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Breakthrough Research on Dengue Virus Interaction with Human Plasmin

In a significant advancement, biological scientists from the National University of Singapore (NUS) have revealed the intricate mechanism by which the dengue virus uses its envelope protein to capture human plasmin during a blood meal. This process enhances the permeability of the mosquito midgut, ultimately facilitating viral infection.

Plasmin, a critical protease with five distinct kringle-domains (labeled KR1-5), plays a vital role in both digesting blood clots and breaking down the extracellular matrix, aiding cellular movement within tissues. While the ability of bacteria to capture human plasmin for host tissue digestion during metastasis is well-documented, the appropriation of plasmin by viruses, particularly in relation to infection, has largely remained unexplored.

Dengue virus is predominantly transmitted to humans through mosquito bites. For the virus to effectively infect human hosts, it must first traverse the mosquito midgut to reach the salivary glands. However, the mechanisms enabling this traversal have been poorly understood. Researchers discovered that the acidic motifs on the KR-4 and KR-5 domains of plasmin interact synergistically with two basic lysine-containing regions located on domain I of the dengue virus envelope protein. This interaction notably increases the permeability of the mosquito midgut, thus aiding in the virus’s infection process. Identifying these binding sites presents a promising avenue for developing strategies to disrupt this interaction and potentially prevent the spread of the dengue virus.

The study, spearheaded by Associate Professor MOK Yu Keung of the NUS Department of Biological Science, utilized an insect cell system to express individual domains of human plasmin alongside the dengue virus envelope protein. Kinetic binding experiments confirmed that both KR-4 and KR-5 domains are essential for synergistic binding to the dengue virus. Additionally, advancements in hydrogen-deuterium mass spectrometry identified specific lysine-containing regions on domain I of the dengue envelope protein that engage with plasmin, correcting earlier misconceptions that implicated KR1-3 domains in this interaction.

The findings of this important research have been published in the journal Protein Science on January 25, 2025.

Assoc. Prof. Mok expressed satisfaction with the findings, stating, “We are glad to have clarified inaccuracies in the literature. Our findings reveal new mechanisms of dengue virus pathogenesis, which could pave the way for innovative approaches to tackle vector-borne viruses.”

Looking forward, the research group aims to explore the interactions between plasmin and other arboviruses, including Zika and Chikungunya. Additionally, they plan to elucidate the crystal structure of the protein complex formed between plasmin kringle-domains and the dengue virus envelope protein, which could further enhance our understanding of viral infection processes.

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