Respuesta inmunitaria en infecciones

RESEARCH INTEREST

During 2025, Group 12 focused on advancing the understanding of host-parasite interactions in Trypanosoma cruzi infection, with particular emphasis on immune receptor signaling, iron metabolism, and the regulatory role of microRNAs. One of the objectives was to dissect the molecular and functional interaction between SLAMF1 and trans-sialidase SLAMF1 ligands (TS-SLs), and to determine the consequences of this interaction on receptor signaling and parasite replication. The initial hypothesis arose from the observation that measles virus hemagglutinin, a natural ligand of SLAMF1, shares structural similarities with T. cruzi trans-sialidases (TSs). To experimentally address this possibility, SLAMF1 immunoprecipitation and co-immunoprecipitation assays were performed. Proteomic analysis of the co-immunoprecipitated proteins identified several TSs as candidate SLAMF1-binding proteins, providing strong evidence that TSs act as SLAMF1 ligands. These findings support the existence of a previously unrecognized host–parasite interaction with potential consequences for SLAMF1-mediated signaling and parasite replication. Given that TSs are established therapeutic and vaccine targets, these results are particularly relevant. In this context, a computational drug repurposing study predicting inhibitors against TSs was identified, opening promising perspectives for future research aimed at interfering with TS activity and SLAMF1–TS interactions. In parallel, transcriptomic analyses highlighted the relevance of iron metabolism in SLAMF1-mediated signaling. Notably, this work identified for the first time a potential role for lipocalin-2 in regulating iron availability during T. cruzi infection, suggesting that modulation of iron homeostasis is an important component of SLAMF1-dependent pathways and may contribute to the control of parasite proliferation. Moreover, the effects of host microRNAs on host gene expression and T. cruzi replication, as well as on the characterization of parasite-derived microRNAs and their impact on host responses and parasite biology were evaluated. Although T. cruzi is not expected to produce microRNAs due to the absence of canonical processing enzymes, parasite-derived microRNAs were detected in cultures of epimastigotes and purified trypomastigotes, suggesting the existence of an alternative and still unknown processing machinery. Functional studies showed that T. cruzi microRNAs enhance the production of pro-inflammatory cytokines following stimulation with LPS and parasites, demonstrating their capacity to modulate the host immune response. The project resulted in several peer-reviewed publications in high-quality international journals. The inclusion of Dr. Concepción Abrusci Bernal as co-responsible of the group strengthened its multidisciplinary profile in biotechnology. Moreover, collaborations in periodontitis research, including work with Dr. Julien Santi-Rocca, were consolidated and resulted in joint publications. Taken together, these activities reinforced interdisciplinary links, enhanced the overall impact of the research, and enabled the joint submission of competitive research proposals currently under evaluation. The group also benefited from the continued scientific contribution of Dr. Manuel Fresno as an emeritus researcher, reinforcing expertise and continuity.TCFL5 is a member of the bHLH transcription factor family with multiple isoforms in both humans and mice. Complete elimination of these isoforms drastically reduces the tumorigenic properties of colon cancer cells. Interestingly, the two main isoforms (TCFL5 and CHA) exhibited reciprocal regulation and distinct functions within the cell, with CHA exerting a tumor-promoting effect. The expression of TCFL5/CHA is essential for NFKB2 activity, which regulates the expression of anti-apoptotic genes such as BCL2 and also controls the expression of the pluripotency markers SOX2, NANOG, and KLF4. We have also identified a set of genes regulated by TCFL5/CHA in leukemia cell lines and established their role in the prognosis and development of B- and T-cell acute lymphoblastic leukemia and in normal hematopoiesis. The expression of TCFL5 and CHA was associated with increased disease severity in patient samples of lymphoma and multiple myeloma. Last but not least, using Tcfl5-deficient mice, we discovered that TCFL5 is involved in germinal center formation and in the differentiation stage from pro-B to pre-B cells, two processes that are not only characterized by a high proliferation rate but also depend on MYC. The absence of TCFL5 led to a drastic decrease in the levels of key molecules involved in BCR signaling, such as SYK and BLNK, resulting in an inability to respond to stimuli, increased cell death, and an abnormal cell cycle. Using Tcfl5-deficient mice, we discovered that TCFL5 is expressed in the early stages of mouse embryonic development during the preimplantation period and plays a role in the differentiation of embryonic cells into germline precursors by controlling the expression of genes important for this differentiation. Finally, regarding infection by the protozoan parasite T. cruzi, we are investigating the impact of T. cruzi genetic variability on the clinical outcome and immunopathology of Chagas disease, as well as on drug susceptibility. All of this is aimed at improving the understanding and prevention of Chagas disease. Different genetic lineages have been identified in Trypanosoma cruzi, the causative agent of Chagas disease. However, our understanding of its comparative biology and pathogenesis remains fragmentary. We have identified different T-cell-dependent immune responses in both patients and murine models, which vary depending on the infecting strain. In addition, we are investigating how the parasite enters, infects, and evades destruction by myeloid cells, identifying Slamf1 (CD150) as a new receptor for T. cruzi. In contrast, we have discovered that Slamf8 (CD353) is a cell surface receptor that is expressed following the activation of macrophages by IFN-? and plays a negative role in infection by repressing NADPH oxidase. We have studied the role that CD4+ T cell subsets and myeloid subclasses, including myeloid-derived suppressor cells (MDSCs), may play in the immunopathogenesis of Chagas disease, with a particular focus on myocarditis in animal models and in patients. The different immunopathogenic responses of the heart depend on host genetics. However, systems biology approaches have allowed us to define immunopathogenic markers independent of host and parasite genetics. We have identified numerous metabolic alterations in T. cruzi infection that suggest a state of stress in the heart, some of which can be used as biomarkers. Serum miRNAs are also excellent biomarkers of Chagas disease progression.