Respiratory syncytial virus (RSV) is the leading cause of severe viral respiratory infections in infants worldwide (7
). In the 1960s, a formalin-inactivated RSV vaccine (FIRSV) was administered to infants in the United States (6
). Subsequent exposure of vaccinated children to RSV resulted in increased morbidity and mortality. The mechanism of illness was never clarified, hampering the development of safe vaccines against the virus. Four decades later, there is still no licensed vaccine against RSV.
Recently, a mouse model of enhanced RSV disease (ERD) that uses airway hyperreactivity (AHR) and pneumonia, characteristic manifestations of ERD in children (6
), as primary correlates of disease enhancement (34
) was established. Using this model and postmortem lung sections from affected children, deposition of immune complexes that fix complement in the lungs was shown to play a critical role in AHR during ERD (34
The complement components associated with AHR during ERD have not been characterized, but a role for C3a in AHR has been described for rodent models of asthma (3
). Conversely, C5aR signaling has been reported to decrease susceptibility to asthma, presumptively by promoting interleukin-12 (IL-12), IL-23, and IL-27 production and enhancing production of IL-4 and IL-13 (12
). However, conflicting data suggest that C5a may decrease IL-12 production in certain models and enhance AHR (5
). In fact, a recent paper described a dual role for C5a in allergic asthma during allergen sensitization (protective) and in an established inflammatory response (proinflammatory) (28
). It is conceivable that C3a and C5 may modulate each other in the lungs, but no direct regulatory role between them in AHR and airway inflammation has been described.
Interestingly, while complement components determine AHR, ERD pneumonia has been attributed to cytokine release by CD4+
Th2 cells (8
). Often, pneumonia in mice has been characterized by the presence of a peribronchiolar and perivascular inflammatory infiltration (8
) associated with abundant pulmonary eosinophils in bronchoalveolar lavage (BAL) fluid (18
). However, both hallmark signs of ERD, AHR and pneumonia, are thought to occur in parallel, and there is no evidence that the complement and T-cell-mediated processes are interrelated (9
To elucidate the complement components associated with AHR and examine whether complement affects the severity of pneumonia or eosinophilia during ERD, we characterized the AHR and lung histopathologies of mice with functional deficiencies in the complement cascade. In this paper, we demonstrate that C3a is critical for AHR during ERD and that AHR is negatively regulated by C5, which modulates the levels of C3aR expression in the lungs of mice. We also show that severity of lung eosinophilia, long regarded as a surrogate marker of ERD pneumonia (18
), does not correlate with severity of lung inflammation, suggesting that these are independent manifestations of the disease. Furthermore, lung eosinophilia and mucus production correlate with AHR and are modulated by the effect of C5 on C3aR expression.