Involvement of the Mannose Receptor in Infection of Macrophages by Influenza Virus

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.

Section: Results 129sv/ev Bmdms Can Be Infected With Influenza Virus mentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Campbell

Nicol

Dransfield

et al. 2015

“…Expression of the macrophage mannose receptor is upregulated in M2-polarized macrophages [78,82]. Having been shown to be involved in IAV infection of macrophages [45], upregulation of the mannose receptor might explain the increased susceptibility of M2 macrophages to IAV infection, although this has not been tested directly.…”

Section: Iav Replication and Macrophage Phagocytosismentioning

confidence: 99%

“…Glycosylation of the HA protein may impact on the ability of the virus to interact efficiently with C-type lectins, such as the mannose receptor and the galactose-type lectin, which, in addition to sialic acid receptors, act as attachment and entry receptors for IAVs [41,[43][44][45]. In support of this hypothesis, IAV infection of macrophages with RG-Braz-HA in the presence of mannan or asialofetuin, which have been shown to block Ctype lectin interactions, is reduced to levels similar to that of PR8 [27].…”

Section: Mechanism Of Iav Restriction In Macrophagesmentioning

confidence: 99%

Influenza virus replication in macrophages: balancing protection and pathogenesis

Cline

Beck

Bianchini

2017

Macrophages are essential for protection against influenza A virus infection, but are also implicated in the morbidity and mortality associated with severe influenza disease, particularly during infection with highly pathogenic avian influenza (HPAI) H5N1 virus. While influenza virus infection of macrophages was once thought to be abortive, it is now clear that certain virus strains can replicate productively in macrophages. This may have important consequences for the antiviral functions of macrophages, the course of disease and the outcome of infection for the host. In this article, we review findings related to influenza virus replication in macrophages and the impact of productive replication on macrophage antiviral functions. A clear understanding of the interactions between influenza viruses and macrophages may lead to new antiviral therapies to relieve the burden of severe disease associated with influenza viruses.

“…Resident peritoneal macrophages were obtained by lavage of the peritoneal cavity as described previously (Reading et al, 2000) but using RPMI-based medium. Cells (1610 6 in 1 ml) were seeded into the wells of 24-well tissue culture plates (Nunc), and after 4 h incubation, non-adherent cells were removed by washing and the adherent macrophages were incubated overnight in RF10.…”

Section: Methodsmentioning

confidence: 99%

Virus–cell interactions in the induction of type 1 interferon by influenza virus in mouse spleen cells

Miller

Anders

2003

Self Cite

Inactivated influenza A virus and fixed, virus-infected cells induce type 1 interferon (IFN-a/b) production in murine splenocytes. In this study, we have explored the nature of the virus-spleen cell interaction that leads to IFN-a/b induction and the reason for the poor response to some virus strains. IFN-a/b induction by horse serum-sensitive, but not -resistant, strains of influenza virus was inhibited in the presence of horse serum, indicating that binding of the virus to sialylated cell receptors is a necessary step in the induction process. Furthermore, influenza viruses A/PR/8/34 (H1N1) and A/WS/33 (H1N1), which were poor inducers of IFN-a/b in spleen cells, were shown to have a more active neuraminidase than strains that induced higher IFN levels, and IFN-a/b induction by A/PR/8/34 (H1N1) and A/WS/33 (H1N1) was restored in the presence of a neuraminidase inhibitor. Growth of virus in different cell types altered the level of IFN-a/b induced in spleen cells by particular virus strains, suggesting that the nature of the carbohydrate moieties on the viral glycoproteins may also influence IFN-a/b induction in this system. Consistent with this notion, treatment of egg-grown virus with periodate to oxidize viral carbohydrate greatly reduced its capacity for IFN-a/b induction. Furthermore, induction of IFN-a/b was inhibited in the presence of the saccharides yeast mannan and laminarin. Together these findings indicate: (i) a requirement for interaction of the virus with sialylated receptors on the IFN-producing cell; (ii) an influence of viral carbohydrate on the response; and (iii) possible involvement of a lectin-like receptor on the IFN-producing cell in the induction of IFN-a/b or in regulation of this response. INTRODUCTIONThe type 1 interferons (IFN-a and -b) are key components of antiviral host defence and modulators of the immune system. Produced within hours of viral infection, IFN-a/b induces an antiviral state in uninfected cells (Isaacs & Lindenmann, 1957) that helps to contain spread of the virus (Muller et al., 1994). IFN-a/b also activates natural killer cells and macrophages (Biron et al., 1999;Bogdan, 2000), promotes the maturation and activation of dendritic cells (DCs) (Luft et al., 1998;Gallucci et al., 1999;), and displays potent adjuvant activity for T and B cell responses in vivo (Le Bon et al., 2001).Many cell types can produce IFN-a/b in response to virus infection. Double-stranded RNA (dsRNA) synthesized during the virus replicative cycle (Jacobs & Langland, 1996) is considered a likely trigger, since synthetic dsRNA, e.g. polyinosinic-polycytidylic acid [poly(I)?poly(C)] is known to be a potent inducer of type 1 IFN (De Clercq, 1981). A second pathway of IFN-a/b induction that is independent of virus replication or gene expression is seen in the response of certain cells of haemopoietic origin to enveloped viruses. These so-called 'natural' IFN-producing cells (IPCs), found in human and porcine peripheral blood and mouse spleen, produce type 1 IFN in response to physically and chemical...