T cell-dependence of Lassa fever pathogenesis

Area of Science:

• Immunology
• Virology
• Pathogenesis

Background:

• Lassa virus (LASV) causes Lassa fever (LF), a significant public health issue in West Africa.
• Understanding LASV pathogenesis and immune control mechanisms is crucial but remains limited.

Purpose of the Study:

• To investigate the role of T cells and MHC class I (MHC-I) in Lassa fever pathogenesis using a humanized mouse model.
• To elucidate the mechanisms underlying LASV immune control and disease progression.

Main Methods:

• Utilized mice expressing humanized MHC-I (HHD mice) and MHC-I knockout mice to study LASV infection.
• Employed T cell depletion strategies in infected HHD mice.
• Assessed viral load, disease severity, and inflammatory markers like inducible NO synthase and IL-12p40.

Main Results:

• Humanized MHC-I mice failed to control LASV infection, developing severe Lassa fever.
• MHC-I-restricted T cell responses were critical for LASV control.
• T cell depletion prevented severe disease in HHD mice, despite high viremia, suggesting T cells drive pathology.
• LASV infection induced systemic inflammation characterized by monocyte/macrophage activation.

Conclusions:

• T cells play a dual role in Lassa fever, offering protection but also contributing to immunopathogenesis.
• T cell-driven inflammation exacerbates Lassa fever severity.
• Consideration of T cell-mediated pathology is essential for developing effective Lassa fever vaccines.