Dengue: Historical Aspects Myrna Cristina Bonaldo, Samuel Goldenberg, Ricardo Galler, Claudia Nunes Duarte dos Santos Current Topics in Microbiology and Immunology, 2026
Trypanosomatid Extracellular Vesicles as Potential Immunogens for Chagas Disease Juliana Bernardi Aggio, Verônica Vitória Vedam, Líndice Mitie Nisimura, Rosiane Valeriano da Silva, Maria Izabel Lovo-Martins, et al. International Journal of Molecular Sciences, 2025 Chagas disease remains a significant public health concern, with limited treatment options and an urgent need for novel preventive strategies. Extracellular vesicles (EVs) from Trypanosoma cruzi have been shown to modulate host immune responses, often favoring parasite persistence. In this study, we characterized EVs derived from the non-pathogenic trypanosomatids Trypanosoma rangeli and Phytomonas serpens and evaluated their potential as immunogens capable of inducing cross-protection against T. cruzi infection. Isolated EVs were characterized by Nanoparticle Tracking Analysis (NTA) and electron microscopy. A comparative proteomic analysis of EVs was performed using Mass Spectrometry-Based Proteomic Analysis (LC-MS/MS). The effects of EVs on immunomodulation and T. cruzi infection were assessed through in vitro and in vivo assays, using peripheral blood mononuclear cells (PBMCs) and BALB/c mice. The proteomic analysis identified shared proteins between the EVs of T. rangeli, P. serpens, and T. cruzi, including immunogenic candidates such as calpain-like cysteine peptidase and elongation factor 2. In vitro, pre-stimulation with the T. rangeli EVs reduced infection rates of the host cells by T. cruzi. In vivo, immunization with the EVs from T. rangeli and P. serpens led to a significant reduction in parasitemia in the BALB/c mice challenged with T. cruzi, though this did not translate into improved survival compared to controls. Interestingly, the EVs from T. cruzi also reduced parasitemia but did not confer protection against mortality. These findings suggest that while non-pathogenic trypanosomatid EVs exhibit potential immunogenic properties and can reduce parasitic load, their efficacy in preventing disease progression remains limited. Further research is needed to explore the mechanisms underlying these effects and to optimize EV-based strategies for protective immunity against Chagas disease.
TcZC3HTTP, a regulatory element that contributes to Trypanosoma cruzi cell proliferation Bruno Accioly Alves Romagnoli, Aline Castro Rodrigues Lucena, Eden Ribeiro Freire, Isadora Filipaki Munhoz da Rocha, Lysangela Ronalte. Alves, et al. Microbiology Spectrum, 2024 Post-transcriptional regulation of gene expression is a critical process for adapting to and surviving Trypanosoma cruzi , a parasite with a complex life cycle. RNA-binding proteins (RBPs) are key players in this regulation, forming ribonucleoprotein complexes (messenger ribonucleoproteins) and RNA granules that control transcript stability, localization, degradation, and translation modulation. Understanding the specific roles of individual RBPs is crucial for unraveling the details of this regulatory network. In this study, we generated null mutants of the TcZC3HTTP gene, a specific RBP in the Trypanosoma family characterized by a C3H zinc finger and a DNAJ domain associated with RNA and protein binding, respectively. Through cell growth assays, we demonstrated that the absence of TcZC3HTTP or the expression of an additional tagged version impacted epimastigote growth, indicating its contribution to cell proliferation. TcZC3HTTP was found to associate with mRNAs involved in cell cycle and division in epimastigotes, while in nutritionally stressed parasites it exhibited associations with mRNAs coding for other RBPs and rRNA. Furthermore, our analysis identified that TcZC3HTTP protein partners were different during normal growth conditions compared to starvation conditions, with the latter showing enrichment of ribosomal proteins and other RBPs. Therefore, this study provides insights into TcZC3HTTP’s role in the post-transcriptional regulation of gene expression during normal growth and nutritional stress in T. cruzi , uncovering its versatile functions in different cellular contexts. IMPORTANCE Understanding how Trypanosoma cruzi , the causative agent of Chagas disease, regulates gene expression is crucial for developing targeted interventions. In this study, we investigated the role of TcZC3HTTP, an RNA-binding protein, in post-transcriptional regulation. Our findings demonstrate that TcZC3HTTP is relevant for the growth and proliferation of epimastigotes, a stage of the parasite’s life cycle. We identified its associations with specific mRNAs involved in cell cycle and division and its interactions with enzymes and other RNA-binding proteins (RBPs) under normal and starvation conditions. These insights shed light on the regulatory network underlying gene expression in T. cruzi and reveal the multifaceted functions of RBPs in this parasite. Such knowledge enhances our understanding of the parasite’s biology and opens avenues for developing novel therapeutic strategies targeting post-transcriptional gene regulation in T. cruzi .
