Chronic Trypanosoma cruzi infection activates the TWEAK/Fn14 axis in cardiac myocytes and fibroblasts driving structural and functional changes that affect the heart

Santamaría, Miguel H.; Ríos, Luisa Delgado; Corral, Ricardo S.

doi:10.1016/j.exppara.2023.108491

Cited by 1 publication

(1 citation statement)

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“…CXCL12 also plays a role in protozoan parasite clearance [ 22 , 23 ] and shows increased levels in established CCC [ 24 ]. TNFSF12/TWEAK signaling activates NF-kB-mediated production of proinflammatory mediators [ 25 ], while HCLS1 is an established mediator more broadly of leukocyte recruitment and chemotaxis [ 26 ] and is an upregulated hub gene in hearts from established end-stage CCC patients and T. cruzi -infected mice [ 23 ]. Other markers that were comparatively less expressed at the baseline in the progressors included HCLS1, COLEC12, and MILR1, which is suggestive of impaired pathogen-induced leukocyte activation and antigen presentation [ 27 , 28 , 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Parasite DNA and Markers of Decreased Immune Activation Associate Prospectively with Cardiac Functional Decline over 10 Years among Trypanosoma cruzi Seropositive Individuals in Brazil

Sunderraj,

Cunha,

Avila

et al. 2023

IJMS

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Parasitemia and inflammatory markers are cross-sectionally associated with chronic Chagas cardiomyopathy (CCC) among patients with Trypanosoma cruzi. However, the prospective association of the parasite load and host immune response-related characteristics with CCC (that is, progressors) among T. cruzi seropositive individuals has only been partially defined. In a cohort of T. cruzi seropositive patients in Montes Claros and São Paulo, Brazil who were followed over 10 years, we identified the association of a baseline T. cruzi parasite load and systemic markers of inflammation with a decline in cardiac function and/or the presence of cardiac congestion 10 years later. The progressors (n = 21) were individuals with a significant decline in the left ventricular ejection fraction and/or elevated markers of cardiac congestion after 10 years. The controls (n = 31) had normal markers of cardiac function and congestion at the baseline and at the follow-up. They were matched with the progressors on age, sex, and genetic ancestry. The progressors had higher mean parasite loads at the baseline than the controls (18.3 vs. 0.605 DNA parasite equivalents/20 mL, p < 0.05). Of the 384 inflammation-related proteins analyzed, 47 differed significantly at a false discovery rate- (FDR-) corrected p < 0.05 between the groups. There were 44 of these 47 proteins that were significantly higher in the controls compared to in the progressors, including the immune activation markers CCL21, CXCL12, and HCLS1 and several of the tumor necrosis factor superfamily of proteins. Among the individuals who were seropositive for T. cruzi at the baseline and who were followed over 10 years, those with incident CCC at the 10-year marker had a comparatively higher baseline of T. cruzi parasitemia and lower baseline markers of immune activation and chemotaxis. These findings generate the hypothesis that the early impairment of pathogen-killing immune responses predisposes individuals to CCC, which merits further study.

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