Increasing dengue outbreaks in temperate Brazil is linked to Aedes aegypti invasion and infestation level driving widespread virus transmission

Dengue fever, caused by the dengue virus (DENV), is the most important mosquito-borne disease impacting human health globally, it is particularly prevalent in tropical regions where Aedes vectors thrive. However, due to a recent expansion of the main dengue vectors to subtropical and temperate zones in the last decades there is an increasing human population at risk. Brazil is a global hotspot for dengue, accounting for 70% of all dengue cases reported worldwide in 2024. Noteworthy, dengue became endemic even in the southernmost Brazilian state of Rio Grande do Sul, which until recently had only imported cases. In this study, we integrated entomological, epidemiological, and high-resolution genomic data to investigate DENV transmission dynamics in Southern Brazil over nine years. From 2015 to 2023, we detected a partial to full invasion of the state municipalities by Aedes aegypti, with dengue cases increasing substantially from 2020 onwards. The suitability index for transmission effectively predict the intensity of the outbreaks in the region, providing a two-month lead time before the surge in cases, representing an interesting proxy to forecast the outbreak size in the next few years. Invaded municipalities that surpassed a given case incidence level also increased, and by 2023, nearly half of the municipalities of the state surpassed that threshold, suggesting that dengue became endemic in the region. By analyzing 665 newly generated DENV genomes, we observed persistent overwintering lineages driving seasonal outbreaks, with the Northwest and Metropolitan regions serving as the main transmission hubs for dengue spread in the state. These regions were also the first to experience the endemic establishment of dengue lineages, making them key areas for targeted control efforts to mitigate further local outbreaks and the virus spread to other regions. These findings underscore the expansion of DENV-affected areas and increasing outbreaks into temperate zones, likely driven by the spread of the vector, associated with increased infestation level of the vector and widespread viral transmission in an immunologically naive population. In this context, enhanced control efforts are critical to mitigate the dengue burden in previously non-endemic areas.