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Dengue virus (DENV) infection is a significant global health threat, with increasing incidence in endemic regions and expanding geographic range due to factors like global warming. Current models for studying DENV pathogenesis often lack the complexity of the human immune system, hindering the development of effective therapies and vaccines. To address this, we have established the first in vitro whole-blood model using hirudin, preserving critical immune components and cellular interactions. This model reveals granulocytes as previously unrecognized targets of productive DENV infection, challenging existing paradigms of viral tropism. Our ex vivo analysis of patient blood samples confirms the clinical relevance of this finding and validates our model’s utility. This unique model offers a powerful platform for future studies to dissect the complex interactions between DENV and the host immune system, including the roles of different leukocyte populations, ultimately informing the development of novel therapeutic strategies to combat this devastating disease.

With sequencing as a standard frontline protocol to identify emerging viruses such zika virus and SARS-CoV2, direct utilization of sequence data to program antivirals against the viruses could accelerate drug development to treat their infections. CRISPR-Cas effectors are promising candidates that could be programmed to inactivate viral genetic material based on sequence data but several challenges such as delivery and design of effective crRNA need to be addressed to realize practical use. Here, we showed that virus-like particle (VLP) could deliver PspCas13b-crRNA ribonucleoprotein (RNP) in nanomolar range to efficiently suppress dengue virus infection in primary human target cells. Shortening spacer length could significantly enhance RNA-targeting efficiency of PspCas13b in mammalian cells compared to the natural length of 30 nucleotides without compromising multiplex targeting by a crRNA array. Our results demonstrate the potentials of applying PspCas13b RNP to suppress RNA virus infection, with implications in targeting host RNA as well.