Alterations in NF-κB and RBP-Jκ by Arenavirus Infection of Macrophages In Vitro and In Vivo

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Abstract
Pichinde virus is an arenavirus that infects guinea pigs and serves as an animal model for human Lassa fever. An attenuated Pichinde virus variant (P2) and a virulent variant (P18) are being used to delineate pathogenic mechanisms that culminate in shock. In guinea pigs, the infection has been shown to begin in peritoneal macrophages following intraperitoneal inoculation and then spreads to the spleen and other reticuloendothelial organs. We show here that infection of the murine monocytic cell line P388D1 with either Pichinde virus variant resulted in the induction of inflammatory cytokines and effectors, including interleukin-6 and tumor necrosis factor alpha. Since these genes are regulated in part by the cellular transcription factors NF-κB and RBP-Jκ, we compared the activities of NF-κB and RBP-Jκ in P388D1 cells following infection with Pichinde virus. The attenuated P2 virus inhibited NF-κB activation and caused a shift in the size of the RBP-Jκ complex. The virulent P18 virus showed less inhibition of NF-κB and failed to alter the size of the RBP-Jκ complex. Peritoneal cells from P2-infected guinea pigs showed induction of NF-κB RelA/p50 heterodimer and p50/p50 homodimer and manifested an increase in the size of RBP-Jκ. By contrast, P18 induced large amounts of the NF-κB p50/p50 dimer but failed to induce RelA/p50 or to cause an increase in the RBP-Jκ size. Taken together, these changes suggest that the attenuated viral strain induces an “activation” of macrophages, while the virulent form of the virus does not.