Abstract
The pathogenesis of Lassa fever (LF), a hemorrhagic fever endemic to West Africa, remains unclear. We previously compared Lassa virus (LASV) with its genetically close, but nonpathogenic homolog Mopeia virus (MOPV) and demonstrated that the strong activation of antigen-presenting cells (APC), including type I IFN production, observed in response to MOPV probably plays a crucial role in controlling infection. We show here that human macrophages (MP) produce large amounts of CC and CXC chemokines in response to MOPV infection, whereas dendritic cells (DC) release only moderate amounts of CXC chemokines. However, in the presence of autologous T cells, DCs produced CC and CXC chemokines. Chemokines were produced in response to type I IFN synthesis, as the levels of both mediators were strongly correlated and the neutralization of type I IFN resulted in an inhibition of chemokine production. By contrast, LASV induced only low levels of CXCL-10 and CXCL-11 production. These differences in chemokine production may profoundly affect the generation of virus-specific T-cell responses and may therefore contribute to the difference of pathogenicity between these two viruses. In addition, a recombinant LASV (rLASV) harboring the NP-D389A/G392A mutations, which abolish the inhibition of type I IFN response by nucleoprotein (NP), induced the massive synthesis of CC and CXC chemokines in both DC and MP, confirming the crucial role of arenavirus NP in immunosuppression and pathogenicity. Finally, we confirmed, using PBMC samples and lymph nodes obtained from LASV-infected cynomolgus monkeys, that LF was associated with high levels of CXC chemokine mRNA synthesis, suggesting that the very early synthesis of these mediators may be correlated with a favourable outcome.
Highlights
Lassa virus (LASV) is the causal agent of Lassa fever (LF), a hemorrhagic fever endemic to West Africa [1]
We found that Mopeia virus (MOPV) and the mutant LASV, but not wild-type LASV, strongly induced CC and CXC chemokine production by dendritic cells and macrophages, in a type I IFN-dependent manner
We compare the abilities of LASV and MOPV to induce the production of CC and CXC chemokines in human antigen-presenting cells (APC), cultured alone or in the presence of T cells
Summary
Lassa virus (LASV) is the causal agent of Lassa fever (LF), a hemorrhagic fever endemic to West Africa [1]. The virus is transmitted to humans through contact with infected Mastomys sp., rodents living close to housing and constituting a natural reservoir of LASV. LF affects about 300,000 people each year, resulting in 5,000–6,000 deaths. There is no approved vaccine against the disease, and the only treatment available, ribavirin, is neither fully effective nor useful in the field, due to its limited availability and the need to initiate treatment soon after infection [2]. LF is a major public health concern in the countries in which it is endemic, and this problem is exacerbated by the tendency of the zone of endemicity to expand [3]
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