Anti-Respiratory Syncytial Virus (RSV) Neutralizing Antibody Decreases Lung Inflammation, Airway Obstruction, and Airway Hyperresponsiveness in a Murine RSV Model

Abstract

Numerous studies have described a strong association between respiratory syncytial virus (RSV) infection in infancy and the development of recurrent wheezing and airway hyperresponsiveness. We evaluated the effect of an anti-RSV neutralizing monoclonal antibody (palivizumab) on different aspects of RSV disease by using a murine model. BALB/c mice were intranasally inoculated with RSV A2. Palivizumab or an isotype-matched control antibody was administered once at 24 h before inoculation, 1 h after inoculation, or 48 h after inoculation. Regardless of the timing of administration, all mice treated with the neutralizing antibody showed significantly decreased RSV loads in bronchoalveolar lavage (BAL) and lung specimens compared with those of infected controls. Pulmonary histopathologic scores, airway obstruction measured by plethysmography, and airway hyperresponsiveness after methacholine challenge were significantly reduced in mice treated with the anti-RSV antibody 24 h before inoculation compared with those for untreated controls. Concentrations of interferon-gamma, interleukin-10, macrophage inflammatory protein 1␣, regulated on activation normal T-cell expressed and secreted (RANTES), and eotaxin in BAL fluids were also significantly reduced in mice treated with palivizumab 24 h before inoculation. This study demonstrates that reduced RSV replication was associated with significant modulation of inflammatory and clinical markers of acute disease severity and significant improvement of the long-term pulmonary abnormalities. Studies to determine whether strategies aimed at preventing or reducing RSV replication could decrease the long-term morbidity associated with RSV infection in children should be considered.Respiratory syncytial virus (RSV) is the leading viral pathogen associated with lower respiratory tract disease in infants and young children worldwide. In addition to acute morbidity, numerous studies have described a strong association between RSV infection in infancy and the development of recurrent wheezing and airway hyperresponsiveness (AHR) (34,45,50). More recently, RSV has also been demonstrated to be an important cause of severe respiratory illness among the elderly and immunocompromised individuals (11, 12). Accordingly, efforts have been focused on both prevention and treatment of this common infection.Despite almost half a century of active clinical research on humans, as well as with animal and in vitro models, to define the immunopathogenesis of the disease, no effective vaccine is available yet, and the relationship between RSV and AHR remains to be completely characterized. In the United States, RSV is responsible for more than 150,000 hospitalizations per year in the pediatric population (49), resulting in an estimated annual cost of $300 million to $500 million for children below the age of 5 years (51, 57). Moreover, the long-term morbidity associated with severe RSV infection results in health care burdens and costs disproportionately greater than the estimated hospitalization costs ...

Pathogenesis of Human Metapneumovirus Lung Infection in BALB/c Mice and Cotton Rats

“…Many similarities can be found between hMPV and hRSV replication in BALB/c mice. Following an intranasal challenge, hRSV lung titers peak on day 4 postinfection with no viruses usually recovered beyond day 7 (22,29). On the other hand, hMPV titers peaked on day 5 in our model and viruses could still be recovered on day 12 but not by day 21 (Fig.…”

Genomewide Association Analysis of Respiratory Syncytial Virus Infection in Mice

“…In our initial report, we described a difference in weight loss between AKR/J and C57BL/6J mice, with AKR/J mice demonstrating higher titers and greater weight loss (56). One of the most convincing demonstrations of the association between RSV titers and clinical indicators of disease in mice was described by Ramilo and associates (41). Their study demonstrated that reduced RSV replication (lower titer) was associated Representative transcripts increased more in C57BL/6J than in AKR/J mouse lungs during RSV infection and indicative of T-cell and nucleosome involvement.…”

Effects of Anti-G and Anti-F Antibodies on Airway Function after Respiratory Syncytial Virus Infection

“…Prophylactic Effects of Anti-RSV-G and Anti-RSV-F mAbs in the Response to Primary RSV Infection Previous studies in a mouse model showed a prophylactic effect of palivizumab on AHR and airway inflammation (19). Mice were infected on Day 0 at 6 weeks of age; anti-RSV-G (3G12) or anti-RSV-F was administered intraperitoneally at 15 mg/kg on Day 21.…”

“…Differences in efficacy were more obvious when treatment was initiated after infection. Anti-RSV-F failed to demonstrate therapeutic effects in RSV disease in animals (19) or humans (5), even though the viral titer was lower after treatment. These results suggested that once infection was established, host responses continued to contribute to disease pathogenesis.…”

“…Neutralizing antibodies can directly block these interactions and lead to reduced numbers of airway infiltrating cells (15,19,27,28). Airway inflammation, initiated either by innate immune responses or neurogenic responses, contribute to development of AHR (29).…”