Heterologous flavivirus exposure provides varying degrees of cross-protection from Zika virus in a mouse model of infection

The 2015/16 Zika virus epidemic in South and Central America left the scientific community urgently trying to understand the disease and the factors which modulate Zika virus pathogenesis. Multiple other flaviviruses are endemic in areas where Zika virus emerged in 2015/16. Therefore, it is hypothesized that a key to understanding how Zika virus infection and disease progresses, is to study Zika virus infection in the context of prior flavivirus exposure. Humans and animal studies have highlighted the idea that having been previously exposed to a heterologous flavivirus may modulate the immune response to Zika virus. However, it is still unclear 1) how this impacts viral burden and pathology, and 2) the factors which correlate with the multiple metrics of disease. In this murine study, we longitudinally examine multiple factors involved in Zika disease, linking viral burden over time with increased neurological disease severity and weight loss. We show that prior heterologous flavivirus exposure with dengue virus type 2 or 3, or the vaccine strain of yellow fever, provides protection from mortality in a lethal Zika challenge. Reduction in viral burden and Zika disease in the context of prior flavivirus exposure varies depending on the infecting primary virus; with primary Zika infection being most protective from Zika challenge, followed by dengue 2, yellow fever, and dengue 3. This study demonstrates a protective effect of prior heterologous flavivirus exposure on Zika virus pathogenesis, and defines the relationship between prior flavivirus exposure and the potential for Zika virus disease. IMPORTANCEThe emergence and re-emergence of various vector-borne diseases in recent years highlights the need to understand the mechanisms of protection for each pathogen. In this study, we investigated the impact of prior exposure to Zika, dengue serotypes 2, 3, and the vaccine strain of yellow fever on pathogenesis and disease outcomes in a mouse model of Zika virus infection. We found that prior exposure to a heterologous flavivirus was protective from mortality, neurological disease, weight loss, and severe viral burden during a lethal Zika challenge. Using a longitudinal study design, we were able to link multiple disease parameters including viral burden over time with neurological disease severity and weight loss in the context of heterologous infection. This study demonstrates a role for heterologous flavivirus exposure in modulating flavivirus pathophysiology. Given the cyclic nature of most flavivirus outbreaks, this work will contribute to the forecasting of disease severity for future outbreaks.