Leukotriene Dependent Exacerbation of Respiratory Infections in Mice with Defective C5a Signaling

Influenza A, rhinovirus and the human respiratory syncytial virus (RSV) are leading causes of severe lower respiratory tract infections in young children, immunocompromised patients and the elderly. Up to 50% of the children under the age of 16 with these viral infections represent with bacterial co-infections. There are hints from the literature that these bacterial co-infections may aggravate the clinical symptoms substantially, while the reason for this observation especially in premature babies is still unknown. In search for a clinical relevant animal model of RSV-infection we compared BALB/c with DBA/2 N mice during infection, the later suffering from a complement factor 5 (C5) deficiency. It turned out that DBA/2 N mice, especially when co-infected with mycoplasma spp, showed significantly more clinical symptoms, higher viral replication in lung homogenate, strong influx of inflammatory cells and increased airway hyperreactivity (AHR). This data was confirmed by co-infection of RSV and mycoplasma spp. in a C5a-receptor knock-out (C5aR1-KO) also showing enhanced clinical signs of infection like weight loss, prominent invasion of inflammatory cells into the lung and AHR. The connection between infection based AHR and induction of cysteinyl leukotrienes (CysLT) by viral pathogens is known; interestingly, we observed that co-infection in C5aR1-KO-mice led to higher levels of CysLT, which in turn resulted in a more distinctive AHR. Cell influx into BALF and AHR could be reduced by treatment with Zileuton inhibiting the synthesis of CysLT by the 5-Lipoxygenase. Furthermore, the application of recombinant C5a dampened the inflammatory effect after co-infection. In summary our data show a possible link between signaling through the C5aR and the regulation of the synthesis of CysLT. Since CysLT was already recognized as important targets in inflammatory airway disease the modulation of this signaling axis may be another meaningful concept to treat symptoms of severe airway infections.