Complement C5 Activation during Influenza A Infection in Mice Contributes to Neutrophil Recruitment and Lung Injury

Abstract

Influenza virus A (IAV) causes annual epidemics and intermittent pandemics that affect millions of people worldwide. Potent inflammatory responses are commonly associated with severe cases of IAV infection. The complement system, an important mechanism of innate and humoral immune responses to infections, is activated during primary IAV infection and mediates, in association with natural IgM, viral neutralization by virion aggregation and coating of viral hemmagglutinin. Increased levels of the anaphylatoxin C5a were found in patients fatally infected with the most recent H1N1 pandemic virus. In this study, our aim was to evaluate whether targeting C5 activation alters inflammatory lung injury and viral load in a murine model of IAV infection. To address this question C57Bl/6j mice were infected intranasally with 104 PFU of the mouse adapted Influenza A virus A/WSN/33 (H1N1) or inoculated with PBS (Mock). We demonstrated that C5a is increased in bronchoalveolar lavage fluid (BALF) upon experimental IAV infection. To evaluate the role of C5, we used OmCI, a potent arthropod-derived inhibitor of C5 activation that binds to C5 and prevents release of C5a by complement. OmCI was given daily by intraperitoneal injection from the day of IAV infection until day 5. Treatment with OmCI only partially reduced C5a levels in BALF. However, there was significant inhibition of neutrophil and macrophage infiltration in the airways, Neutrophil Extracellular Traps (NETs) formation, death of leukocytes, lung epithelial injury and overall lung damage induced by the infection. There was no effect on viral load. Taken together, these data suggest that targeting C5 activation with OmCI during IAV infection could be a promising approach to reduce excessive inflammatory reactions associated with the severe forms of IAV infections.

Myeloid Derived Hypoxia Inducible Factor 1-alpha Is Required for Protection against Pulmonary Aspergillus fumigatus Infection

“…Though our data strongly support a major role for the neutrophil chemoattractant CXCL1 in mediating the HIF C phenotype, other neutrophil chemoattractants/receptors that are known to be involved in neutrophil recruitment during various lung infections may be involved in the HIF1α phenotype including CCL3-CCL6-/CCR1 [66], C5a/C5aR [67], and LTB4/LTB4R1 [68], [69]. However, production of the other CXCR2 ligands CXCL2 [53] and CXCL5 [54] that are known to have roles in neutrophil recruitment were not different within the BALF of WT and HIF C mice.…”

Protective Immunity and Safety of a Genetically Modified Influenza Virus Vaccine

“…Single cell suspensions from mice spleens were prepared as previously described [51], [52]. Spleen cells were adjusted to 1 × 10 6 cells per well in cell culture medium.…”

Sepsis and septic shock

“…Similarly, the blockade of C5a with antibodies in rats or mice with sepsis caused by caecal ligation puncture was highly effective in diminishing the severity of sepsis and improving outcome 44,45 . In addition, severe inflammatory responses and their associated organ damage during avian H5N1 and H1N1 viral infections have also been linked to complement activation, especially the overproduction of C5a 46,47 . Along these lines, a monoclonal antibody raised against human C5a greatly attenuated H7N9-induced lung damage in non-human primates, reducing the viral load and the levels of several different cytokines in this setting 48 .…”