Susceptibility of bone marrow-derived macrophages to influenza virus infection is dependent on macrophage phenotype

Abstract

The role of the macrophage in influenza virus infection is complex. Macrophages are critical for resolution of influenza virus infections but implicated in morbidity and mortality in severe infections. They can be infected with influenza virus and consequently macrophage infection is likely to have an impact on the host immune response. Macrophages display a range of functional phenotypes, from the prototypical pro-inflammatory classically activated cell to alternatively activated anti-inflammatory macrophages involved in immune regulation and wound healing. We were interested in how macrophages of different phenotype respond to influenza virus infection and therefore studied the infection of bone marrow-derived macrophages (BMDMs) of classical and alternative phenotype in vitro. Our results show that alternatively activated macrophages are more readily infected and killed by the virus than classically activated. Classically activated BMDMs express the pro-inflammatory markers inducible nitric oxide synthase (iNOS) and TNF-a, and TNF-a expression was further upregulated following infection. Alternatively activated macrophages express Arginase-1 and CD206; however, following infection, expression of these markers was downregulated whilst expression of iNOS and TNF-a was upregulated. Thus, infection can override the anti-inflammatory state of alternatively activated macrophages. Importantly, however, this results in lower levels of proinflammatory markers than those produced by classically activated cells. Our results showed that macrophage phenotype affects the inflammatory macrophage response following infection, and indicated that modulating the macrophage phenotype may provide a route to develop novel strategies to prevent and treat influenza virus infection.

Influenza virus replication in macrophages: balancing protection and pathogenesis

“…M2 macrophages were more susceptible to apoptotic cell death than classically activated M1 macrophages following IAV infection [83]. While IAV-infected M1 macrophages expressed the highest levels of pro-inflammatory cytokines such as TNF-a, IAV infection of M2 macrophages was able to override the anti-inflammatory cytokine profile of these cells and cause them to secret TNF-a and other M1-like cytokines.…”

“…However, despite being more susceptible to IAV infection and supporting greater production of viral RNA, M2 macrophages did not support productive IAV replication to a greater extent than M1 macrophages [83].…”

Hypercapnia Suppresses Macrophage Antiviral Activity and Increases Mortality of Influenza A Infection via Akt1

“…A critical role for AMØs in host defense against influenza viruses is well-established, as depletion of AMØs using clodronate or various genetic strategies increases viral replication, lung injury and mortality following IAV infection in pigs and mice (30)(31)(32)(33)(34). While influenza viruses readily infect MØs, some studies show that IAV infection of AMØs is abortive, as a result of block(s) to production of live virus (54)(55)(56)(57). In mice infected with IAV in the present study, AMØs expressed viral NP, NS1 and M2 proteins and, when isolated, released viable virus at titers orders of magnitude higher than the original inoculum, consistent with productive infection of AMØs in vivo.…”

Dissecting host cell death programs in the pathogenesis of influenza

“…Thus, AM4 represent a logical target for IAV to induce cell death and, indeed, several studies have reported early apoptosis post-infection in AM4 [110e112]. Similarly, recruited M4 are highly permissive to IAV infection and susceptible to IAV-induced cell death [26,113]. Collectively, these findings suggest that in contrast to the biphasic role of epithelial cell apoptosis in preventing or promoting pathogenesis, highly virulent IAV rapidly infects and induces early death in pulmonary M4 to suppress antiviral responses.…”

“…In addition to inhibiting the early antiviral responses, IAV-induced M4 apoptosis might skew the balance from a protective to pathological immune response. During IAV infection, it has been shown that mice lacking type I IFN signaling die from an uncontrolled inflammatory response, as IFN-I signaling was essential to induce anti-inflammatory IL-10 production by "regulatory" M4 [126]da subset of M4 known to be more susceptible to IAV-induced apoptosis [113].…”