Bryan Castillo-Rojas

All Publications

• The inflammasome pathway is activated by dengue virus non-structural protein 1 and is protective during dengue virus infection PLOS PATHOGENS Wong, M. P., Juan, E. Y. W., Pahmeier, F., Chelluri, S. S., Wang, P., Castillo-Rojas, B., Blanc, S. F., Biering, S. B., Vance, R. E., Harris, E. 2024; 20 (4): e1012167

  Abstract

  Dengue virus (DENV) is a medically important flavivirus causing an estimated 50-100 million dengue cases annually, some of whom progress to severe disease. DENV non-structural protein 1 (NS1) is secreted from infected cells and has been implicated as a major driver of dengue pathogenesis by inducing endothelial barrier dysfunction. However, less is known about how DENV NS1 interacts with immune cells and what role these interactions play. Here we report that DENV NS1 can trigger activation of inflammasomes, a family of cytosolic innate immune sensors that respond to infectious and noxious stimuli, in mouse and human macrophages. DENV NS1 induces the release of IL-1β in a caspase-1 dependent manner. Additionally, we find that DENV NS1-induced inflammasome activation is independent of the NLRP3, Pyrin, and AIM2 inflammasome pathways, but requires CD14. Intriguingly, DENV NS1-induced inflammasome activation does not induce pyroptosis and rapid cell death; instead, macrophages maintain cellular viability while releasing IL-1β. Lastly, we show that caspase-1/11-deficient, but not NLRP3-deficient, mice are more susceptible to lethal DENV infection. Together, these results indicate that the inflammasome pathway acts as a sensor of DENV NS1 and plays a protective role during infection.

  View details for DOI 10.1371/journal.ppat.1012167

  View details for Web of Science ID 001209049700004

  View details for PubMedID 38662771

  View details for PubMedCentralID PMC11075848

• SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling NATURE COMMUNICATIONS Biering, S. B., de Sousa, F., Tjang, L., Pahmeier, F., Zhu, C., Ruan, R., Blanc, S. F., Patel, T. S., Worthington, C. M., Glasner, D. R., Castillo-Rojas, B., Servellita, V., Lo, N. T. N., Wong, M. P., Warnes, C. M., Sandoval, D. R., Clausen, T., Santos, Y. A., Fox, D. M., Ortega, V., Naar, A. M., Baric, R. S., Stanley, S. A., Aguilar, H. C., Esko, J. D., Chiu, C. Y., Pak, J. E., Beatty, P., Harris, E. 2022; 13 (1): 7630

  Abstract

  Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well as in distal organs. While it is appreciated that an exaggerated inflammatory response is associated with barrier dysfunction, the triggers of vascular leak are unclear. Here, we report that cell-intrinsic interactions between the Spike (S) glycoprotein of SARS-CoV-2 and epithelial/endothelial cells are sufficient to induce barrier dysfunction in vitro and vascular leak in vivo, independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-β signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-β signaling axis are required for S-mediated barrier dysfunction. Notably, we show that SARS-CoV-2 infection caused leak in vivo, which was reduced by inhibiting integrins. Our findings offer mechanistic insight into SARS-CoV-2-triggered vascular leak, providing a starting point for development of therapies targeting COVID-19.

  View details for DOI 10.1038/s41467-022-34910-5

  View details for Web of Science ID 000969991400003

  View details for PubMedID 36494335

  View details for PubMedCentralID PMC9734751