Immunoactivation induced by chronic viral infection inhibits viral replication and drives immunosuppression through sustained IFN-I responses.
Acute or chronic viral infections can lead to generalized immunosuppression. Several mechanisms, such as immunopathology of CD8(+) T cells, inhibitory receptors, or regulatory T (Treg) cells, contribute to immune dysfunction. Moreover, patients with chronic viral infections usually do not respond to vaccination, a finding that has not been previously explained. Recently, we reported that CD169(+) macrophages enforce viral replication, which is essential for guaranteeing antigen synthesis and efficient adaptive immune responses. In the present study, we used a chronic lymphocytic choriomeningitis virus infection mouse model to determine whether this mechanism is affected by chronic viral infection, which may impair the activation of adaptive immunity. We found that enforced viral replication of a superinfecting virus is completely blunted in chronically infected mice. This absence of enforced viral replication in CD169(+) macrophages is not explained by CD8(+) T-cell-mediated immunopathology but rather by prolonged IFN-I responses. Consequently, the absence of viral replication impairs both antigen production and the adaptive immune response against the superinfecting virus. These findings indicate that chronic infection leads to sustained IFN-I action, which is responsible for the absence of an antiviral immune response against a secondary viral infection.
Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany.|Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Nadine
N
Honke
Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany.|Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Namir
N
Shaabani
Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
Katja
K
Merches
Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
Asmae
A
Gassa
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Anke
A
Kraft
Institute of Virology, University Medical Center, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
Katrin
K
Ehrhardt
Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Dieter
D
Häussinger
Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin and German Rheumatism Research Center, Berlin, Germany.
Max
M
Löhning
Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Ulf
U
Dittmer
Institute of Virology, University Medical Center, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
Hartmut
H
Hengel
Clinic for Primary Immunodeficiency, Medical Outpatient Unit and Immunodeficiency Laboratory, Department of Biomedicine, University Hospital, Basel, Switzerland.
Mike
M
Recher
Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.|Department of Molecular Medicine II, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Philipp A
PA
Lang
Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Essen, Germany.|Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Karl S
KS
Lang
D056704:Adaptive Immunity; D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D007165:Immunosuppression Therapy; D007370:Interferon Type I / Q000378:metabolism; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000378:metabolism; D054243:Vesicular Stomatitis / Q000276:immunology*; D018116:Vesiculovirus / Q000502:physiology*; D014779:Virus Replication
D007370:Interferon Type I; D063267:Sialic Acid Binding Ig-like Lectin 1
CD169+ macrophages; Chronic infection; Enforced virus replication; Lymphocytic choriomeningitis virus; Vesicular stomatitis virus