Abstract
Live attenuated viruses are historically among the most effective viral vaccines. Development of a safe vaccine requires the virus to be less virulent, a phenotype that is historically arrived by empirical evaluation often leaving the mechanisms of attenuation unknown. The yellow fever virus 17D live attenuated vaccine strain has been developed as a delivery vector for heterologous antigens; however, the mechanisms of attenuation remain elusive. The successful and safe progress of 17D as a vaccine vector and the development of live attenuated vaccines (LAVs) to related flaviviruses requires an understanding of the molecular mechanisms leading to attenuation. Using subcutaneous infection of interferon-deficient mouse models of wild type yellow fever virus (WT YFV) pathogenesis and 17D-mediated immunity, we found that, in the absence of type I IFN (IFN-α/β), type II interferon (IFN-γ) restricted 17D replication, but not that of WT YFV, by 1–2 days post-infection. In this context, IFN-γ responses protected 17D-infected animals from mortality, largely restricted the virus to lymphoid organs, and eliminated viscerotropic disease signs such as steatosis in the liver and inflammatory cell infiltration into the spleen. However, WT YFV caused a disseminated infection, gross liver pathology, and rapid death of the animals. In vitro, IFN-γ treatment of myeloid cells suppressed the replication of 17D significantly more than that of WT YFV, suggesting a direct differential effect on 17D virus replication. Together these data indicate that an important mechanism of 17D attenuation in vivo is increased sensitivity to IFN-γ stimulated responses elicited early after infection.
Highlights
Yellow fever virus (YFV) is the prototypical member of the Flavivirus genus of the Flaviviridae family, which includes many other important arthropod-borne pathogens such as dengue, Zika, West Nile, and Japanese encephalitis viruses
Flaviviruses are more effective at antagonism of human type I IFN signaling than the analogous mouse responses.[17,18]
We found that 17D-204 was more sensitive than WT virus strain Angola[71] to the antiviral state induced by IFN-γ in vitro in specific myeloid cell subtypes likely important to YFV pathogenesis
Summary
Yellow fever virus (YFV) is the prototypical member of the Flavivirus genus of the Flaviviridae family, which includes many other important arthropod-borne pathogens such as dengue, Zika, West Nile, and Japanese encephalitis viruses. Flaviviruses are more effective at antagonism of human type I IFN signaling than the analogous mouse responses.[17,18] mice deficient in the type I interferon (IFN-α/β) receptor (AB6) are susceptible to viscerotropic disease and lethality after subcutaneous (s.c.) infection with wild-type YFV strains Asibi and Angola71.19 Interestingly, s.c. infection of 17D in AB6 mice, which mimics vaccination, does not cause discernable disease and results in life-long immunity against challenge of WT virus strain Angola71.16 mice lacking both type I and type II IFN receptors (AGB6) are susceptible to lethal infection by 17D by either subcutaneous or intra-peritoneal routes.[14,19,20] The fact that the additional deficiency of type II IFN (IFN-γ) receptors renders 17D infection lethal in AB6 mice suggests that the type II IFN system plays a critical role in attenuation of 17D in vivo. We found that 17D-204 was more sensitive than WT virus strain Angola[71] to the antiviral state induced by IFN-γ in vitro in specific myeloid cell subtypes likely important to YFV pathogenesis This is suggestive that IFN-γ sensitivity is a primary attenuation mechanism for 17D in vivo. We investigated tissue pathology at 4 dpi, which is the peak of viral replication in most visceral organs in both AB6 and AGB6 mice and 11 dpi, when the AGB6 animals displayed neurologic
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