Hijacking the neonatal FC receptor: the novel biology of arterivirus entry, transmission, and persistence

The National Institute of Allergy and Infectious Diseases awarded the University of Wisconsin System $615,446 on April 3, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to support research into arterivirus entry, transmission, and persistence mechanisms.

The research examines how arteriviruses—an understudied family of RNA viruses related to coronaviruses—enter cells, evade immunity, and cause disease. The work focuses on the neonatal Fc receptor (FcRn) and its role as an entry factor that arteriviruses use alongside the macrophage receptor CD163 to gain cellular entry. The project maps critical interaction sites on FcRn by creating chimeric FcRn molecules incorporating features of arterivirus-permissive and arterivirus-resistant orthologs to define the domains, motifs, and residues involved in arterivirus–FcRn binding. A parallel effort generates chimeric arteriviruses containing combinations of glycoproteins from different arterivirus species to identify the viral glycoproteins and domains critical for entry. The research aims to clarify which macrophage subpopulations support arterivirus replication and to predict and prevent arterivirus emergence in humans, given that some arteriviruses have demonstrated capacity to infect human cells.

The award is administered through the University of Wisconsin–Madison Division and performs at Madison, Wisconsin. The period of performance extends from April 3, 2026, through March 31, 2031.

Abstract

Understanding novel mechanisms by which animal viruses enter cells, evade immunity, and cause disease has scientific and public health importance. Arteriviruses are an understudied family of RNA viruses (related to coronaviruses) that infect a wide variety of mammals. The host and viral factors that determine arterivirus disease, persistence, and cross-species transmission remain unknown and unpredictable. This lack of understanding has implications for predicting/thwarting arterivirus emergence in humans, as some arteriviruses have been shown to infect human cells. Macrophages are exclusively infected by most arteriviruses, but the subpopulation(s) of macrophages that support arterivirus replication remain poorly defined. The process by which arteriviruses enter cells is highly novel and also poorly understood. Each virion displays an unusually large set of surface glycoproteins (7-11 depending on the virus) that are unlike any known viral fusion machinery. The macrophage-specific molecule CD163 is a required arterivirus receptor, yet CD163 by itself is insufficient to mediate arterivirus entry. We recently identified the neonatal FC receptor (fcrn) as an important entry factor that arteriviruses use together with CD163 to gain entry into cells. Aim 1 of this project builds upon this discovery to define the molecular details of the arterivirus:fcrn interaction. In aim 1A, we will map the site(s) on fcrn that are critical for arterivirus engagement by creating chimeric fcrn molecules that incorporate features of arterivirus-permissive and -resistant fcrn orthologs, with the goal of defining the domains, motifs, and residues involved in arterivirus/fcrn interactions. In aim 1B, we will generate chimeric arteriviruses that contain combinations of glycoproteins from different arteriviruses, seeking to define the viral glycoproteins, domains, motifs, and residues involved in fcrn engagement. In aim 1C, we will continue to develop our understanding of the host factors required for arterivirus entry by performing screens to identify additional host factors that are functionally redundant with fcrn for the viral entry process. In aim 2, we will use the murine arterivirus (lactate dehydrogenase-elevating virus, LDV), which causes life-long viremia in adult mice, to understand several aspects of arterivirus infection in vivo. In aim 2A, we will use a nanoluciferase-expressing LDV to perform body-wide imaging and identify the tissues that support LDV infection over time. In aim 2B, we will hone in key tissues and identify the macrophage populations within these tissues that support LDV infection and determine how persistent arterivirus infection impacts recovery of target cell populations. Finally, in aim 2C we will use fcrn-knockout mice to determine whether arteriviruses hijack fcrn's physiologic role in placental biology, potentially explaining the high efficiency with which arteriviruses transmit vertically. This project will provide insights into novel mechanisms of viral entry, macrophage infection and dysfunction, viral persistence, and vertical transmission through the study of the neglected "pre-emergent" family of mammalian viruses, the arteriviruses.