cGAS-STING Pathway Activation during Trypanosoma cruzi Infection Leads to Tissue-Dependent Parasite Control

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.