Distinctive TLR7 Signaling, Type I IFN Production, and Attenuated Innate and Adaptive Immune Responses to Yellow Fever Virus in a Primate Reservoir Host

Abstract

Why cross-species transmissions of zoonotic viral infections to humans are frequently associated with severe disease when viruses responsible for many zoonotic diseases appear to cause only benign infections in their reservoir hosts is unclear. Sooty mangabeys (SMs), a reservoir host for SIV, do not develop disease following SIV infection, unlike nonnatural HIV-infected human or SIV-infected rhesus macaque (RM) hosts. SIV infections of SMs are characterized by an absence of chronic immune activation, in association with significantly reduced IFN-α production by plasmacytoid dendritic cells (pDCs) following exposure to SIV or other defined TLR7 or TLR9 ligands. In this study, we demonstrate that SM pDCs produce significantly less IFN-α following ex vivo exposure to the live attenuated yellow fever virus 17D strain vaccine, a virus that we show is also recognized by TLR7, than do RM or human pDCs. Furthermore, in contrast to RMs, SMs mount limited activation of innate immune responses and adaptive T cell proliferative responses, along with only transient antiviral Ab responses, following infection with yellow fever vaccine 17D strain. However, SMs do raise significant and durable cellular and humoral immune responses comparable to those seen in RMs when infected with modified vaccinia Ankara, a virus whose immunogenicity does not require TLR7/9 recognition. Hence, differences in the pattern of TLR7 signaling and type I IFN production by pDCs between primate species play an important role in determining their ability to mount and maintain innate and adaptive immune responses to specific viruses, and they may also contribute to determining whether disease follows infection.

Viral entry route determines how human plasmacytoid dendritic cells produce type I interferons

“…This mixed cell population consisted of several cell types, only 0.4% of which were pDCs. Therefore, in this previous study (53), IFN-a may have been produced mainly by pDCs that sensed other infected blood cells through TLR7.…”

Infection Dynamics of Sylvatic Dengue Virus in a Natural Primate Host, the African Green Monkey

“…1). Mandl and others 19 showed that the YFV-17D live-attenuated vaccine strain replicated to lower levels and for shorter duration in YFV reservoir (sooty mangabeys [Cercocebus atys]) than novel (rhesus macaques [Macaca mulatta]) hosts. Moreover, neutralizing antibody responses to YFV-17D were significantly lower in sooty mangabeys than in rhesus macaques 28 days post-infection (pi); neutralizing antibodies waned to undetectable levels by 120 days pi in sooty mangabeys but were maintained at high levels in rhesus macaques.…”

“…Monkeys were anesthetized with ketamine at an intramuscular (i.m.) dose of 10 mg/kg body weight on day 0 of the study; and other flaviviruses 19 in NHPs and DENV vaccine candidates in humans. 23 Inocula were administered in a total volume of 1 mL, with 0.5 mL administered to each upper arm.…”

Immune activation alters cellular and humoral responses to yellow fever 17D vaccine

“…This immune response involves the coordinated induction of several effector arms of innate immunity as well as adaptive immunity (10,11). Studies have suggested that the ability of YF-17D to infect dendritic cells and activate multiple Toll-like receptors may be essential for generating this potent immune response (8,(12)(13)(14). The YF-17D vaccine provides a model to study the immune response to vaccination in human populations, including both cellular and humoral responses, and to dissect the mechanisms of effective vaccine responses (10,(15)(16)(17)(18).…”