Transcriptome Analysis of Human Peripheral Blood Mononuclear Cells Exposed to Lassa Virus and to the Attenuated Mopeia/Lassa Reassortant 29 (ML29), a Vaccine Candidate

Zapata, Juan Carlos; Carrion, Ricardo; Patterson, Jean L.; Crasta, Oswald; Zhang, Yan; Mani, Sachin; Jett, Marti; Poonia, Bhawna; Djavani, Mahmoud; White, David M.; Lukashevich, Igor S.; Salvato, Maria S.

The most affected gene, IFI6, is the first IFN-stimulated gene known to inhibit apoptosis [46] . Among other most affected genes were IFI35, IFITM1, IRF-7, and SP110. While the function of the IFI35 gene is not well-defined, the IFITM proteins have roles in immune cell signaling and adhesion, cancer, germ cell physiology, and bone mineralization. IFITMs are also viral restriction factors that block entry of Influenza, Ebola, Dengue and West Nile viruses but not arenavirus-envelope pseudotyped particles [47] [48] [49] . IRF-7 is over-expressed in LASVexposed PBMC and others found that it could be up-regulated in 3-day LASV-infected monocyte-derived macrophages [50] . IRF-7 is also known to limit the burst size of LCMV in culture but is Table S1 in the supplemental material. Green color represents down-regulated genes (two-fold or more when compared with non-exposed control). Red color represents up-regulated genes (two-fold or more when compared with non-exposed control). doi:10.1371/journal.pntd.0002406.g001 not ultimately essential for LCMV clearance in vivo [51] . IRF-7 and IRF-3 are transcription factors which together with NF-kB and ATF-2/cJUN induce production of IFN-I. IRF-3 is required for the activation of IFN-b, which in turn, primes the expression of most IFN-a genes by IFN-induced IRF-7 through the STAT-1 pathway. Human SP110 plays an important role in resistance to intracellular pathogens such as human mycobacteria and intracellular cancers. Recently cellular proteins have been described that mediate the interaction of SP110 and viral proteins during viral infections [52] . Among apoptosis-related genes, the most striking difference was observed in the expression of matrix metalloproteinase, MMP-1 (interstitial collagenase), up-regulated .65-fold in LASV-exposed cells versus ML-29-exposed cells ( Table 2 ). Proteins of the MMP family normally breakdown extracellular matrix during embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. MMP-1 is known to interact with Tat, the HIV transactivating protein, and this interaction results in the degradation of Tat and depression of Tat-mediated neurotoxicity and transactivation [53] .