Aggressive organ penetration and high vector transmissibility of epidemic dengue virus-2 Cosmopolitan genotype in a transmission mouse model

Dengue virus (DENV) causes dengue fever and severe hemorrhagic fever in humans and is primarily transmitted by Aedes aegypti and A. albopictus mosquitoes. The incidence of DENV infection has been gradually increasing in recent years due to global urbanization and international travel. Understanding the virulence determinants in host and vector transmissibility of emerging epidemic DENV will be critical to combat potential outbreaks. The DENV serotype 2 (DENV-2), which caused a widespread utbreak in Taiwan in 2015 (TW2015), is of the Cosmopolitan genotype and is hylogenetically related to the virus strain linked to another large outbreak in Indonesia in 2015. We found that the TW2015 virus was highly virulent in type I and type II interferon-deficient mice, with robust replication in spleen, lung, and intestine. The TW2015 virus also had high transmissibility to Aedes mosquitoes and could be effectively spread in a continuous mosquitoes-mice-mosquitoes-mice transmission cycle. By making 16681-based mutants carrying different segments of the TW2015 virus, we identified structural pre-membrane (prM) and envelope (E) genes as key virulence determinants in the host, with involvement in the high transmissibility of the TW2015 virus in mosquitoes. The transmission mouse model will make a useful platform for evaluation of DENV with high epidemic potential and development of new strategies against dengue outbreaks. Author summary Dengue fever and dengue hemorrhagic fever in humans are caused by Aedes mosquito-mediated dengue virus infection. Large dengue outbreaks occurred in recent years and many tropical and subtropical countries became hyperendemic with all four dengue virus serotypes. We characterized the endemic dengue virus TW2015, which caused large outbreaks in Taiwan and Indonesia in 2015. Compared to other dengue viruses, the TW2015 virus was highly virulent in mice, with robust replication in spleen, lung, and intestine. The TW2015 virus had high transmissibility between mice and mosquitoes. The TW2015 structural genes that function in attachment of the virus particle to the cell surface during infection may be responsible for the high virulence of the virus in mice and its high transmissibility in mosquitoes. Our study revealed the key components of the dengue virus that contribute to its high likelihood of causing dengue outbreaks. These results will aid in the development of new approaches to prevent future dengue epidemics.