La Crosse virus (LACV) is a mosquito-transmitted arbovirus and the main cause of virus-mediated neurological diseases in children. To date, little is known about the role of C-type lectin receptors (CLRs)—an important class of pattern recognition receptors—in LACV recognition. DC-SIGN remains the only well-described CLR that recognizes LACV. In this study, we investigated the role of additional CLR/LACV interactions. To this end, we applied a flow-through chromatography method for the purification of LACV to perform an unbiased high-throughput screening of LACV with a CLR-hFc fusion protein library. Interestingly, the CARD9-associated CLRs Mincle, Dectin-1, and Dectin-2 were identified to strongly interact with LACV. Since CARD9 is a common adaptor protein for signaling via Mincle, Dectin-1, and Dectin-2, we performed LACV infection of Mincle^−/− and CARD9^−/− DCs. Mincle^−/− and CARD9^−/− DCs produced less amounts of proinflammatory cytokines, namely IL-6 and TNF-α, albeit no reduction of the LACV titer was observed. Together, novel CLR/LACV interactions were identified; however, the Mincle/CARD9 axis plays a limited role in early antiviral responses against LACV.

Rift Valley fever (RVF) is a zoonotic and emerging disease, caused by the RVF virus (RVFV). In ruminants, it leads to “abortion storms” and enhanced mortality rates in young animals, whereas in humans it can cause symptoms like severe hemorrhagic fever or encephalitis. The role of the innate and adaptive immune response in disease initiation and progression is still poorly defined. The present study used the attenuated RVFV strain clone 13 to investigate viral spread, tissue tropism, and histopathological lesions after intranasal infection in C57BL/6 wild type (WT) and type I interferon (IFN-I) receptor I knockout (IFNAR^−/−) mice. In WT mice, 10⁴ PFU RVFV (high dose) resulted in a fatal encephalitis, but no hepatitis 7–11 days post infection (dpi), whereas 10³ PFU RVFV (low dose) did not cause clinical disease or significant histopathological lesions in liver and the central nervous system (CNS). In contrast, IFNAR^−/− mice infected with 10³ PFU RVFV developed hepatocellular necrosis resulting in death at 2–5 dpi and lacked encephalitis. These results show that IFNAR signaling prevents systemic spread of the attenuated RVFV strain clone 13, but not the dissemination to the CNS and subsequent fatal disease. Consequently, neurotropic viruses may be able to evade antiviral IFN-I signaling pathways by using the transneuronal instead of the hematogenous route.

Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus endemic to Africa and the Arabian Peninsula, which causes diseases in humans and livestock. C-type lectin receptors (CLRs) represent a superfamily of pattern recognition receptors that were reported to interact with diverse viruses and contribute to antiviral immune responses but may also act as attachment factors or entry receptors in diverse species. Human DC-SIGN and L-SIGN are known to interact with RVFV and to facilitate viral host cell entry, but the roles of further host and vector CLRs are still unknown. In this study, we present a CLR–Fc fusion protein library to screen RVFV–CLR interaction in a cross-species approach and identified novel murine, ovine, and Aedes aegypti RVFV candidate receptors. Furthermore, cross-species CLR binding studies enabled observations of the differences and similarities in binding preferences of RVFV between mammalian CLR homologues, as well as more distant vector/host CLRs.