Carneiro, P. H. | Search bioRxiv

bioRxiv2025

Therapeutic Potential of Cyclodextrins Targeting Dengue Virus and SARS-CoV-2 Infection and Pathogenesis

Cyclodextrins (CDs) are cyclic oligosaccharides with promising therapeutic applications, including antiviral activity. During viral infections, pathogenesis arises not only from viral replication but also from viral proteins that act as "toxins", disrupting cellular barriers and inducing endothelial dysfunction, a hallmark of severe diseases such as dengue and COVID-19. Dengue virus (DENV) NS1 and SARS-CoV-2 Spike proteins induce endothelial hyperpermeability, contributing to severe complications. Here we explored the potential of a panel of 18 CDs in mitigating endothelial dysfunction caused by these viral proteins and evaluated the CDs antiviral activity in vitro and in vivo. The effect of CDs on endothelial hyperpermeability was assessed using a trans-endothelial electrical resistance assay with human pulmonary microvascular endothelial cells exposed to DENV NS1 and SARS-CoV-2 Spike proteins. Antiviral efficacy of CDs was evaluated in Vero cells infected with DENV2 and Calu-3 cells infected with SARS-CoV-2, and in vivo protection was assessed in a lethal DENV2 mouse model. CDs effectively inhibited DENV NS1-induced endothelial hyperpermeability in vitro, demonstrating their potential to counteract NS1-mediated barrier disruption. In the murine model, CD1 treatment provided partial protection against DENV-induced morbidity and mortality. Further, CDs significantly reduced SARS-CoV-2 infection in vitro and inhibited Spike-induced endothelial dysfunction. These findings indicate that CDs can prevent endothelial hyperpermeability induced by DENV NS1 and SARS-CoV-2 Spike proteins and exhibit antiviral activity against SARS-CoV-2, positioning them as promising candidates for mitigating endothelial complications associated with viral infections. Further research is needed to explore the clinical relevance of CDs and their mechanisms of action.

microbiology↗

bioRxiv2025

Interplay between Hyperglycemia and Chikungunya Virus Infection: Pathophysiological Insights from Murine Model

Chikungunya fever (CHIKF) is a re-emerging viral disease characterized by acute systemic manifestations and debilitating musculoskeletal symptoms that can persist after viral clearance. Although typically self-limiting in healthy individuals, clinical outcomes are significantly worsened in patients with pre-existing comorbidities, particularly diabetes mellitus (DM). Epidemiological data links DM to heightened CHIKF severity and a greater risk of developing chronic arthropathy, yet the mechanism underpinning this association remains poorly understood. In this study, we established an in vivo streptozotocin (STZ)-induced diabetic C57BL/6 mice as a model to investigate the impact of DM on CHIKV pathogenesis. STZ induces selective pancreatic {beta}-cell destruction and persistent hyperglycemia. Diabetic animals infected with CHIKV exhibited aggravated joint inflammation, increased nociceptive sensitivity, and elevated serum markers of muscle and hepatic injury, including creatine kinase (CK) and alanine aminotransferase (ALT). Histopathological analyses revealed that CHIKV infection alone disrupted joint architecture. However, in the diabetic context, these alterations were significantly exacerbated, with enhanced inflammatory infiltrates, chondrocyte loss, osteocyte necrosis, and fibrotic remodeling. These results demonstrate that the diabetic metabolic environment profoundly amplifies CHIKV-induced tissue damage and impairs resolution of inflammation, offering a plausible mechanistic explanation for the poorest CHIKF outcomes observed in diabetic patients. Thus, this model provides a valuable platform for exploring the molecular drivers of CHIKF severity and chronicity, especially among DM patients, as well as for development of pharmacological tools to mitigate CHIKV-associated complications in metabolically vulnerable populations. ImportanceChikungunya virus is responsible for a re-emerging disease that causes intense joint pain and long-lasting inflammation, especially in vulnerable individuals. People with diabetes are known to suffer more severe and persistent symptoms, but the biological reasons behind this have remained unclear. In this study, we used a diabetic mouse model to investigate how a high-glucose environment influences the course of Chikungunya virus infection. We found that diabetic mice experienced more intense joint damage, increased pain sensitivity, and signs of broader organ injury compared to non-diabetic animals. Microscopic analyses of tissues showed greater inflammation and structural damage in the joints of diabetic animals. These findings suggest that diabetes directly worsens the effects of Chikungunya virus infection by amplifying inflammation and delaying healing. This model helps explain why diabetic patients have worse outcomes and may assist in developing new treatments to protect high-risk populations from long-term complications of this infection.

immunology↗