STAT2 Limits Host Species Specificity of Human Metapneumovirus

Abstract

<jats:p>The host tropism of viral infection is determined by a variety of factors, from cell surface receptors to innate immune signaling. Many viruses encode proteins that interfere with host innate immune recognition in order to promote infection. STAT2 is divergent between species and therefore has a role in species restriction of some viruses. To understand the role of STAT2 in human metapneumovirus (HMPV) infection of human and murine tissues, we first infected STAT2−/− mice and found that HMPV could be serially passaged in STAT2−/−, but not WT, mice. We then used in vitro methods to show that HMPV inhibits expression of both STAT1 and STAT2 in human and primate cells, but not in mouse cells. Transfection of the murine form of STAT2 into STAT2-deficient human cells conferred resistance to STAT2 inhibition. Finally, we sought to understand the in vivo role of STAT2 by infecting hSTAT2 knock-in mice with HMPV, and found that mice had increased weight loss, inhibition of type I interferon signaling, and a Th2-polarized cytokine profile compared to WT mice. These results indicate that STAT2 is a target of HMPV in human infection, while the murine version of STAT2 restricts tropism of HMPV for murine cells and tissue.</jats:p>

Zoonotic Origins of Human Metapneumovirus: A Journey from Birds to Humans

“…The mouse model has been useful in elucidating some aspects of viral pathogenesis and in the development of vaccines and antivirals. Two mouse strains that have been shown to be permissive are BALB/c [129,130] and C57BL/6 mice [131,132] which show airway obstruction, hyperresponsiveness, weight loss, ruffled fur, and huddling behavior upon inoculation with HMPV [133][134][135]. However, it must be noted that inconsistency in data does arise, possibly due to variation in the experimental setup.…”

Mechanisms of Viral Degradation of Cellular Signal Transducer and Activator of Transcription 2

“…NS5, therefore, acts as an important determinant of host tropism for these viruses. It is important to note here that STAT2 plays a role in determining such host tropism in several other viruses as well, such as human metapneumovirus (HMPV), which can infect cells containing human STAT2 but not those expressing murine STAT2 [ 79 ]. The NS5 protein of YFV, which sequesters STAT2 instead of degrading it, also binds hSTAT2 and not mSTAT2 [ 80 , 81 ].…”

Human Disease Phenotypes Associated with Loss and Gain of Function Mutations in STAT2: Viral Susceptibility and Type I Interferonopathy

“…The result is that certain viral pathogens only cause disease in humans. Examples include dengue [40] and Zika [41] virus and human metapneumovirus [48].…”