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.
Highlights
The fast activation of the complement system (CS) after a microorganism infects a potential host is an important step in clearance of many pathogens [1]
We found significantly increased C5a levels in bronchoalveolar lavage fluid (BALF) of Influenza virus A (IAV) infected animals from the third to the sixth day of infection, peaking at day 6 after infection (Figure 1, left)
We demonstrate here that an arthropod derived inhibitor of C5 activation decreases the recruitment of neutrophils and macrophages to the alveolar space and reduces consequent epithelial damage and lung pathology in IAV infected mice
Summary
The fast activation of the complement system (CS) after a microorganism infects a potential host is an important step in clearance of many pathogens [1]. Anaphylatoxins like C3a and C5a, products of the CS cascade, are commonly involved in exacerbated inflammatory reactions that can cause direct harm to the host following infections [2,3,4]. Influenza A virus (IAV), an eight segmented, single stranded, negative-sense RNA virus that belongs to the Orthomyxoviridae family, [5], is known to activate the CS [6]. IAVs have developed mechanisms of evading CS within the host, as shown by the antiC1q action of influenza protein M1 [8]. The pathology caused by IAV is due mainly to excessive inflammatory responses that culminate in lung damage and acute respiratory distress [9]
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