The characterization of RNA-binding proteins and RNA metabolism-related proteins in fungal extracellular vesicles Marianna Dallastella, Willian Klassen de Oliveira, Marcio L. Rodrigues, Samuel Goldenberg, Lysangela R. Alves Frontiers in Cellular and Infection Microbiology, 2023 RNA-binding proteins (RBPs) are essential for regulating RNA metabolism, stability, and translation within cells. Recent studies have shown that RBPs are not restricted to intracellular functions and can be found in extracellular vesicles (EVs) in different mammalian cells. EVs released by fungi contain a variety of proteins involved in RNA metabolism. These include RNA helicases, which play essential roles in RNA synthesis, folding, and degradation. Aminoacyl-tRNA synthetases, responsible for acetylating tRNA molecules, are also enriched in EVs, suggesting a possible link between these enzymes and tRNA fragments detected in EVs. Proteins with canonical RNA-binding domains interact with proteins and RNA, such as the RNA Recognition Motif (RRM), Zinc finger, and hnRNP K-homology (KH) domains. Polyadenylate-binding protein (PABP) plays a critical role in the regulation of gene expression by binding the poly(A) tail of messenger RNA (mRNA) and facilitating its translation, stability, and localization, making it a key factor in post-transcriptional control of gene expression. The presence of proteins related to the RNA life cycle in EVs from different fungal species suggests a conserved mechanism of EV cargo packing. Various models have been proposed for selecting RNA molecules for release into EVs. Still, the actual loading processes are unknown, and further molecular characterization of these proteins may provide insight into the mechanism of RNA sorting into EVs. This work reviews the current knowledge of RBPs and proteins related to RNA metabolism in EVs derived from distinct fungi species, and presents an analysis of proteomic datasets through GO term and orthology analysis, Our investigation identified orthologous proteins in fungal EVs on different fungal species.
Chagas disease treatment: a 120-year-old challenge to public health Samuel Goldenberg Memorias do Instituto Oswaldo Cruz, 2022 Chagas disease (CD), also known as American trypanosomiasis, results in more than 8,000 deaths per year. Reports of new cases of CD through vector transmission have decreased due to vector control policies, improvements in the quality of life of people living in rural regions, and compulsory blood screening in several countries. Nevertheless, there is a contingent of more than 6 million individuals who remain infected with Trypanosoma cruzi, which require medical assistance and lifelong treatment, and this number may increase due to impacts on public health policies resulting from the Coronavirus disease 19 (COVID-19) pandemic. To date, there is no perspective on an efficacious vaccine against trypanosomiasis, and the alternative is the development of safe and efficient chemotherapies to treat this disease. The drugs currently available for treating CD, nifurtimox and benznidazole, were introduced more than 50 years ago. However, the effectiveness of nifurtimox and benznidazole is restricted to the initial phases of the disease, they are not suitable for the treatment of chronic cases and they can impart various collateral effects. Other formulations (e.g., posaconazole, fexinidazole and inhibitors of ergosterol synthesis) or combinations of benznidazole with other compounds have been tested but have worse performances than benznidazole, the typical treatment. Hence, the discovery of new drugs or drug repositioning is a top priority. Recent technological achievements, such as high content screening, associated with the unveiling of the functional genomes of trypanosomes, should contribute to the detection and validation of new targets for CD chemotherapy. An ideal drug would be effective against all strains and distinct typing units (DTUs) of the parasite and could be employed to treat all clinical forms of the disease. This is an important requirement to avoid the failure of the treatment due to strain