The immunomodulating V and W proteins of Nipah virus determine disease course

Abstract

The viral determinants that contribute to Nipah virus (NiV)-mediated disease are poorly understood compared with other paramyxoviruses. Here we use recombinant NiVs (rNiVs) to examine the contributions of the NiV V and W proteins to NiV pathogenesis in a ferret model. We show that a V-deficient rNiV is susceptible to the innate immune response in vitro and behaves as a replicating non-lethal virus in vivo. Remarkably, rNiV lacking W expression results in a delayed and altered disease course with decreased respiratory disease and increased terminal neurological disease associated with altered in vitro inflammatory cytokine production. This study confirms the V protein as the major determinant of pathogenesis, also being the first in vivo study to show that the W protein modulates the inflammatory host immune response in a manner that determines the disease course.

Nipah Virus C and W Proteins Contribute to Respiratory Disease in Ferrets

“…These rNiV M mutants were characterized in vitro, followed by studies in the ferret model. In contrast to the findings of studies with hamsters, our results suggest that the C protein plays only a minor role in the respiratory component of disease and no role in the neurological component of NiV disease in the ferret model, which is similar to the previously reported role of the W protein (16). We also determined that the C and W proteins have either the same or complementary targets, since rNiV M -C ko W ko -infected ferrets had very little respiratory disease but still developed severe neurological disease with 60% mortality.…”

“…A single NiV outbreak occurred in Malaysia and Singapore in 1998 to 1999 (6), whereas outbreaks occur almost annually in Bangladesh and northeastern India (7)(8)(9)(10)(11)(12); an outbreak also occurred in the Philippines in 2014 (13). Little is known about NiV pathogenesis (14,15), and the viral determinants that contribute to the pulmonary and encephalitic components of NiV-mediated disease have not yet been identified; however, we recently reported on the contributions of the V and W proteins in the ferret model of NiV disease (16).…”

“…The recently developed ferret model of NiV infection models all major aspects of NiV-mediated disease in humans regardless of the dose (2), including both respiratory disease and complex neurological disease, as well as systemic vasculitis (22,25). Indeed, the ferret model has already proven very useful in deciphering the determinants of NiV pathogenesis (16).…”

The Future of Preventing and Treating Nipah Virus Infection

“…The last 5 years have shown light on the importance of the NiV Matrix protein, Phosphoprotein, and the accessory proteins V, W and C in the pathogenesis of NiV in small animal models [1,[7][8][9]12]. Studies in the near future will confirm if these interactions are also important in pathogenesis in nonhuman primates.…”

“…Fruit bats from the genus Pteropus (flying foxes) serve as the host for NiV in nature, and they can transmit the virus to humans through intermediate livestock hosts [3] or through contaminated date palm sap [4,5] followed by human-to-human transmission [6]. Advances in understanding the pathogenesis of NiV have occurred in the two decades since NiV was discovered [1,[7][8][9][10][11][12][13], but little progress has been made in terms of preventing and treating human infections. This should be the focus of NiV research in the coming decade with three areas of synergizing emphasis: prevention through vaccination; prevention through modifying risk factors; and the development of therapeutics and techniques capable of treating patients currently infected to reduce morbidity and mortality.…”