SummaryBackgroundChronic Chagas disease has indeterminate and cardiac forms associated with distinct immune profiles. Infection with SARS-CoV-2, compared with other causes of hospital admission, represented the highest risk factor for in-hospital mortality among patients with Chagas disease during the COVID-19 pandemic. Nevertheless, whether SARS-CoV-2 infection disrupts pre-existing Trypanosoma cruzi-specific immunity and affects cardiac progression remains unclear.MethodsWe investigated adults with chronic Chagas disease followed during the COVID-19 pandemic and stratified by Chagas disease clinical form and COVID-19 status. Clinical progression was assessed during 1-yr follow-up. Peripheral blood mononuclear cells were stimulated with T. cruzi lysate, and antigen-induced CD4 and CD8 T-cell responses were quantified by flow cytometry and expressed as log2 stimulation indices. Serum cytokines, chemokines, growth factors, and cardiovascular risk-associated proteins were measured by multiplex assays. Hierarchical clustering and Spearman correlation networks were used to assess coordinated immune changes.FindingsAmong 172 patients, 37 had mild COVID-19 and 135 had no history of COVID-19. Cardiac progression was more frequent in patients with mild COVID-19 than in those without COVID-19 (16·2% vs 5·2%; adjusted OR 3·64, 95% CI 1·06–12·33; p=0·035). Indeterminate patients without COVID-19 showed IL-10/IL-17/LAP-skewed T. cruzi-specific responses, whereas this profile was reduced in indeterminate patients with COVID-19, in favor of higher IL-1β and enhanced CD8 response. Cardiac patients with COVID-19 retained a Th1-skewed profile, with higher TNF, IL-6, CD4+IFN-γ+ responses, and denser serum networks linking inflammatory cytokines, chemokines, and cardiovascular risk-associated proteins, with a loss of correlations between regulatory and inflammatory T cell populations.InterpretationMild SARS-CoV-2 infection was associated with cardiac progression and immune-network remodeling in chronic Chagas disease, marked by loss of regulatory and Th17 features in indeterminate disease and amplification of inflammatory coordination in cardiomyopathy.FundingFiocruz, FAPERJ, CNPq, CAPES and GIISER (Gates Foundation).

The autoimmune regulator (Aire) gene is essential for the establishment of central tolerance by promoting the ectopic expression of tissue-restricted antigens in medullary thymic epithelial cells (mTECs). Although Aire deficiency impairs negative selection, its impact on thymic architecture, output, and early T cell development remains incompletely understood. Here, we used a murine Aire-deficient model carrying a CRISPR-Cas9-induced deletion within exon 6, disrupting the SAND domain, to investigate the consequences of Aire loss on thymic structure and function. Aire-deficient mice exhibited focal alopecia and marked disorganization of the thymic medulla. T cell receptor excision circle (TREC) analyses revealed altered peripheral TREC dynamics and a reduced sj/betaTREC ratio, indicating altered thymic output and impaired intrathymic precursor expansion. Complementary flow-cytometric analysis showed a significant reduction in the proportion of CD4⁺CD8⁺ double-positive thymocytes in heterozygous mutants, supporting altered intrathymic maturation. Serum IL-27, IL-28B, and IL-31 were decreased in homozygous mutants, whereas IL-22 and IL-23 remained unchanged. Despite these alterations, TCRVbeta repertoire sequencing revealed no significant differences in rearrangements, clonality, or V/J gene usage. Together, these findings indicate that Aire deficiency disrupts thymic architecture and output, while preserving overall TCR repertoire diversity.

COVID-19 perturbs the renin-angiotensin system (RAAS) and inflammatory pathways, shaping disease severity. Soluble ACE2 (sACE2) and angiotensin II (Ang II) are central regulators of vascular and immune homeostasis. We profiled plasma from COVID-19 patients and controls using ELISA, together with 48 cytokine profiling and clinical data. Both sACE2 and Ang II were significantly elevated in patients. Increased Ang II was associated with oxygen supplementation and dyspnea, and negatively correlated with IL-3, whereas sACE2 correlated with IL-13 and FGF. Comorbidities modulated cytokine expression: diabetes mellitus was linked to reduced LIF and MCP-1, hypertension to decreased LIF and increased IP-10, and obesity to elevated IL-12p70. Age correlated with TNF and HGF, and reduced oxygen saturation was associated with lower LIF. These findings reveal that acute COVID-19 disrupts RAAS and amplifies immune dysregulation, with Ang II emerging as a pivotal mediator of respiratory compromise and inflammatory imbalance, underscoring its potential as a biomarker and therapeutic relevance.

Visceral leishmaniasis (VL) is a severe disease caused by Leishmania infantum in Brazil. Relapses have increased among immunocompetent patients; however, the underlying factors remain unclear. Persistently low CD4+ T cell counts had been associated with VL relapses, suggesting impaired immune reconstitution. Here, we investigated whether immune activation and thymic function influence immune recovery in VL and shape the TCRVβ repertoire, predisposing patients to relapse. Patients with VL, followed for 12 months, were stratified according to relapse (R-VL,n=5) or non-relapse (NR-VL,n=10). Immune activation, senescence, and the TCRVβ repertoire were evaluated using flow cytometry, and thymic function was assessed through sjTREC quantification in CD4+ and CD8+ T cells. Plasma IL-7 levels were also measured. R-VL patients exhibited sustained immune activation, in contrast to the decline observed in NR-VL. Both groups showed high levels of immunosenescence throughout the follow-up period. All patients had low sjTREC levels during active VL; however, post-treatment levels were even lower in R-VL patients and were associated with reduced IL-7 levels. TCRVβ repertoire analysis showed differential mobilization between patients in the NR-VL and R-VL groups. Correlation analysis suggested that deficient thymic output may impair T cell replenishment, which is crucial for parasite control. Linear mixed-effects modeling showed that CD4+ T cell counts were influenced by synergistic effect between sjTREC and IL-7, as well were correlated with activation. In conclusion, our study showed that VL relapse is associated with multifactorial dysfunction that compromises immune reconstitution, highlighting the roles of sustained immune activation, thymic impairment, and peripheral disturbances in clinical outcomes.