resistance, as observed for the drugs commonly used for CD prophylaxis. It is surprising that although T. cruzi presents several special features compared to other eukaryotic organisms, such as mRNA polycistronic transcription, glycosomes, kinetoplasts with a network of maxiand minicircles, and extensive mitochondrial RNA editing, it is a challenge to develop specific drugs acting on the functioning enzymes that confer uniqueness to trypanosomatids in nature. It is possible that treatment failure in CD may be due to the existence of dormant forms (persisters) of T. cruzi that persist after acute infection. Accordingly, it is not clear in which tissues/cells the parasites hide in chronic phase patients and what, other than immune failure, determines the evolution to a chronic symptomatic form of disease. The absence of an animal model that mimics the complexity of the disease has impaired progress in the study of CD, despite the claims from several authors that postulate the reliability of their models. Nonetheless, progress in parasite-host interactions should increase due to the improvement of high-precision bioluminescence imaging, which allows the visualization of T. cruzi during infection in animal models after parasite inoculation. In addition, new genetic manipulation tools, such as CRISPR-Cas technology, would allow the manipulation of target genes to obtain further insight into parasite-host interactions. The actual strategies for CD prophylaxis are mainly focused on targeting the parasite. Additional efforts should be invested in addressing the treatment of CD to address issues related to human host responses, particularly the modulation of the host immune response, hence allowing a broader understanding of the complex pathophysiology of CD. Accordingly, the prognostic of the disease would be a remarkable breakthrough because preventive measures could be implemented to avoid or diminish damage to patients. The accompanying article by Kratz et al. provides a fully referenced comprehensive review of some of the topics discussed above. Carlos Chagas first described the disease 120 years ago, which was a remarkable scientific contribution. Despite the numerous studies performed since that description, we still face the challenge of eradicating this important neglected disease.
Brazilian science: towards extinction? Samuel Goldenberg, Marcio L Rodrigues, Wilson Savino Memorias do Instituto Oswaldo Cruz, 2022 Brazilian science is under attack. In this manuscript, we will discuss the most recent events that, if not reverted, will make Brazilian science inviable. We urge the scientific community in Brazil and abroad to stand up and resist in defense of more than a century of essential scientific contributions.
Species-selective targeting of pathogens revealed by the atypical structure and active site of Trypanosoma cruzi histone deacetylase DAC2 Martin Marek, Elizabeth Ramos-Morales, Gisele F.A. Picchi-Constante, Theresa Bayer, Carina Norström, et al. Cell Reports, 2021 Writing and erasing of posttranslational modifications are crucial to phenotypic plasticity and antigenic variation of eukaryotic pathogens. Targeting pathogens' modification machineries, thus, represents a valid approach to fighting parasitic diseases. However, identification of parasitic targets and the development of selective anti-parasitic drugs still represent major bottlenecks. Here, we show that the zinc-dependent histone deacetylases (HDACs) of the protozoan parasite Trypanosoma cruzi are key regulators that have significantly diverged from their human counterparts. Depletion of T. cruzi class I HDACs tcDAC1 and tcDAC2 compromises cell-cycle progression and division, leading to cell death. Notably, tcDAC2 displays a deacetylase activity essential to the parasite and shows major structural differences with human HDACs. Specifically, tcDAC2 harbors a modular active site with a unique subpocket targeted by inhibitors showing substantial anti-parasitic effects in cellulo and in vivo. Thus, the targeting of the many atypical HDACs in pathogens can enable anti-parasitic selective chemical impairment.
