Abstract
ABSTRACTYellow fever virus (YFV) is an arthropod-borne flavivirus, infecting ~200,000 people worldwide annually and causing about 30,000 deaths. The live attenuated vaccine strain, YFV-17D, has significantly contributed in controlling the global burden of yellow fever worldwide. However, the viral and host contributions to YFV-17D attenuation remain elusive. Type I interferon (IFN-α/β) signaling and type II interferon (IFN-γ) signaling have been shown to be mutually supportive in controlling YFV-17D infection despite distinct mechanisms of action in viral infection. However, it remains unclear how type III IFN (IFN-λ) integrates into this antiviral system. Here, we report that while wild-type (WT) and IFN-λ receptor knockout (λR−/−) mice were largely resistant to YFV-17D, deficiency in type I IFN signaling resulted in robust infection. Although IFN-α/β receptor knockout (α/βR−/−) mice survived the infection, mice with combined deficiencies in both type I signaling and type III IFN signaling were hypersusceptible to YFV-17D and succumbed to the infection. Mortality was associated with viral neuroinvasion and increased permeability of the blood-brain barrier (BBB). α/βR−/− λR−/− mice also exhibited distinct changes in the frequencies of multiple immune cell lineages, impaired T-cell activation, and severe perturbation of the proinflammatory cytokine balance. Taken together, our data highlight that type III IFN has critical immunomodulatory and neuroprotective functions that prevent viral neuroinvasion during active YFV-17D replication. Type III IFN thus likely represents a safeguard mechanism crucial for controlling YFV-17D infection and contributing to shaping vaccine immunogenicity.
Highlights
Yellow fever virus (YFV) is an arthropod-borne flavivirus, infecting ~200,000 people worldwide annually and causing about 30,000 deaths
Infected with 107 PFU YFV-17D, both ␣RϪ/Ϫ and ␣RϪ/Ϫ RϪ/Ϫ mice displayed clinical manifestations of disease, as well as significant weight loss and temperature drop, between days 5 and 10 postinfection, the WT mice and RϪ/Ϫ mice did not exhibit any clinical signs of disease (Fig. 1C and D; see Fig. S1 in the supplemental material). ␣RϪ/Ϫ mice progressed to clinically apparent disease that reached a peak around day 7 postinfection but recovered over time. ␣RϪ/Ϫ RϪ/Ϫ mice exhibited similar initial signs of morbidity, but the symptoms worsened and the animals became moribund or died (Fig. 1C)
Induction of a protective immune response to YFV-17D is likely activation was characterized by quantifying the expression of activation or exhaustion markers in CD4ϩ or CD8ϩ T-cell populations using a set of eight markers (CD45RA, CD127, CCR7, CD44, CD62L, PD1, CD27, and CD28)
Summary
Yellow fever virus (YFV) is an arthropod-borne flavivirus, infecting ~200,000 people worldwide annually and causing about 30,000 deaths. We analyzed the role of type III interferon (IFN)-mediated signaling, a host immune defense mechanism, in controlling YFV-17D infection and attenuation in different mouse models. Despite the compromised functionality of their innate immune system and an absence of human-specific interactions, mice with impaired type I IFN signaling are regularly used to model YFV pathogenesis and immunogenicity. They represent an interesting complementary tool for evaluating the contribution of host determinants of YFV pathogenesis or YFV-17D attenuation prior to experiments in more relevant models such as macaques or humanized mice
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