TY - JOUR
T1 - IL-27 LIMITS TYPE 2 IMMUNOPATHOLOGY FOLLOWING PARAINFLUENZA VIRUS INFECTION
AU - Muallem, Gaia
AU - Wagage, Sagie
AU - Sun, Yan
AU - DeLong, Jonathan H.
AU - Valenzuela, Alex
AU - Christian, David A.
AU - Harms Pritchard, Gretchen
AU - Fang, Qun
AU - Buza, Elizabeth L.
AU - Jain, Deepika
AU - Elloso, M. Merle
AU - López, Carolina B.
AU - Hunter, Christopher A.
N1 - Funding Information:
We thank the Penn Vet Imaging core and the University of Pennsylvania Flow Cytometry & Cell Sorting Facility. We acknowledge the NIH Tetramer Core Facility (contract HHSN272201300006C) for provision of the SeV NP tetramer. We thank the Penn Vet Histology Core and Amy Durham, VMD for her valuable comments and insight.
Publisher Copyright:
© 2017 Muallem et al.
PY - 2017/1
Y1 - 2017/1
N2 - Respiratory paramyxoviruses are important causes of morbidity and mortality, particularly of infants and the elderly. In humans, a T helper (Th)2-biased immune response to these infections is associated with increased disease severity; however, little is known about the endogenous regulators of these responses that may be manipulated to ameliorate pathology. IL-27, a cytokine that regulates Th2 responses, is produced in the lungs during parainfluenza infection, but its role in disease pathogenesis is unknown. To determine whether IL-27 limits the development of pathogenic Th2 responses during paramyxovirus infection, IL-27-deficient or control mice were infected with the murine parainfluenza virus Sendai virus (SeV). Infected IL-27-deficient mice experienced increased weight loss, more severe lung lesions, and decreased survival compared to controls. IL-27 deficiency led to increased pulmonary eosinophils, alternatively activated macrophages (AAMs), and the emergence of Th2 responses. In control mice, IL-27 induced a population of IFN-γ+/IL-10+CD4+T cells that was replaced by IFN-γ+/IL-17+and IFN-γ+/IL-13+CD4+T cells in IL-27-deficient mice. CD4+T cell depletion in IL-27-deficient mice attenuated weight loss and decreased AAMs. Elimination of STAT6 signaling in IL-27-deficient mice reduced Th2 responses and decreased disease severity. These data indicate that endogenous IL-27 limits pathology during parainfluenza virus infection by regulating the quality of CD4+T cell responses and therefore may have therapeutic potential in paramyxovirus infections.
AB - Respiratory paramyxoviruses are important causes of morbidity and mortality, particularly of infants and the elderly. In humans, a T helper (Th)2-biased immune response to these infections is associated with increased disease severity; however, little is known about the endogenous regulators of these responses that may be manipulated to ameliorate pathology. IL-27, a cytokine that regulates Th2 responses, is produced in the lungs during parainfluenza infection, but its role in disease pathogenesis is unknown. To determine whether IL-27 limits the development of pathogenic Th2 responses during paramyxovirus infection, IL-27-deficient or control mice were infected with the murine parainfluenza virus Sendai virus (SeV). Infected IL-27-deficient mice experienced increased weight loss, more severe lung lesions, and decreased survival compared to controls. IL-27 deficiency led to increased pulmonary eosinophils, alternatively activated macrophages (AAMs), and the emergence of Th2 responses. In control mice, IL-27 induced a population of IFN-γ+/IL-10+CD4+T cells that was replaced by IFN-γ+/IL-17+and IFN-γ+/IL-13+CD4+T cells in IL-27-deficient mice. CD4+T cell depletion in IL-27-deficient mice attenuated weight loss and decreased AAMs. Elimination of STAT6 signaling in IL-27-deficient mice reduced Th2 responses and decreased disease severity. These data indicate that endogenous IL-27 limits pathology during parainfluenza virus infection by regulating the quality of CD4+T cell responses and therefore may have therapeutic potential in paramyxovirus infections.
UR - http://www.scopus.com/inward/record.url?scp=85010931205&partnerID=8YFLogxK
U2 - 10.1371/journal.ppat.1006173
DO - 10.1371/journal.ppat.1006173
M3 - Article
C2 - 28129374
AN - SCOPUS:85010931205
SN - 1553-7366
VL - 13
JO - PLoS pathogens
JF - PLoS pathogens
IS - 1
M1 - e1006173
ER -