Severe Human Lassa Fever Is Characterized by Nonspecific T-Cell Activation and Lymphocyte Homing to Inflamed Tissues

J Virol. 2020 Oct 14;94(21):e01367-20. doi: 10.1128/JVI.01367-20. Print 2020 Oct 14.


Lassa fever (LF) is a zoonotic viral hemorrhagic fever caused by Lassa virus (LASV), which is endemic to West African countries. Previous studies have suggested an important role for T-cell-mediated immunopathology in LF pathogenesis, but the mechanisms by which T cells influence disease severity and outcome are not well understood. Here, we present a multiparametric analysis of clinical immunology data collected during the 2017-2018 Lassa fever outbreak in Nigeria. During the acute phase of LF, we observed robust activation of the polyclonal T-cell repertoire, which included LASV-specific and antigenically unrelated T cells. However, severe and fatal LF cases were characterized by poor LASV-specific effector T-cell responses. Severe LF was also characterized by the presence of circulating T cells with homing capacity to inflamed tissues, including the gut mucosa. These findings in LF patients were recapitulated in a mouse model of LASV infection, in which mucosal exposure resulted in remarkably high lethality compared to skin exposure. Taken together, our findings indicate that poor LASV-specific T-cell responses and activation of nonspecific T cells with homing capacity to inflamed tissues are associated with severe LF.IMPORTANCE Lassa fever may cause severe disease in humans, in particular in areas of endemicity like Sierra Leone and Nigeria. Despite its public health importance, the pathophysiology of Lassa fever in humans is poorly understood. Here, we present clinical immunology data obtained in the field during the 2018 Lassa fever outbreak in Nigeria indicating that severe Lassa fever is associated with activation of T cells antigenically unrelated to Lassa virus and poor Lassa virus-specific effector T-cell responses. Mechanistically, we show that these bystander T cells express defined tissue homing signatures that suggest their recruitment to inflamed tissues and a putative role of these T cells in immunopathology. These findings open a window of opportunity to consider T-cell targeting as a potential postexposure therapeutic strategy against severe Lassa fever, a hypothesis that could be tested in relevant animal models, such as nonhuman primates.

Keywords: Lassa fever; Lassa virus; T cells; T-cell homing; host response; pathogenesis; viral hemorrhagic fever.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • CD4-Positive T-Lymphocytes / virology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / virology
  • Child
  • Child, Preschool
  • Disease Outbreaks*
  • Female
  • Gene Expression Regulation
  • HLA-DR Antigens / genetics
  • HLA-DR Antigens / immunology
  • Humans
  • Infant
  • Infant, Newborn
  • Integrin beta1 / genetics
  • Integrin beta1 / immunology
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / pathology
  • Intestinal Mucosa / virology
  • Lassa Fever / genetics
  • Lassa Fever / immunology*
  • Lassa Fever / mortality
  • Lassa Fever / virology
  • Lassa virus / growth & development
  • Lassa virus / immunology
  • Lassa virus / pathogenicity*
  • Lymphocyte Activation*
  • Lysosomal-Associated Membrane Protein 1 / genetics
  • Lysosomal-Associated Membrane Protein 1 / immunology
  • Male
  • Mice
  • Middle Aged
  • Nigeria / epidemiology
  • Retrospective Studies
  • Severity of Illness Index
  • Skin / immunology
  • Skin / pathology
  • Skin / virology
  • Survival Analysis
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology


  • HLA-DR Antigens
  • Integrin beta1
  • Itgb1 protein, human
  • Lysosomal-Associated Membrane Protein 1
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma