Critical Role of Airway Macrophages in Modulating Disease Severity during Influenza Virus Infection of Mice

Abstract

Airway macrophages provide a first line of host defense against a range of airborne pathogens, including influenza virus. In this study, we show that influenza viruses differ markedly in their abilities to infect murine macrophages in vitro and that infection of macrophages is nonproductive and no infectious virus is released. Virus strain BJx109 (H3N2) infected macrophages with high efficiency and was associated with mild disease following intranasal infection of mice. In contrast, virus strain PR8 (H1N1) was poor in its ability to infect macrophages and highly virulent for mice. Depletion of airway macrophages by clodronate-loaded liposomes led to the development of severe viral pneumonia in BJx109-infected mice but did not modulate disease severity in PR8-infected mice. The severe disease observed in macrophage-depleted mice infected with BJx109 was associated with exacerbated virus replication in the airways, leading to severe airway inflammation, pulmonary edema, and vascular leakage, indicative of lung injury. Thymic atrophy, lymphopenia, and dysregulated cytokine and chemokine production were additional systemic manifestations associated with severe disease. Thus, airway macrophages play a critical role in limiting lung injury and associated disease caused by BJx109. Furthermore, the inability of PR8 to infect airway macrophages may be a critical factor contributing to its virulence for mice.

Influenza virus replication in macrophages: balancing protection and pathogenesis

“…In this case, virus nucleoprotein (NP) accumulated in 20 % of infected cells, but virus release was undetected [26]. Other studies support the findings of early experiments [11,[27][28][29]. However, certain seasonal H1N1 and H3N2 strains are capable of limited productive replication in mouse bone marrow-derived macrophages (BMDMs) or human MDMs, respectively [30][31][32][33].…”

“…Thus, the response of these cells to IAV infection is likely to be of critical importance to disease outcome. The importance of macrophages for protection against IAV infection is well established, as ablation of macrophages enhances IAV-associated immunopathology and mortality [8][9][10][11][12]. The importance of macrophages during IAV infection goes beyond protection from virus-induced pneumonia.…”

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

“…It is notable, however, that the apparently more permissive state of alternatively activated macrophages did not lead to production of higher levels of infectious virus than are found in classically activated cells. Although there is evidence for productive influenza virus infections in human macrophages (Hoeve et al, 2012;Perrone et al, 2008;van Riel et al, 2011;Yu et al, 2011), a number of publications have reported that influenza virus infection is abortive in murine macrophages (Rodgers & Mims, 1981;Tate et al, 2010Tate et al, , 2011. Our data show that whilst there is some replication of A/WSN/33 in murine BMDMs, the ability to produce infectious virus is not related to the activation state of the macrophage.…”

“…Previous studies have reported that influenza viruses can infect macrophages with varying efficiency in a virus strain-dependent manner (Reading et al, 2000;Rodgers & Mims, 1981;Tate et al, 2010). We wished to investigate the ability of A/WSN/33 to infect macrophages from mice on the 129Sv/Ev background and therefore we derived macrophages from femurs of female 129Sv/Ev mice (6-8 weeks old) by culture for 7 days in medium containing macrophage colony-stimulating factor (M-CSF).…”

“…Infection of monocyte-derived macrophages in vitro with highly pathogenic viruses leads to production of higher levels of inflammatory cytokines and chemokines than are produced in response to infection with low-pathogenicity seasonal viruses (Cheung et al, 2002;Zhou et al, 2006), suggesting that infection of macrophages may be, at least in part, responsible for the increased pathogenicity of these viruses. In vivo studies, however, have shown that a virus strain that readily infects macrophages in vitro is less pathogenic in mice than a related virus that fails to infect macrophages (Tate et al, 2010). In this instance, depletion of macrophages increases the virulence, suggesting that macrophage infection can attenuate pathogenesis.…”