MyD88 activation in cardiomyocytes contributes to the heart immune response to acute Trypanosoma cruzi infection with no effect on local parasite control

• Published in: PLoS neglected tropical diseases 2018-08, Vol.12 (8), p.e0006617
• Main Authors: Santana, Danni Yohani, Salgado, Rafael Moysés, Fevereiro, Marina, Silva do Nascimento, Rogério, Fonseca, Raissa, Saraiva Câmara, Niels Olsen, Epiphanio, Sabrina, Marinho, Cláudio Romero Farias, Barreto-Chaves, Maria Luiza, D' Império-Lima, Maria Regina, Álvarez, José M
• Format: Article
• Language: English
• Subjects: Activation; Animals; Biology and Life Sciences; Cardiac muscle; Cardiomyocytes; Cardiomyopathy; Cardiovascular diseases; Care and treatment; Cell Line; Chagas Cardiomyopathy - immunology; Chagas Cardiomyopathy - metabolism; Chagas disease; Chemokines; Complications and side effects; Cytokines; Cytokines - genetics; Cytokines - metabolism; Defence mechanisms; Development and progression; Disease control; DNA; Gene expression; Gene Expression Regulation - drug effects; Genetic aspects; Genotype; Health aspects; Heart; Human diseases; Humans; Immune response; Immune system; Immunity; Immunology; In vivo methods and tests; Infections; Infiltration; Inflammation; Inflammatory response; Interleukin 1; Interleukin 18; Leukocytes; Medicine and Health Sciences; Mice; Mice, Knockout; Mice, Transgenic; Muscles; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - metabolism; Myocardium - immunology; Myocardium - metabolism; Myocytes, Cardiac - metabolism; Nucleotide sequence; Parasite control; Parasites; Parasitism; Pathology; PCR; Proteins; Protozoa; Receptors; Research and Analysis Methods; RNA, Messenger; Selective Estrogen Receptor Modulators - pharmacology; Spleen; Strain; Tamoxifen; Tamoxifen - pharmacology; Toll-like receptors; Transcription; Tropical diseases; Trypanosoma cruzi; Trypanosoma cruzi - immunology; Trypanosomiasis; Tumor necrosis factor-α; Vector-borne diseases; γ-Interferon
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0006617

Cardiomyopathy is the most serious consequence of Chagas disease, a neglected human disorder caused by Trypanosoma cruzi infection. Because T. cruzi parasites invade cardiomyocytes, we sought to investigate whether these cells recognize the parasite in vivo by receptors signaling through the MyD88 adaptor, which mediates the activation pathway of most Toll-like receptors (TLRs) and IL-1/IL-18 receptors, and influence the development of acute cardiac pathology. First, we showed that HL-1 cardiac muscle cell line expresses MyD88 gene and protein at resting state and after T. cruzi infection. To evaluate the role in vivo of MyD88 expression in cardiomyocytes, we generated Mer+MyD88flox+/+ mice in which tamoxifen treatment is expected to eliminate the MyD88 gene exclusively in cardiomyocytes. This Cre-loxP model was validated by both PCR and western blot analysis; tamoxifen treatment of Mer+MyD88flox+/+ mice resulted in decreased MyD88 gene and protein expression in the heart, but not in the spleen, while had no effect on littermates. The elimination of MyD88 in cardiomyocytes determined a lower increase in CCL5, IFNγ and TNFα gene transcription during acute infection by T. cruzi parasites of the Y strain, but it did not significantly modify heart leukocyte infiltration and parasitism. Together, our results show that cardiomyocytes can sense T. cruzi infection through MyD88-mediated molecular pathways and contribute to the local immune response to the parasite. The strong pro-inflammatory response of heart-recruited leukocytes may overshadow the effects of MyD88 deficiency in cardiomyocytes on the local leukocyte recruitment and T. cruzi control during acute infection.