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Published on: July 31, 2019
cGAS-STING Pathway Activation during Trypanosoma cruzi Infection Leads to Tissue-Dependent Parasite Control
Natasha Perumal1,2, Brooke White1, Fernando Sanchez-Valdez1
1Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA.
Abstract:
Host cell invasion by Trypanosoma cruzi is a markedly silent process, with limited host transcriptional changes indicative of innate immune recognition, except for a modest type I IFN (IFN-I) response. In this study, we show that T. cruzi-induced IFN-β production was nearly abolished in primary murine cGAS-/- or stimulator of IFN genes (STING)-deficient (STINGGt) macrophages and fibroblasts. T. cruzi infection did not impact the ability of IFN-regulatory factor reporter macrophages to respond to classical cGAS-STING agonists, indicating that the limited IFN-β induction is not due to active parasite suppression. cGAS-/-, STINGGt, and IFN-α/β receptor-/- (IFNAR-/-) macrophages infected with T. cruzi yielded significantly higher numbers of amastigotes compared with wild-type macrophages; however, the impact of the STING pathway during infection in vivo is more complex. Despite an initial increase in parasite growth, STINGGt and IFNAR-/- mice ultimately had lower parasite burden in footpads as compared with wild-type mice, demonstrating a role for IFN-I expression in potentiating parasite growth at the infection site. STING pathway activation had little impact on parasite levels in the skeletal muscle; however, in the heart, cGAS-/- and STINGGt mice, but not IFNAR-/- mice, accumulated higher acute parasite loads, suggesting a protective role of STING sensing of T. cruzi in this organ that was independent of IFN-I. Together, these results demonstrate that host cGAS-STING senses T. cruzi infection, enhancing parasite growth at the site of entry, and contributes to acute-phase parasite restriction in the heart, a major site of tissue damage in chronic T. cruzi infection.
Insights
The cGAS-STING pathway senses Trypanosoma cruzi infection, initially boosting parasite growth at entry sites. However, it later restricts parasite numbers in the heart, a key organ for chronic infection damage.
Area of Science:
- Immunology
- Infectious Diseases
- Cell Biology
Background:
- Trypanosoma cruzi invasion is typically a stealthy process with minimal host immune response.
- A modest type I interferon (IFN-I) response is observed, but its role in T. cruzi infection is not fully understood.
Purpose of the Study:
- To investigate the role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in host cell response to T. cruzi infection.
- To elucidate the impact of cGAS-STING signaling on parasite load and host immune response in different tissues.
Main Methods:
- Utilized gene-deficient murine macrophages (cGAS-/-, STINGGt, IFNAR-/-) and fibroblasts for in vitro infection studies.
- Assessed parasite burden and host immune responses in footpads and hearts of infected wild-type and gene-deficient mice.
- Employed reporter macrophages to evaluate IFN-regulatory factor activation.
Main Results:
- T. cruzi infection induced IFN-β production dependent on cGAS and STING in macrophages and fibroblasts.
- Absence of cGAS, STING, or IFN-α/β receptor led to increased amastigote numbers in vitro.
- In vivo, STING/IFN-I signaling initially promoted parasite growth at the infection site but ultimately reduced parasite burden in footpads.
- STING activation, independent of IFN-I, conferred protection against acute parasite load in the heart.
Conclusions:
- Host cGAS-STING signaling senses T. cruzi infection, influencing parasite growth dynamics.
- The pathway enhances parasite proliferation at the invasion site but contributes to parasite restriction in the heart during acute infection.
- STING-dependent, IFN-I-independent mechanisms play a protective role in the heart, a critical site for Chagas disease pathology.
