Dengue Virus-Susceptible Animal Models: Research Progress, Core Bottlenecks, and Future Perspectives.

Dengue fever (DF) is an acute mosquito-borne infectious disease caused by dengue virus (DENV), primarily transmitted by Aedes aegypti and Aedes albopictus. Nearly 4 billion people worldwide are at risk of infection, and the 2024 epidemic reached an unprecedented scale. Severe cases can lead to hemorrhage, shock, and even death, prompting the WHO to classify it as a potential pandemic pathogen. Current prevention and control measures face prominent bottlenecks, including limited applicable populations for vaccines, lack of specific antiviral drugs, and increasing insecticide resistance in mosquito vectors. Notably, susceptible animal models serve as core tools for elucidating the pathogenic mechanisms of dengue virus, screening antiviral drugs, and evaluating vaccine protective efficacy, holding irreplaceable significance. This review systematically summarizes the characteristics, application scenarios, and research progress of mainstream and potential susceptible animal models, including non-human primates, mice, pigs, tree shrews, and bats. It covers model systems with different immune statuses, genetically modified types, and species-specific traits. Among these, mouse models are the most widely used due to their high flexibility and controllable cost, while non-human primate models have become key carriers for preclinical vaccine evaluation by virtue of their high homology with human immune responses. However, current models generally suffer from core bottlenecks, such as incomplete simulation of core severe phenotypes, insufficient restoration of immune mechanisms, unclear viral receptor mechanisms, and lack of unified standards for inoculation doses and evaluation indicators. These limitations make it difficult to accurately replicate key severe disease mechanisms, including antibody-dependent enhancement (ADE) and cytokine storms. Future model development should focus on core requirements-including intact immunity, broad-spectrum susceptibility, and accurate simulation of clinical pathological features-prioritize solving the simulation challenges of ADE and cytokine storms, and establish standardized experimental systems and evaluation criteria. By comprehensively summarizing the advantages and limitations of the existing models, this review provides a systematic reference for the optimization and upgrading of dengue virus-susceptible animal models. It also holds important guiding significance for promoting the in-depth development of basic dengue research, innovation in prevention and control technologies, and clinical transformation and application.