Alveolar-like Macrophages Attenuate Respiratory Syncytial Virus Infection

Abstract

Respiratory Syncytial Virus (RSV) is the leading cause of acute lower respiratory infections in young children and infection has been linked to the development of persistent lung disease in the form of wheezing and asthma. Despite substantial research efforts, there are no RSV vaccines currently available and an effective monoclonal antibody targeting the RSV fusion protein (palivizumab) is of limited general use given the associated expense. Therefore, the development of novel approaches to prevent RSV infection is highly desirable to improve pediatric health globally. We have developed a method to generate alveolar-like macrophages (ALMs) from pluripotent stem cells. These ALMs have shown potential to promote airway innate immunity and tissue repair and so we hypothesized that ALMs could be used as a strategy to prevent RSV infection. Here, we demonstrate that ALMs are not productively infected by RSV and prevent the infection of epithelial cells. Prevention of epithelial infection was mediated by two different mechanisms: phagocytosis of RSV particles and release of an antiviral soluble factor different from type I interferon. Furthermore, intratracheal administration of ALMs protected mice from subsequent virus-induced weight loss and decreased lung viral titres and inflammation, indicating that ALMs can impair the pathogenesis of RSV infection. Our results support a prophylactic role for ALMs in the setting of RSV infection and warrant further studies on stem cell-derived ALMs as a novel cell-based therapy for pulmonary viral infections.

Airway Administration of Bacterial Lysate OM-85 Protects Mice Against Respiratory Syncytial Virus Infection

“…Importantly, macrophage polarization is also likely involved in RSV infection ( 66 , 67 ). Although there is evidence showing that alveolar macrophages necroptosis drives disease pathogenesis during RSV infection ( 68 ), there are also evidence indicating that AM can control/attenuate RSV pathology ( 44 , 68 – 71 ). Our study showed that OM–85 treatment used as preventive measure consistently maintained AM population in the lungs, while RSV–infected untreated animals presented a pronounced reduction in these cells.…”

Therapeutic stem cell‐derived alveolar‐like macrophages display bactericidal effects and resolve Pseudomonas aeruginosa‐induced lung injury

“… 17 and kill respiratory syncytial virus (RSV) and prevent RSV‐induced lung injury. 18 Here, we further characterized ALMs for their efficacy to treat bacterial lung infections. We evaluated the non‐pharmacological antimicrobial functions of ALMs, specifically for bacteria known to colonize the lungs of immune‐compromised individuals, such as P .…”

“…A . ) 17 and kill respiratory syncytial virus (RSV) and prevent RSV‐induced lung injury 18 . Here, we further characterized ALMs for their efficacy to treat bacterial lung infections.…”

“…17 Previously, we have demonstrated that ALMs reduce lung injury in mouse models of acute and chronic lung diseases, can internalize dead Staphylococcus aureus (S.A.) 17 and kill respiratory syncytial virus (RSV) and prevent RSV-induced lung injury. 18 Here, we further characterized ALMs for their efficacy to treat bacterial lung infections. We evaluated the non-pharmacological antimicrobial functions of ALMs, specifically for bacteria known to colonize the lungs of immune-compromised individuals, such as P.A.…”

M1-like, but not M0- or M2-like, macrophages, reduce RSV infection of primary bronchial epithelial cells in a media-dependent fashion

“…To determine the role of macrophages in RSV infection, in vivo models have typically been used that deplete alveolar macrophages, or adoptively transfer specific types of macrophages into the lungs again after depletion. However, there are conflicting findings in these reports, with some suggesting macrophages are protective [ 23 – 26 ], while others suggest they contribute to the pathology [ 27 , 28 ] of infection. To add to the complexity, modifying the phenotype of alveolar macrophage during infection may also provide a protective effect against viral infection [ 29 , 30 ].…”