Sendai virus C protein affects macrophage function, which plays a critical role in modulating disease severity during Sendai virus infection in mice

Abstract

Sendai virus (SeV) accessory protein C limits the generation of double-stranded RNAs, defective interfering RNAs, or both, during viral transcription and replication, thereby limiting interferon-β production. Our recent in vitro analyses on murine macrophage cell lines demonstrated that this protein also contributes to restricting macrophage function, including the production of nitric oxide (NO) and inflammatory cytokines in addition to interferon-β, in infected macrophages. This study showed that depletion of airway macrophages by clodronate-loaded liposomes led to the development of severe viral pneumonia in recombinant C gene-knockout SeV (SeVΔC)-infected mice, but did not modulate disease severity in wild-type SeVinfected mice. Furthermore, the severe disease observed in macrophage-depleted, SeVΔC-infected mice was associated with exacerbated virus replication in the lungs, leading to severe airway inflammation and pulmonary edema, indicating lung injury. These results suggested that the antimacrophage activity of SeV C protein might play a critical role in modulating lung injury and associated diseases caused by SeV.

Innate Immune Response-Mediated Inflammation in Viral Pneumonia

“…This study demonstrated that clodronate-loaded liposomes depleted airway macrophages, which caused severe viral pneumonia to develop in SeV-infected mice with the recombinant C gene deletion, but did not affect the extremity of the disease in mice with wild-type SeV. 113 The role of alveolar macrophages in the pathophysiology of MERS was investigated by researchers adopting a mouse model of MERS coronavirus infection. Human dipeptidyl peptidase 4 knockin mice had drastically increased morbidity and mortality when alveolar macrophages were depleted; however, mice with alveolar macrophages were protected from MERS-CoV-induced pneumonia and serious illness.…”

SeV C Protein Plays a Role in Restricting Macrophage Phagocytosis by Limiting the Generation of Intracellular Double-Stranded RNA

“…Further, we demonstrated that host factors involved in the early clearance of SeVΔC in mice are not limited to IFN-β, but might also include macrophage-specific factors. Indeed, in vivo depletion of airway macrophages during SeV ΔC infection enhanced viral replication and infection pathogenesis in mice ( Sakuma et al, 2021 ).…”

“…To this end, we recently investigated the effects of macrophage depletion on SeVΔC pathogenesis and replication in mice. Depletion of airway macrophages via clodronate-loaded liposomes enhanced pathogenesis and viral replication in vivo ( Sakuma et al, 2021 ). Therefore, the suppression macrophage function may represent a major strategy evolved by these viruses to enhance their pathogenicity.…”

“…This ability of the C protein to limit dsRNA also contributes to limited macrophage function, including the production of nitric oxide (NO), pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α, and IFN-β, in infected macrophages ( Odkhuu et al, 2018 ). Further research revealed that the in vivo depletion of airway macrophages during recombinant C gene-knockout SeV (SeVΔC) infection in mice resulted in the development of severe viral pneumonia ( Sakuma et al, 2021 ). Therefore, the anti-macrophage activity of the C protein also appears to play an important role in vivo .…”