Biology subjects

da Silva, M. S.

Publications and source records attributed to da Silva, M. S..

5 recordsLinked to original sources

bioRxiv2026

Reduced levels of inositol hexakisphosphate kinase (IP6K) impair life-cycle transitions and the intracellular development of Trypanosoma cruzi within human cardiomyocytes

Trypanosoma cruzi is the etiological agent of Chagas disease. During its life cycle, T. cruzi undergoes several key differentiation processes that are essential for its survival. The precise mechanisms that regulate these processes remain elusive, and any interference in this cycle would represent a breakthrough in the development of effective therapy against Chagas disease. Here, after depleting a single IP6K allele of T. cruzi, we observed that key differentiation processes (metacyclogenesis, amastigogenesis and trypomastigogenesis) were profoundly impaired. Epimastigote forms of IP6K-deficient T. cruzi exhibited morphological alterations and reduced metacyclogenesis. IP6K-deficient metacyclic forms had reduced infective potential in human cardiomyocytes. IP6K-deficient amastigote forms showed impaired ability to transform into trypomastigotes, with most of the population egressing from human cardiomyocytes without completing trypomastigogenesis. Together, our results suggest that IP6K is critical to sustain the T. cruzi life cycle. Since disruption of both IP6K alleles was lethal and the primary structure of IP6K shares only [~]25% similarity with its human homolog, this kinase emerges as a promising target for drug development against Chagas disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=153 HEIGHT=200 SRC="FIGDIR/small/700787v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1cb37f0org.highwire.dtl.DTLVardef@c59fb8org.highwire.dtl.DTLVardef@791cb7org.highwire.dtl.DTLVardef@14c68fd_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2023

Paradoxical activation of oncogenic signaling as a cancer treatment strategy

Cancer homeostasis depends on a balance between activated oncogenic pathways driving tumorigenesis and engagement of stress-response programs that counteract the inherent toxicity of such aberrant signaling. While inhibition of oncogenic signaling pathways has been explored extensively, there is increasing evidence that overactivation of the same pathways can also disrupt cancer homeostasis and cause lethality. We show here that inhibition of Protein Phosphatase 2A (PP2A) hyperactivates multiple oncogenic pathways and engages stress responses in colon cancer cells. Genetic and compound screens identify combined inhibition of PP2A and WEE1 as synergistic in multiple cancer models by collapsing DNA replication and triggering premature mitosis followed by cell death. This combination also suppressed the growth of patient-derived tumors in vivo. Remarkably, acquired resistance to this drug combination suppressed the ability of colon cancer cells to form tumors in vivo. Our data suggest that paradoxical activation of oncogenic signaling can result in tumor suppressive resistance.

cancer biology↗

bioRxiv2022

Chikungunya virus transmission in the Southernmost state of Brazil was characterized by self-limited cases (2017 to 2019) and a larger 2021 outbreak

Chikungunya is a reemerging arthropod-borne virus that has been causing large outbreaks in the Americas. In Brazil, Asian-Caribbean and ECSA genotypes have been detected and lead to large outbreaks in several states since 2014. In Rio Grande do Sul (RS), the southernmost State, the first autochthonous cases were reported in 2016. We employed genome sequencing and epidemiological investigation to characterize the increasing CHIKF burden in RS between 2017- 2021. Distinct lineages of the ECSA genotype were responsible for human infections between 2017-2021. Until 2020, CHIKV introductions were most travel associated and transmission was limited. Then, in 2021, the largest outbreak occurred in the state associated with the introduction of a new ECSA lineage. New CHIKV outbreaks are likely to occur in the near future due to abundant competent vectors and a susceptible population, exposing more than 11 million inhabitants to an increasing infection risk.

molecular biology↗

bioRxiv2017

Fibroblast Growth Factor 2 lethally sensitizes cancer cells to stress-targeted therapeutic inhibitors

In malignant transformation, cellular stress response pathways are dynamically mobilized to counterbalance oncogenic activity, keeping cancer cells viable. Therapeutic disruption of this riskily balanced homeostasis might change the outcome of many human cancers, particularly those for which no effective therapy is available. Here, we report the use of Fibroblast Growth Factor 2 (FGF2) to demonstrate that further mitogenic activation disrupts cellular homeostasis and strongly sensitizes cancer cells to stress-targeted therapeutic inhibitors. We show that FGF2 enhanced replication and proteotoxic stresses in a K-Ras-driven murine cancer cell model, and combinations of FGF2 and proteasome or DNA damage response-checkpoint inhibitors triggered cell death. CRISPR/Cas9-mediated K-Ras depletion suppressed the malignant phenotype and prevented these synergic toxicities in these murine cells. Moreover, in a panel of human Ewings sarcoma family tumor cells, sub-lethal concentrations of bortezomib (proteasome-inhibitor) or VE-821 (ATR-inhibitor) induced cell death when combined with FGF2. Sustained MAPK-ERK1/2 overactivation induced by FGF2 underlies these synthetic lethalities, once late pharmacological inhibition of this pathway restored cell homeostasis and prevented these described synergies. Our results highlight how mitotic signaling pathways frequently overridden in malignant transformation might be exploited to disrupt the risky robustness of cancer cells, ultimately sensitizing them to stress-targeted therapies. This approach provides a new therapeutic rationale for human cancers, with important implications for tumors still lacking effective treatment, and for those that frequently relapse after available therapies.

cancer biology↗

bioRxiv2017

Analysis of the immunological biomarker profile during acute Zika virus infection reveals the overexpression of CXCL10, a chemokine already linked to neuronal damage

Infection with Zika virus (ZIKV) manifests in a broad spectrum of disease ranging from mild illness to severe neurological complications. To define immunologic correlates of ZIKV infection, we characterized the levels of circulating cytokines, chemokines and growth factors in 54 infected patients of both genders, at five different time-points after symptoms onset using microbeads multiplex immunoassay; statistical analysis and data mining compared to 100 age-matched controls. ZIKV-infected patients present a striking systemic inflammatory response with high levels of pro-inflammatory mediators. Despite the strong inflammatory pattern, IL-1Ra and IL-4 are also induced during acute infection. Interestingly, the inflammatory cytokines, IL-1{beta}, IL-13, IL-17, TNF-, IFN-{gamma}; chemokines, CXCL8, CCL2, CCL5; and the growth factor G-CSF display a bimodal distribution accompanying viremia. While this is the first manuscript to document bimodal distributions of viremia in ZIKV infection, bimodal viremia has been documented in other viral infections with primary viremia peaks during mild systemic disease and a secondary viremia with distribution of the virus to organs and tissues. Moreover, biomarker network analysis demonstrated distinct dynamics in consonance with the bimodal viremia profiles at different time-points during ZIKV infection. Such robust cytokine and chemokine response has been associated with blood-brain barrier permeability and neuroinvasiveness in other flaviviral infections. High-dimensional data analysis further established CXCL10, a chemokine involved in fetal neuron apoptosis and Guillain-Barre syndrome, as the most promising biomarker of acute ZIKV infection for a potential clinical application.\n\nAuthor SummaryInfection with Zika virus manifests in a broad spectrum of disease ranging from mild illness to severe neurological complications. This study characterized the levels of circulating cytokines, chemokines and growth factors in Zika-infected patients showing an inflammatory immune response. Specifically, this study identified a chemokine, CXCL10, known to be involved in fetal neuron apoptosis and Guillain-Barre syndrome, as the most promising biomarker to characterize acute Zika virus infection.

immunology↗