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.
