Zibo Han1,2, Jian Rao1,2, Zhengde Xie3,4,5,6, Conghui Wang1,2, Baoping Xu3,4,5,6, Suyun Qian3,4,5,6, Yingying Wang1,2, Junlin Zhu1,2, Bin Yang1,2, Fengwen Xu1, Xiaobo Lei1,2, Fei Guo1, Zhendong Zhao1, Lili Ren1,2,7, Jianwei Wang1,2,7. 1. National Health Commission Key Laboratory of Systems Biology of Pathogens and. 2. Christophe Mérieux Laboratory, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China. 3. Beijing Key Laboratory of Pediatric Respiratory Infection Diseases. 4. Key Laboratory of Major Diseases in Children, Ministry of Education, and. 5. Laboratory of Infection and Virology, Beijing Pediatric Research Institute, National Clinical Research Center for Respiratory Diseases and National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, People's Republic of China; and. 6. Research Unit of Critical Infection in Children and. 7. Key Laboratory of Respiratory Disease Pathogenomics, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
Abstract
Rationale: Respiratory syncytial virus (RSV) is the leading cause of childhood respiratory infections worldwide; however, no vaccine is available, and treatment options are limited. Identification of host factors pivotal to viral replication may inform the development of novel therapies, prophylaxes, or diagnoses. Objectives: To identify host factors involved in RSV replication and to evaluate their potential for disease management. Methods: A gain-of-function screening was performed on the basis of a genome-wide human complementary DNA library screen for host factors involved in RSV replication. The antiviral mechanism of CXCL4 (chemokine [C-X-C motif] ligand 4) was analyzed. Its clinical role was evaluated via nasopharyngeal aspirates and plasma samples from patients with RSV infection and different disease severities.Measurements and Main Results: Forty-nine host factors restricting RSV replication were identified by gain-of-function screening, with CXCL4 showing the strongest antiviral effect, which was secretion dependent. CXCL4 blocked viral attachment through binding to the RSV main receptor heparan sulfate, instead of through interacting with RSV surface proteins. Intranasal pretreatment with CXCL4 alleviated inflammation in RSV-infected mice, as shown by decreased concentrations of tumor necrosis factor and viral load in BAL fluid samples as well as by viral nucleocapsid protein histological staining in lungs. Compared with non-RSV infections, RSV infections induced elevated CXCL4 concentrations both in plasma and airway samples from mice and pediatric patients. The airway CXCL4 concentration was correlated with viral load and disease severity in patients (P < 0.001).Conclusions: Our results suggest that CXCL4 is an RSV restriction factor that can block viral entry and serve as an indicator of clinical severity in RSV infections.
Rationale: Respiratory syncytial virus (RSV) is the leading cause of childhood respiratory infections worldwide; however, no vaccine is available, and treatment options are limited. Identification of host factors pivotal to viral replication may inform the development of novel therapies, prophylaxes, or diagnoses. Objectives: To identify host factors involved in RSV replication and to evaluate their potential for disease management. Methods: A gain-of-function screening was performed on the basis of a genome-wide human complementary DNA library screen for host factors involved in RSV replication. The antiviral mechanism of CXCL4 (chemokine [C-X-C motif] ligand 4) was analyzed. Its clinical role was evaluated via nasopharyngeal aspirates and plasma samples from patients with RSV infection and different disease severities.Measurements and Main Results: Forty-nine host factors restricting RSV replication were identified by gain-of-function screening, with CXCL4 showing the strongest antiviral effect, which was secretion dependent. CXCL4 blocked viral attachment through binding to the RSV main receptor heparan sulfate, instead of through interacting with RSV surface proteins. Intranasal pretreatment with CXCL4 alleviated inflammation in RSV-infectedmice, as shown by decreased concentrations of tumor necrosis factor and viral load in BAL fluid samples as well as by viral nucleocapsid protein histological staining in lungs. Compared with non-RSVinfections, RSVinfections induced elevated CXCL4 concentrations both in plasma and airway samples from mice and pediatric patients. The airway CXCL4 concentration was correlated with viral load and disease severity in patients (P < 0.001).Conclusions: Our results suggest that CXCL4 is an RSV restriction factor that can block viral entry and serve as an indicator of clinical severity in RSVinfections.
Authors: Erick Forno; Steven H Abman; Jagdev Singh; Mary E Robbins; Hiran Selvadurai; Paul T Schumacker; Paul D Robinson Journal: Am J Respir Crit Care Med Date: 2021-08-01 Impact factor: 30.528