Microbial Ligand Costimulation Drives Neutrophilic Steroid-Refractory Asthma.
Asthma is a heterogeneous disease whose etiology is poorly understood but is likely to involve innate responses to inhaled microbial components that are found in allergens. The influence of these components on pulmonary inflammation has been largely studied in the context of individual agonists, despite knowledge that they can have synergistic effects when used in combination. Here we have explored the effects of LPS and β-glucan, two commonly-encountered microbial agonists, on the pathogenesis of allergic and non-allergic respiratory responses to house dust mite allergen. Notably, sensitization with these microbial components in combination acted synergistically to promote robust neutrophilic inflammation, which involved both Dectin-1 and TLR-4. This pulmonary neutrophilic inflammation was corticosteroid-refractory, resembling that found in patients with severe asthma. Thus our results provide key new insights into how microbial components influence the development of respiratory pathology.
Aberdeen Fungal Group, Infection, Immunity and Inflammation Programme, University of Aberdeen, United Kingdom.  Institute of Infectious Disease and Molecular Medicine, Faculty of Health Science, University of Cape Town, South Africa.
Sabelo
S
Hadebe
International Centre for Genetic Engineering and Biotechnology and Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Science, University of Cape Town, South Africa.
Frank
F
Kirstein
VIB Inflammation Research Center, Laboratory of Immunoregulation and Mucosal Immunology, University Ghent, Ghent, Belgium.
Kaat
K
Fierens
Department of Paediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Kong
K
Chen
Aberdeen Fungal Group, Infection, Immunity and Inflammation Programme, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Science, University of Cape Town, South Africa.
Rebecca A
RA
Drummond
Aberdeen Fungal Group, Infection, Immunity and Inflammation Programme, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Science, University of Cape Town, South Africa.
Simon
S
Vautier
Aberdeen Fungal Group, Infection, Immunity and Inflammation Programme, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Science, University of Cape Town, South Africa.
Sara
S
Sajaniemi
Pathology, Division of Applied Medicine, Institute of Medical Sciences, Foresterhill, University of Aberdeen, Aberdeen, United Kingdom.
Graeme
G
Murray
Department of Surgery and Center for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, United States of America.
David L
DL
Williams
Aberdeen Fungal Group, Infection, Immunity and Inflammation Programme, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Science, University of Cape Town, South Africa.
Pierre
P
Redelinghuys
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Todd A
TA
Reinhart
Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Beth A
BA
Fallert Junecko
Department of Paediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
Jay K
JK
Kolls
VIB Inflammation Research Center, Laboratory of Immunoregulation and Mucosal Immunology, University Ghent, Ghent, Belgium; Department of Pulmonary Medicine, ErasmusMC, Rotterdam, The Netherlands.
Bart N
BN
Lambrecht
International Centre for Genetic Engineering and Biotechnology and Division of Immunology, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Science, University of Cape Town, South Africa.
Frank
F
Brombacher
Aberdeen Fungal Group, Infection, Immunity and Inflammation Programme, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Science, University of Cape Town, South Africa.
Gordon D
GD
Brown
D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004351:Drug Resistance; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology*; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D039981:Pyroglyphidae / Q000276:immunology; D013256:Steroids / Q000008:administration & dosage / Q000494:pharmacology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D047071:beta-Glucans / Q000276:immunology*
D008070:Lipopolysaccharides; D013256:Steroids; D047071:beta-Glucans