Abstract
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.
Highlights
Influenza A viruses (IAVs) have a worldwide distribution and cause annual epidemics of acute respiratory illness
PR8 infection is abortive in RAW264.7, peritoneal cavity (PEC) macrophages and bronchoalveolar lavage (BAL) macrophages [11, 28, 32], and was, at best, shown to be only moderately productive in human Alveolar macrophages (AMs) by Wang et al it is unlikely that the decreased phagocytic capacity and CLEC7A expression following IAV infection are due to productive virus replication
A better understanding of the complex interactions between lung-resident and infiltrating macrophages with the inflammatory milieu present in the lungs before and during virus infection is necessary to piece together an accurate picture of what role macrophages play during IAV infection
Summary
Influenza A viruses (IAVs) have a worldwide distribution and cause annual epidemics of acute respiratory illness. While only H1N1 and H3N2 IAV are currently established in humans, novel strains emerge periodically, often from wild or domestic birds, to cause human disease [1,2,3] While these outbreaks are not always widespread, they often come with a higher mortality rate than seasonal influenza virus. As we point out below, certain measures of macrophage dysregulation during IAV infection require virus entry and protein/ nucleic acid accumulation independent of the release of new infectious virions, suggesting that productive replication may not always be required for changes in macrophage function to occur that will negatively impact on the host’s ability to clear virus infection. Studies on IAV replication in macrophages were performed prior to the emergence of HPAI H5N1 viruses in humans and the implication of macrophages in disease severity. Chan et al [30] Cline et al [39] Londrigan et al [27] Marvin et al [32] Perrone et al [17] Rodgers and Mims [24] Tate et al [11] Tate et al [28] Wells et al [25] Friesenhagen et al [38] Hoeve et al [31] Marvin et al [32] Mok et al [35] Perrone et al [17] Rodgers and Mims [26] Sakabe et al [36] Van Riel et al [37] Wang et al [29] Yu et al [33]
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