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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
Macrophage impairment underlies airway occlusion in primary respiratory syncytial virus bronchiolitis
Jennifer L Reed1, Yambasu A Brewah, Tracy Delaney
1Respiratory, Inflammation, and Autoimmunity Group, MedImmune, Gaithersburg, Maryland, USA. jennifer.reed@fda.hhs.gov
Abstract:
Although respiratory syncytial virus (RSV) infection is the most important cause of bronchiolitis in infants, the pathogenesis of RSV disease is poorly described. We studied histopathologic changes in a panel of lung tissue specimens obtained from infants with fatal cases of primary RSV infection. In these tissues, airway occlusion with accumulations of infected, apoptotic cellular debris and serum protein was consistently observed. Similar observations were found after RSV infection in New Zealand black (NZB) mice, which have constitutive deficiencies in macrophage function, but not in BALB/c mice. A deficiency in the number of alveolar macrophages in NZB mice appears to be central to enhanced disease, because depletion of alveolar macrophages in BALB/c mice before RSV exposure resulted in airway occlusion. In mice with insufficient numbers of macrophages, RSV infection yielded an increased viral load and enhanced expression of type I interferon-associated genes at the height of disease. Together, our data suggest that innate, rather than adaptive, immune responses are critical determinants of the severity of RSV bronchiolitis.
Insights
Respiratory syncytial virus (RSV) bronchiolitis in infants involves airway occlusion from cellular debris. Macrophage deficiency exacerbates RSV disease, highlighting innate immunity
Area of Science:
- Pediatric Infectious Diseases
- Immunology
- Respiratory Medicine
Background:
- Respiratory syncytial virus (RSV) is a leading cause of infant bronchiolitis.
- The precise mechanisms driving RSV disease pathogenesis remain unclear.
- Infant bronchiolitis necessitates a deeper understanding of RSV infection dynamics.
Purpose of the Study:
- To elucidate the histopathologic features of fatal infant RSV infections.
- To investigate the role of macrophages in RSV bronchiolitis pathogenesis.
- To identify key immune responses determining RSV disease severity.
Main Methods:
- Analysis of lung tissue from infants with fatal RSV infections.
- Comparative study of RSV infection in New Zealand black (NZB) and BALB/c mice.
- Experimental depletion of alveolar macrophages in BALB/c mice prior to RSV exposure.
Main Results:
- Infant RSV infections consistently showed airway occlusion with cellular debris and protein.
- NZB mice, with macrophage deficiencies, exhibited exacerbated RSV disease.
- Macrophage-deficient BALB/c mice developed airway occlusion after RSV exposure.
- RSV infection in macrophage-deficient mice led to increased viral load and heightened type I interferon responses.
Conclusions:
- Airway occlusion by cellular debris is a critical feature of severe RSV bronchiolitis.
- Innate immune responses, particularly macrophage function, are crucial in determining RSV disease severity.
- Targeting innate immunity may offer new therapeutic strategies for RSV bronchiolitis.
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