MASP-2, the effector enzyme of the lectin pathway of complement activation, modulates the immune response in models of intranasal S. pneumoniae infection and experimental poly-microbial peritonitis

The aim of this project was to investigate the role of lectin pathway of complement activation in the innate immune defence against S. pneumoniae infection and polymicrobial septic peritonitis. In this study the only available model of total lectin pathway deficiency was used, a gene targeted mouse line deficient of the lectin pathway effector enzyme MASP-2. MASP-2 deficiency increases the susceptibility of mice to S. pneumoniae infection and MASP-2 deficient mice showed a significantly higher bacterial load in blood and in lung tissues after intra nasal challenge with S. pneumoniae when compared to their wild type littermates. The MASP-2 deficient mice showed also a significantly higher rate of mortality when compared to the control wild type littermates after S. pneumoniae infection. The failure of the MASP-2 deficient mice to clear the infection is due to an impaired C3 deposition on the surface of S. pneumoniae and hence impaired opsonophagocytosis. The delayed inflammatory response of MASP-2 deficient mice may be also another factor that results in their inability to clear the infection. In the CLP model of poly-microbial peritonitis, the MASP-2 deficient mice showed no significantly increased in mortality after CLP when compared to their MASP-2 sufficient littermates. Bacterial clearance however was significantly reduced in peritoneal lavage of MASP-2 deficient mice. Significant differences in the cytokine expression profiles between MASP-2 deficient and MASP-2 sufficient animals was also observed with TNF-α and IL-1β expression being significantly reduced in MASP-2 deficient animals following CLP. We conclude that MASP-2 deficiency compromises bacterial clearance, but limits the inflammatory response to septic peritonitis considerably, thus leading to a relative reduction of the inflammation driven mortality during septic shock. The finding that the deficiency of MASP-2 may lead to a reduced inflammatory response during sepsis in CLP model and to the protection of mice from the lethal effect of a TNF-α driven severe inflammatory response has prompted the idea to generate antibodies against human and murine MASP-2 that could deplete MASP-2 and transiently inhibit lectin pathway functional activity. These antibodies could be used as therapeutic intervention during sepsis and septic shock. In addition, these antibodies may also serve as therapeutic agents to limit lectin pathway mediated ischaemia/reperfusion injury following myocardial infarction and other forms of ischemic diseases.