Evolution and pathology in chagas disease--a review

Area of Science:

• Parasitology
• Genetics
• Immunology
• Pathogenesis

Background:

• Chagas disease, caused by Trypanosoma cruzi, leads to severe pathologies in one-third of chronically infected individuals.
• A hallmark of Chagas disease pathology is the destruction of host cells by immune infiltrates.
• Trypanosoma cruzi's kinetoplast DNA (kDNA) can integrate into the host genome, with potential for transmission across generations.

Purpose of the Study:

• To investigate the role of kDNA integration in Chagas disease pathogenesis.
• To explore the potential for autoimmunity triggered by parasite DNA integration.
• To understand the mechanisms underlying diverse Chagas disease manifestations.

Main Methods:

• Analysis of kDNA integration into vertebrate host genomes (mammals and birds).
• Examination of mutations, gene alterations, and genomic remodeling resulting from kDNA integration.
• Study of chimeric product generation through juxtaposition of kDNA and host DNA.
• Investigation of germline transmission of kDNA mutations and resulting lesions in birds.

Main Results:

• kDNA integration leads to mutations, gene knock-outs, and genomic shuffling in the host.
• Novel chimeric gene products can be generated by kDNA insertions near host open reading frames.
• Germline transmission of kDNA mutations in birds produced lesions similar to human Chagas disease.
• Lesions in birds refractory to infection suggest autoimmunity plays a role in pathogenesis.

Conclusions:

• Trypanosoma cruzi kDNA integration and subsequent mutations contribute significantly to Chagas disease pathology.
• The generation of novel genetic products and genomic alterations may drive disease manifestations.
• Autoimmunity, potentially triggered by integration-induced phenotypic changes, is a likely major factor in Chagas disease pathogenesis.