T Cell-Dependence of Lassa Fever Pathogenesis

Lukas Flatz,Uwe-Karsten Hanisch,Doron Merkler,Stephan Günther,Tommy Regen,Toni Rieger,Mario Kreutzfeldt,Mariann Schedensack,Admar Verschoor,Daniel D Pinschewer,Lukas Bestmann,Andreas Bergthaler,Wolfgang Brück

doi:10.1371/journal.ppat.1000836

Abstract

Lassa virus (LASV), the causative agent of Lassa fever (LF), is endemic in West Africa, accounting for substantial morbidity and mortality. In spite of ongoing research efforts, LF pathogenesis and mechanisms of LASV immune control remain poorly understood. While normal laboratory mice are resistant to LASV, we report that mice expressing humanized instead of murine MHC class I (MHC-I) failed to control LASV infection and develop severe LF. Infection of MHC-I knockout mice confirmed a key role for MHC-I-restricted T cell responses in controlling LASV. Intriguingly we found that T cell depletion in LASV-infected HHD mice prevented disease, irrespective of high-level viremia. Widespread activation of monocyte/macrophage lineage cells, manifest through inducible NO synthase expression, and elevated IL-12p40 serum levels indicated a systemic inflammatory condition. The absence of extensive monocyte/macrophage activation in T cell-depleted mice suggested that T cell responses contribute to deleterious innate inflammatory reactions and LF pathogenesis. Our observations in mice indicate a dual role for T cells, not only protecting from LASV, but also enhancing LF pathogenesis. The possibility of T cell-driven enhancement and immunopathogenesis should be given consideration in future LF vaccine development.

Highlights

Lassa virus (LASV) is the causative agent of Lassa fever (LF) [1]
We propose a concept whereby the body’s immune defense either defeats LASV rapidly or, if unsuccessful, becomes an essential facilitator of disease. This latter paradoxical postulate stems from observations in genetically engineered (HHD) mice, which we found to be susceptible to LF
We further found that LF correlated with widespread activation of macrophages, which again depended on T cells

Summary

Introduction

Lassa virus (LASV) is the causative agent of Lassa fever (LF) [1]. It accounts for an estimated number of 3009000 infections and several thousand deaths in endemic areas each year [2], while imported cases have been reported from around the globe [3]. The virus is listed category A by the Center for Disease Control and Prevention [4]. The development of effective vaccination strategies would benefit from further insight into the mechanisms of successful LASV immune control, as well as into the processes underlying LF development and pathogenesis. As with other viral hemorrhagic fevers [6,7], a contribution of the host response to LF pathogenesis has long been a matter of debate.

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