Abstract
Influenza A virus (IAV) is a major human respiratory pathogen causing annual epidemics as well as periodic pandemics. A complete understanding of the virus pathogenesis and host factors involved in the viral lifecycle is crucial for developing novel therapeutic approaches. Sphingomyelin (SM) is the most abundant membrane sphingolipid. It preferentially associates with cholesterol to form distinct domains named lipid rafts. Sphingomyelinases, including acid sphingomyelinase (ASMase), catalyzes the hydrolysis of membrane SM and consequently transform lipid rafts into ceramide-enriched membrane platforms. In this study, we investigated the effect of SM hydrolysis on IAV propagation. Depleting plasma membrane SM by exogenous bacterial SMase (bSMase) impaired virus infection and reduced virus entry, whereas exogenous SM enhanced infection. Moreover, the depletion of virus envelope SM also reduced virus infectivity and impaired its attachment and internalization. Nonetheless, inhibition of ASMase by desipramine did not affect IAV infection. Similarly, virus replication was not impaired in Niemann-Pick disease type A (NPA) cells, which lack functional ASMase. IAV infection in A549 cells was associated with suppression of ASMase activity starting at 6 h post-infection. Our data reveals that intact cellular and viral envelope SM is required for efficient IAV infection. Therefore, SM metabolism can be a potential target for therapeutic intervention against influenza virus infection.
Highlights
Influenza is considered a major public health concern due to the significant morbidity and mortality associated with the disease (Lee et al, 2018)
SM depletion of the plasma membrane or the viral envelope impaired influenza A virus (IAV) attachment and internalization. These results demonstrate that IAV does not require acid sphingomyelinase (ASMase) activity for infection and that intact SM in both cell membrane and viral envelope is essential for efficient IAV entry
Membrane microdomains enriched in SM and cholesterol, were shown to be utilized during different phases of the IAV replication cycle (Rossman and Lamb, 2011)
Summary
Influenza is considered a major public health concern due to the significant morbidity and mortality associated with the disease (Lee et al, 2018). Sphingolipids have been implicated during different aspects of the viral life cycles including attachment (Puri et al, 2004; Rawat et al, 2004; Grassme, 2005), entry (Nieva et al, 1994; Miller et al, 2012; Shivanna et al, 2015; Drake et al, 2017), replication (Weng et al, 2010; Martín-Acebes et al, 2016) and budding (Nguyen and Hildreth, 2000; Ono and Freed, 2001; Tafesse et al, 2013) As such, they are considered a promising therapeutic target against viral infections (Yager and Konan, 2019). The sphingolipid biosynthesis is a promising host target for developing novel therapeutic approaches against influenza infection
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