Sjanna B Besteman1,2, Emily Phung3, Henriette H M Raeven4,5, Gimano D Amatngalim4,5, Matevž Rumpret1,6, Juliet Crabtree7, Rutger M Schepp8, Lisa W Rodenburg4,5, Susanna G Siemonsma1, Nile Verleur2, Rianne van Slooten1, Karen Duran9, Gijs W van Haaften9, Jeffrey M Beekman4,5, Lauren A Chang3, Linde Meyaard1,6, Tjomme van der Bruggen10, Guy A M Berbers8, Nicole Derksen11, Stefan Nierkens1, Kaitlyn M Morabito3, Tracy J Ruckwardt3, Evelyn A Kurt-Jones7, Douglas Golenbock7, Barney S Graham3, Louis J Bont1,2. 1. Center for Translational Immunology, University Medical Centre Utrecht, Utrecht, the Netherlands. 2. Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, the Netherlands. 3. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. 4. Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. 5. Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. 6. Oncode Institute, Utrecht, the Netherlands. 7. Department of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA. 8. National Institute of Public Health and the Environment (RIVM), Bilthoven, the Netherlands. 9. Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands. 10. Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherlands. 11. RSV Patient Network, ReSVinet, Zeist, the Netherlands.
Abstract
BACKGROUND: Recurrent respiratory syncytial virus (RSV) infection requiring hospitalization is rare and the underlying mechanism is unknown. We aimed to determine the role of CD14-mediated immunity in the pathogenesis of recurrent RSV infection. METHODS: We performed genotyping and longitudinal immunophenotyping of the first patient with a genetic CD14 deficiency who developed recurrent RSV infection. We analyzed gene expression profiles and interleukin (IL)-6 production by patient peripheral blood mononuclear cells in response to RSV pre- and post-fusion (F) protein. We generated CD14-deficient human nasal epithelial cells cultured at air-liquid interface (HNEC-ALI) of patient-derived cells and after CRISPR-based gene editing of control cells. We analyzed viral replication upon RSV infection. RESULTS: Sanger sequencing revealed a homozygous single-nucleotide deletion in CD14, resulting in absence of the CD14 protein in the index patient. In vitro, viral replication was similar in wild-type and CD14-/- HNEC-ALI. Loss of immune cell CD14 led to impaired cytokine and chemokine responses to RSV pre- and post-F protein, characterized by absence of IL-6 production. CONCLUSIONS: We report an association of recurrent RSV bronchiolitis with a loss of CD14 function in immune cells. Lack of CD14 function led to defective immune responses to RSV pre- and post-F protein without a change in viral replication.
BACKGROUND: Recurrent respiratory syncytial virus (RSV) infection requiring hospitalization is rare and the underlying mechanism is unknown. We aimed to determine the role of CD14-mediated immunity in the pathogenesis of recurrent RSV infection. METHODS: We performed genotyping and longitudinal immunophenotyping of the first patient with a genetic CD14 deficiency who developed recurrent RSV infection. We analyzed gene expression profiles and interleukin (IL)-6 production by patient peripheral blood mononuclear cells in response to RSV pre- and post-fusion (F) protein. We generated CD14-deficient human nasal epithelial cells cultured at air-liquid interface (HNEC-ALI) of patient-derived cells and after CRISPR-based gene editing of control cells. We analyzed viral replication upon RSV infection. RESULTS: Sanger sequencing revealed a homozygous single-nucleotide deletion in CD14, resulting in absence of the CD14 protein in the index patient. In vitro, viral replication was similar in wild-type and CD14-/- HNEC-ALI. Loss of immune cell CD14 led to impaired cytokine and chemokine responses to RSV pre- and post-F protein, characterized by absence of IL-6 production. CONCLUSIONS: We report an association of recurrent RSV bronchiolitis with a loss of CD14 function in immune cells. Lack of CD14 function led to defective immune responses to RSV pre- and post-F protein without a change in viral replication.
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