Differential cardiomyocyte transcriptomic remodeling during in vitro Trypanosoma cruzi infection using laboratory strains provides implications on pathogenic host responses

Katherine-Sofia Candray-Medina; Yu Nakagama; Masamichi Ito; Shun Nakagama; Evariste Tshibangu-Kabamba; Norihiko Takeda; Yuki Sugiura; Yuko Nitahara; Yu Michimuko-Nagahara; Natsuko Kaku; Yoko Onizuka; Carmen-Elena Arias; Maricela Mejia; Karla Alas; Susana Peña; Yasuhiro Maejima; Issei Komuro; Junko Nakajima-Shimada; Yasutoshi Kido

doi:10.1186/s41182-023-00552-6

Differential cardiomyocyte transcriptomic remodeling during in vitro Trypanosoma cruzi infection using laboratory strains provides implications on pathogenic host responses

Trop Med Health. 2023 Dec 7;51(1):68. doi: 10.1186/s41182-023-00552-6.

Authors

Katherine-Sofia Candray-Medina^{1

2

3}, Yu Nakagama^{4

5}, Masamichi Ito^{6

7}, Shun Nakagama⁸, Evariste Tshibangu-Kabamba^{1

2

9}, Norihiko Takeda¹⁰, Yuki Sugiura¹¹, Yuko Nitahara^{1

2}, Yu Michimuko-Nagahara^{1

2}, Natsuko Kaku^{1

2}, Yoko Onizuka¹², Carmen-Elena Arias³, Maricela Mejia³, Karla Alas³, Susana Peña¹³, Yasuhiro Maejima⁸, Issei Komuro^{14

15}, Junko Nakajima-Shimada¹², Yasutoshi Kido^{1

2}

Affiliations

¹ Department of Parasitology, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.
² Research Center for Infectious Disease Sciences, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.
³ Centro Nacional de Investigaciones Científicas de El Salvador (CICES), Ciudad Universitaria "Dr. Fabio Castillo Figueroa", final avenida "Mártires del 30 de julio", San Salvador, El Salvador.
⁴ Department of Parasitology, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan. ynakagama@gmail.com.
⁵ Research Center for Infectious Disease Sciences, Graduate School of Medicine, Osaka Metropolitan University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan. ynakagama@gmail.com.
⁶ Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
⁷ Department of Advanced Clinical Science and Therapeutics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
⁸ Department of Cardiovascular Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
⁹ Department of Internal Medicine, University of Mbujimayi, #1 avenue de l'Université, Dibindi, 225, Mbujimayi, Democratic Republic of Congo.
¹⁰ Division of Cardiology and Metabolism, Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, 329-0498, Japan.
¹¹ Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Yoshida Nihonmatsucho, Sakyo-ku, Kyoto, 606-8501, Japan.
¹² Department of Molecular and Cellular Parasitology, Graduate School of Health Sciences, Gunma University, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8514, Japan.
¹³ Departamento de Investigación, Hospital Nacional Especializado "Rosales", Ministerio de Salud de El Salvador, Calle Arce No. 827, San Salvador, El Salvador.
¹⁴ International University of Health and Welfare, Minato-Ku, Tokyo, 107-8402, Japan.
¹⁵ Department of Frontier Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Abstract

Background: Chagas disease can lead to life-threatening cardiac manifestations. Regional factors, including genetic characteristics of circulating Trypanosoma cruzi (T. cruzi), have attracted attention as likely determinants of Chagas disease phenotypic expression and Chagas cardiomyopathy (CCM) progression. Our objective was to elucidate the differential transcriptomic signatures of cardiomyocytes resulting from infection with genetically discrete T. cruzi strains and explore their relationships with CCM pathogenesis and progression.

Methods: HL-1 rodent cardiomyocytes were infected with T. cruzi trypomastigotes of the Colombian, Y, or Tulahuen strain. RNA was serially isolated post-infection for microarray analysis. Enrichment analyses of differentially expressed genes (fold-change ≥ 2 or ≤ 0.5) highlighted over-represented biological pathways. Intracellular levels of reactive oxygen species (ROS) were compared between T. cruzi-infected and non-infected HL-1 cardiomyocytes.

Results: We found that oxidative stress-related gene ontology terms (GO terms), 'Hypertrophy model', 'Apoptosis', and 'MAPK signaling' pathways (all with P < 0.01) were upregulated. 'Glutathione and one-carbon metabolism' pathway, and 'Cellular nitrogen compound metabolic process' GO term (all with P < 0.001) were upregulated exclusively in the cardiomyocytes infected with the Colombian/Y strains. Mean intracellular levels of ROS were significantly higher in the T. cruzi-infected cardiomyocytes compared to the non-infected (P < 0.0001).

Conclusions: The upregulation of oxidative stress-related and hypertrophic pathways constitutes the universal hallmarks of the cardiomyocyte response elicited by T. cruzi infection. Nitrogen metabolism upregulation and glutathione metabolism imbalance may implicate a relationship between nitrosative stress and poor oxygen radicals scavenging in the unique pathophysiology of Chagas cardiomyopathy.

Keywords: Chagas disease; Dilated cardiomyopathy; Glutathione metabolism; HL-1; In vitro modeling; Neglected tropical diseases; Oxidative stress; Transcriptome; Trypanosoma cruzi.

Abstract

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