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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection
Published on: December 10, 2013
CCL20/CCR6 blockade enhances immunity to RSV by impairing recruitment of DC
Lara E Kallal1, Matthew A Schaller, Dennis M Lindell
1Department of Molecular & Cellular Pathology, The University of Michigan, Ann Arbor, MI 48109, USA. lkkelley@umich.edu
Abstract:
Chemokines are important mediators of the immune response to pathogens, but can also promote chronic inflammatory states. Chemokine receptor 6 (CCR6) is found on immature DC and effector/memory T cells, and binds a single ligand, CCL20, with high affinity. Here, we investigated the role of CCL20 and CCR6 in a pulmonary viral infection caused by RSV, a ubiquitous virus that can cause severe pulmonary complications. Neutralization of CCL20 during RSV infection significantly reduced lung pathology and favored a Th1 effector response. CCR6-deficient animals recapitulated this phenotype, and additionally showed enhanced viral clearance when compared with WT mice. No differences were observed in migration of T cells to the lungs of CCR6(-/-) animals; however, a significant reduction was observed in numbers of conventional DC (cDC), but not plasmacytoid DC, in CCR6(-/-) mice. A pathogenic phenotype could be reconstituted in CCR6(-/-) mice by supplying cDC into the airway, indicating that mere number of cDC dictates the adverse response. Our data suggest that blockade of the CCL20/CCR6 pathway provides an environment whereby the attenuated recruitment of cDC alters the balance of innate immune cells and mediates the efficient antiviral response to RSV.
Insights
Blocking the CCL20/CCR6 pathway during respiratory syncytial virus infection reduces lung damage and improves viral clearance. This occurs by altering conventional dendritic cell numbers, leading to a more effective antiviral immune response.
Area of Science:
- Immunology
- Virology
- Respiratory Medicine
Background:
- Chemokines mediate immune responses but can also drive chronic inflammation.
- Chemokine receptor 6 (CCR6) and its ligand CCL20 are implicated in immune cell trafficking and inflammatory conditions.
- Respiratory syncytial virus (RSV) causes significant pulmonary complications.
Purpose of the Study:
- To investigate the role of the CCL20/CCR6 pathway in RSV pulmonary infection.
- To determine the impact of CCL20 neutralization and CCR6 deficiency on RSV pathogenesis.
- To elucidate the mechanisms by which CCL20/CCR6 influences the antiviral immune response.
Main Methods:
- RSV infection model in wild-type and CCR6-deficient mice.
- CCL20 neutralization therapy during RSV infection.
- Analysis of lung pathology, immune cell populations (T cells, dendritic cells), and viral clearance.
- Assessment of immune cell migration and reconstitution experiments.
Main Results:
- CCL20 neutralization reduced lung pathology and promoted a Th1 response during RSV infection.
- CCR6-deficient mice exhibited reduced lung pathology and enhanced viral clearance compared to wild-type mice.
- CCR6 deficiency led to a decrease in conventional dendritic cells (cDCs) in the lungs, but not plasmacytoid DCs, without affecting T cell migration.
- Reconstitution of cDCs in CCR6-deficient mice restored the pathogenic phenotype, indicating cDC numbers are critical.
Conclusions:
- The CCL20/CCR6 pathway plays a detrimental role in RSV-induced lung pathology.
- Blocking CCL20/CCR6 signaling attenuates cDC recruitment, shifting the immune balance towards an effective antiviral response.
- Targeting the CCL20/CCR6 pathway represents a potential therapeutic strategy for managing severe RSV infections.
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