A20 (Tnfaip3) deficiency in myeloid cells protects against influenza A virus infection

The innate immune response provides the first line of defense against viruses and other pathogens by responding to specific microbial molecules. Influenza A virus (IAV) produces double-stranded RNA as an intermediate during the replication life cycle, which activates the intracellular pathogen recognition receptor RIG-I and induces the production of proinflammatory cytokines and antiviral interferon. Understanding the mechanisms that regulate innate immune responses to IAV and other viruses is of key importance to develop novel therapeutic strategies. Here we used myeloid cell specific A20 knockout mice to examine the role of the ubiquitin-editing protein A20 in the response of myeloid cells to IAV infection. A20 deficient macrophages were hyperresponsive to double stranded RNA and IAV infection, as illustrated by enhanced NF-κB and IRF3 activation, concomitant with increased production of proinflammatory cytokines, chemokines and type I interferon. In vivo this was associated with an increased number of alveolar macrophages and neutrophils in the lungs of IAV infected mice. Surprisingly, myeloid cell specific A20 knockout mice are protected against lethal IAV infection. These results challenge the general belief that an excessive host proinflammatory response is associated with IAV-induced lethality, and suggest that under certain conditions inhibition of A20 might be of interest in the management of IAV infections.
Author Summary Influenza virus or flu epidemics represent a recurrent threat to the public health, especially for individuals which are part of a high-risk group such as children, elderly or immune-compromised people. Sporadic pandemic flu outbreaks, such as the Spanish flu of 1918, may cause high grades of mortality among healthy persons. A better understanding of how the immune system deals with these pathogens is of key importance. The protein A20 is an important negative regulator of both innate and adaptive immune responses. We show that the specific deletion of A20 in myeloid cells, such as macrophages and neutrophils, improves the resistance against otherwise lethal influenza infections. This protective effect is mediated by an enhanced innate immune response following respiratory challenge with influenza virus. Although exaggerated pulmonary immune responses are believed to be the primary cause of often life threatening influenza virus induced pneumonia, we demonstrate that boosting the innate immune response by selectively targeting the functionality of A20 in myeloid cells is beneficial for the host survival. This finding provides us with a novel valuable approach for treating influenza and potentially other respiratory viral infections.