Treatment With Ruxolitinib and TAK-779 Enhances GII.17 Human Norovirus Replication and Enables Serial Passaging in Human Intestinal Enteroids

Abstract

Human norovirus (HuNoV) is a major cause of acute viral gastroenteritis. Although it can be replicated in vitro using human intestinal enteroids (HIEs), generating high-titer viral laboratory stocks remains challenging due to low infection and passage efficiencies. Interferon response and chemokine signaling may be key host pathways that restrict efficient HuNoV replication. Here, we evaluated the effect of their inhibitors, ruxolitinib—a Janus kinase (JAK) 1/JAK2 inhibitor—and TAK-779—a C-X-C motif chemokine receptor 3 (CXCR3)/C-C motif chemokine receptor (CCR) 5/CCR2 antagonist—on HuNoV replication in wild-type jejunal HIEs. TAK-779 increased GII.17 HuNoV replication by 2.3- and 6.0-fold at 48 and 96 h postinfection (hpi), respectively, compared with the DMSO-treated control. In contrast, ruxolitinib alone did not affect viral replication. Notably, simultaneous treatment with these compounds further enhanced GII.17 replication by 6.0- and 10.7-fold at 48 and 96 hpi, respectively, which enabled serial passaging. These findings imply that the simultaneous suppression of these pathways potentially benefits GII.17 HuNoV replication.