Abstract
Macrophages play a central role in the innate immune response to respiratory viral infections through pro-inflammatory factor secretion and phagocytosis. However, as a countermeasure, viral pathogens have evolved virulence factors to antagonize macrophage function. In our recent in vitro analyses of murine macrophage cell lines, Sendai virus (SeV) accessory protein C inhibited the secretion of pro-inflammatory factors, and C gene-knockout SeV (SeVΔC) caused drastic morphological changes in RAW264.7 macrophages, similar to those observed after stimulation with Lipid A, a well-known activator of actin-rich membrane ruffle formation and phagocytosis. Hence, we sought to determine whether the C protein limits phagocytosis in SeV-infected macrophages through the suppression of membrane ruffling. Phagocytosis assays indicated an upregulation of phagocytosis in both SeVΔC-infected and Lipid A-stimulated macrophages, but not in SeV WT-infected cells. Further, the observed membrane ruffling was associated with phagocytosis. RIG-I is essential for Lipid A-induced phagocytosis; its deficiency inhibited SeVΔC-stimulated phagocytosis and ruffling, confirming the essential role of RIG-I. Moreover, treatment with interferon (IFN)-β stimulation and neutralizing antibodies against IFN-β suggested that SeVΔC-induced phagocytosis and ruffling occurred in an IFN-β-independent manner. A newly isolated SeVΔC strain that does not generate dsRNA further highlighted the importance of dsRNA in the induction of phagocytosis and ruffling. Taken together, the current results suggest that SeV C protein might limit phagocytosis-associated membrane ruffling in an RIG-I-mediated but IFN-independent manner via limiting the generation of intracellular dsRNA.
Highlights
Viral infections of the respiratory tract are a major cause of mortality in children in developing countries (Alemayehu et al, 2019) and a threat of occasional outbreak in immunocompromised patients and the elderly
We demonstrated that Sendai virus (SeV) 4C(−) infection of macrophages induced phagocytosis-associated membrane ruffle formation through the generation of intracellular dsRNA (Figure 8A)
Our observations indicated that SeV C protein suppresses phagocytosis by limiting the generation of intracellular dsRNA
Summary
Viral infections of the respiratory tract are a major cause of mortality in children in developing countries (Alemayehu et al, 2019) and a threat of occasional outbreak in immunocompromised patients and the elderly. Viruses causing these infections belong to the Respirovirus genus in the family Paramyxoviridae. Silencing the C gene in hPIV1 by reverse genetic technology has resulted in the attenuation of the virulence of the virus, demonstrating that the C protein is a primary factor in viral pathogenesis. Understanding the exact function of the C protein will contribute to the elucidation of viral pathogenesis and the development of effective vaccines and antiviral agents
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