Detalle de: Neutral sphingomyelinase 2 inhibition alters inflammatory gene expression signatures in the brain of mice infected with West Nile virus

West Nile virus (WNV) is a neurotropic flavivirus transmitted by the bites of infected mosquitoes. Severe forms of the disease include meningitis, encephalitis, acute flaccid paralysis, or even death, and survivors develop long-lasting sequelae. The damage induced by WNV does not only stem from viral multiplication but also arises from immune-related pathology linked to neuroinflammation. Certain sphingolipids are key players in WNV infection, neurodegenerative diseases and inflammatory disorders. Neutral sphingomyelinase 2 (nSMase2), catalyzes the conversion of sphingomyelin into ceramide and is essential for flavivirus multiplication. Thus, nSMase2 constitutes a promising therapeutic target for the development of dual-acting antiviral and anti-inflammatory therapies against WNV. The effect of an orally bioavailable and brain-penetrating prodrug of the potent nSMase2 inhibitor DPTIP (DPTIP-P1) was studied in WNV-infected mice. While no reduction in the viral load in the brain of infected animals was observed, WNV-induced expression of inflammatory markers was modulated, resulting in a reduced IL-1β expression in brain. Transcriptomic analyses revealed that treatment with the DPTIP prodrug also modulated the expression of various genes related to immune cell function without altering antiviral innate response. Among others, DPTIP-P1 reduced the expression of Lyz2, an inducible genetic marker associated with macrophage infiltration, and modified the expression of genes related to T cell activation such as Trbc1 and Ptnp22. These results identify nSMase2 inhibitors as a new type of immune modulators of WNV infection. The neuroprotective effects exerted by DPTIP-P1 could contribute to mitigate WNV-induced neuroinflammation and sequelae.