Human Alveolar Macrophages May Not Be Susceptible to Direct Infection by a Human Influenza Virus

Abstract

The current studies were undertaken to determine the susceptibility of human alveolar macrophages (AMs) to influenza A virus (IAV) infection in comparison with autologous peripheral blood-derived monocytes-macrophages (PBMs). AMs and PBMs were exposed to IAV in vitro and examined for their ability to bind and internalize IAV, and synthesize viral proteins and RNA. PBMs but not AMs demonstrated binding and internalization of the virus, synthesizing viral proteins and RNA. Exposure of AMs in the presence of a sialidase inhibitor or anti-IAV antibody resulted in viral protein synthesis by the cells. Exposure of AMs to fluorescein isothiocyanate-labeled IAV in the presence of anti-fluorescein isothiocyanate antibody also resulted in viral protein synthesis. Thus, human AMs are apparently not susceptible to direct infection by a human IAV but are likely to be infected indirectly in the setting of exposure in the presence of antibody that binds the challenging strain of IAV.Keywords. human alveolar macrophages; influenza virus; monocytes; macrophages.Human influenza A virus (IAV) predominantly infects the upper airways [1]. In the vast majority of infected individuals, pneumonia does not occur. In the ferret model, infection is confined largely to airway epithelium and is rare in the alveoli [2]. However, isolated ferret alveolar tissues seem to be as susceptible to infection as the airways, suggesting that host defenses prevent viral infection at the alveolar level [2]. Alveolar macrophages (AMs) generally have been considered to be the first leukocyte-based line of defense against respiratory pathogens such as influenza virus [3][4][5][6]. AMs must protect the lungs not only from pathogens but also from constant immunopathological processes due to all types of inhaled material [6], and elimination of AMs in immunized mice can enhance inflammatory responses to antigen [7], suggesting that AMs play a predominantly suppressive role during inflammatory responses in vivo. Our early studies showed that human AMs from healthy volunteer donors differed substantially from autologous peripheral blood blood-derived monocytes-macrophages (PBMs) in support of lymphocyte proliferative responses to both mitogens and antigens, including inactivated IAV [3]. In contrast to significant accessory cell support demonstrated by PBMs, lymphocytes exposed to the inactivated virus in the presence of AMs showed no difference in proliferation compared with the lymphocytes cultured in the absence of any accessory cell. Furthermore, when AMs were added to PBMs plus lymphocytes, with appropriate controls for cell numbers, the AMs suppressed lymphocyte proliferative responses to antigen [8]. Others have reported that human IAV infection of human monocyte and macrophage subpopulations showed increased susceptibility associated with cell differentiation [9]. As differentiated macrophages likely to first encounter IAV, AMs have generally been assessed for infection using immunofluorescent staining for IAV antigens [10][11][12]. van Riel and colleagu...

Diverse and Unexpected Roles of Human Monocytes/Macrophages in the Immune Response to Influenza Virus

“…PBM, as expected, bound and internalized IAV and synthesized viral RNA and proteins. In contrast, AM showed no evidence of IAV infection despite equivalent exposure [2]. The AM did become infected and synthesize IAV proteins if the cells were exposed to the virus in the presence of a sialidase inhibitor or an anti-IAV antibody or, in the case of exposure to a fluorescein isothiocyanate-labeled IAV, in the presence of anti-fluorescein isothiocyanate antibody.…”

“…The AM did become infected and synthesize IAV proteins if the cells were exposed to the virus in the presence of a sialidase inhibitor or an anti-IAV antibody or, in the case of exposure to a fluorescein isothiocyanate-labeled IAV, in the presence of anti-fluorescein isothiocyanate antibody. Thus, human AM are not susceptible to direct infection by IAV but can be infected when exposed to the virus complexed with an antibody [2].…”

“…Monocytes and macrophages are central to the development as well as expression of the human immune response and its defense against influenza A virus (IAV) infection. Such cells are resident in the respiratory tract [1][2][3][4], and additional monocytes/macrophages are rapidly and vigorously recruited to the respiratory tract upon virus challenge [3][4][5]. Those recruited cells are susceptible to infection by IAV, as are co-recruited lymphocytes [6,7].…”

Why respiratory viruses or bacteria have the highest probability to be deposited in the respiratory tract in flu seasons

“…Due to the fact that the most human influenza viruses predominantly infect the upper airways (we do not consider in this part of the study avian influenza and pneumonia) (van Riel et al, 2007;Ettensohn et al, 2016). We suggested that the first step of virus infections is the deposition of viruses on the epithelial cells of upper airways (see remark below #about virus attach).…”

“…Human influenza viruses attached more strongly to human trachea and bronchi (van Riel et al, 2007;Ettensohn et al, 2016). Most strains of rhinovirus and the common cold virus, replicate better in the nasal cavity (Foxman et al, 2015;.…”