Inhibition of Complement Activation Alleviates Acute Lung Injury Induced by Highly Pathogenic Avian Influenza H5N1 Virus Infection

Abstract

The acute lung injury (ALI) that occurs after the highly pathogenic avian influenza H5N1 virus infection is associated with an abnormal host innate immune response. Because the complement system plays a central role in innate immunity and because aberrant complement activation is associated with a variety of autoimmune and inflammatory diseases, we investigated the complement involvement in the pathogenesis of ALI induced by H5N1 virus infection. We showed that ALI in H5N1-infected mice was caused by excessive complement activation, as demonstrated by deposition of C3, C5b-9, and mannose-binding lectin (MBL)-C in lung tissue, and by up-regulation of MBL-associated serine protease-2 and the complement receptors C3aR and C5aR. Treatment of H5N1-infected mice with a C3aR antagonist led to significantly reduced inflammation in lungs, alleviating ALI. Furthermore, complement inhibition with an anti-C5a antibody or complement depletion with cobra venom factor after H5N1 challenge resulted in a similar level of protection to that seen in C3aR antagonist-treated mice. These results indicate that excessive complement activation plays an important role in mediating H5N1-induced ALI and that inhibition of complement may be an effective clinical intervention and adjunctive treatment for H5N1-induced ALI.

Single-dose treatment with a humanized neutralizing antibody affords full protection of a human transgenic mouse model from lethal Middle East respiratory syndrome (MERS)-coronavirus infection

“…Histopathological changes were observed using light microscopy. The extent of lung injury was scored according to the levels of degeneration and necrosis of the bronchi and bronchiolar epithelium, infiltration of inflammatory cells, alveoli degeneration and collapse, expansion of the parenchymal wall, hemorrhage, and interstitial edema (Sun et al, 2013). …”

Viral-derived complement inhibitors: current status and potential role in immunomodulation

“…In their study, inhibition of complement activation by an anti-C5a antibody yielded less neutrophil infiltration, less lung injury and an increased survival rate in H5N1-induced ALI. 74 MG is a neuromuscular disease caused by the presence of autoantibodies against the acetylcholine receptor (AChR). The severity of MG is determined by the complement fixation capacity at the neuromuscular junction.…”

Mutations in human genes that increase the risk for severe influenza infection

“…High levels of C3, C5b-9 and MLB were detected in the lungs of mice infected with influenza A(H5N1) viruses, while the administration of C3aR antagonist significantly reduced the degree of inflammation in the lung tissue [52].…”

“…This hereditary defect should be especially prominent in the case of influenza infection and influenza-caused pneumonia. It is known that the influenza antioxidant therapy can provide significant clinical results in the area of intoxication syndrome relief and prevention of cardiovascular complications [52].…”