines [67]. One hypothesis to explain those polymorphisms is the lower expression of α-galactosyl residues in the YuYu EVs [10] since pre-treatment with tGPI-mucins of Colombiana strain (TcI) resulted in lower ability of infection compared to Y strain (TcII) [26].…”

NLRP3 Inflammasome Activation in THP-1 Target Cells Triggered by Pathogenic Naegleria fowleri

“…In Leishmania amazonensis infection, the NLRP3 inflammasome is engaged in the host response, and the activation of this molecular platform has a crucial role in the restriction of parasite replication both in macrophages and in vivo, with notable IL-1␤ production occurring (23). The NLRP3 inflammasome controls T. cruzi parasitemia by inducing nitric oxide (NO) production via a caspase-1-dependent, IL-1 receptor-independent pathway (24). With inflammasome formation, other protozoa, such as Entamoeba histolytica and Toxoplasma gondii, have been studied for the host inflammatory response, including NLRP family and caspase-1 activation and IL-1␤ production (25,26).…”

“…The activation of the inflammasome in diseases caused by infection with a pathogen, such as malaria, leishmaniasis, trypanosomiasis, amoebiasis, and toxoplasmosis, has been investigated (22)(23)(24)(25)(26), but the role of the inflammasome in pathogenic N. fowleri infection has not been addressed yet. In the present study, to investigate what kinds of inflammasome-related molecules may be expressed in target cells due to N. fowleri infection, human macrophage cells were cocultured indirectly with N. fowleri trophozoites in a noncontact system, and consequently, active IL-1␤ release was estimated.…”