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

TY - JOUR

T1 - Severe Human Lassa Fever Is Characterized by Nonspecific T-Cell Activation and Lymphocyte Homing to Inflamed Tissues

AU - Port, Julia R

AU - Wozniak, David M

AU - Oestereich, Lisa

AU - Pallasch, Elisa

AU - Becker-Ziaja, Beate

AU - Müller, Jonas

AU - Rottstegge, Monika

AU - Olal, Catherine

AU - Gómez-Medina, Sergio

AU - Oyakhliome, Jennifer

AU - Ighodalo, Yemisi

AU - Omomoh, Emmanuel

AU - Olokor, Thomas

AU - Adomeh, Donatus I

AU - Asogun, Danny

AU - Ogbani-Emovon, Ephraim

AU - Hartmann, Kristin

AU - Krasemann, Susanne

AU - Nelson, Emily V

AU - Escudero-Pérez, Beatriz

AU - McElroy, Anita K

AU - Günther, Stephan

AU - Muñoz-Fontela, César

N1 - Copyright © 2020 Port et al.

PY - 2020/10/14

Y1 - 2020/10/14

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Animals

KW - CD4-Positive T-Lymphocytes/immunology

KW - CD8-Positive T-Lymphocytes/immunology

KW - Child

KW - Child, Preschool

KW - Disease Outbreaks

KW - Female

KW - Gene Expression Regulation

KW - HLA-DR Antigens/genetics

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Integrin beta1/genetics

KW - Interferon-gamma/genetics

KW - Intestinal Mucosa/immunology

KW - Lassa Fever/genetics

KW - Lassa virus/growth & development

KW - Lymphocyte Activation

KW - Lysosomal-Associated Membrane Protein 1/genetics

KW - Male

KW - Mice

KW - Middle Aged

KW - Nigeria/epidemiology

KW - Retrospective Studies

KW - Severity of Illness Index

KW - Skin/immunology

KW - Survival Analysis

KW - Tumor Necrosis Factor-alpha/genetics

U2 - 10.1128/JVI.01367-20

DO - 10.1128/JVI.01367-20

M3 - SCORING: Journal article

C2 - 32817220

VL - 94

JO - J VIROL

JF - J VIROL

SN - 0022-538X

IS - 21

ER -