Human metapneumovirus SH protein promotes JAK1 degradation to impair host IL-6 signaling.

Human metapneumovirus (HMPV) is a common cause of severe respiratory illness, especially in children and older adults, in whom it is a leading cause of hospitalization. Prior research suggests that severe HMPV infection is driven by a strong immune response to the virus, and especially by inflammatory immune signals like interferons (IFN). HMPV produces a small hydrophobic protein (SH) that is known to block IFN signaling, but the mechanism by which it functions, and its ability to inhibit other important immune signals remains unexplored. This paper demonstrates that SH can inhibit another related immune signal, IL-6, and demonstrates that SH depletes JAKs, critical proteins involved in both IL-6 and IFN signaling. A robust understanding of how HMPV and related viruses interfere with immune signals important for disease could pave the way for future treatments aimed at mitigating severe infections.