Understanding the Tropism and Pathogenesis of Pararubulaviruses - PROJECT SUMMARY This MPI grant proposal is spearheaded by Drs. Lee and Lim, who bring together complementary expertise in paramyxovirus entry and reverse genetics (Lee) and advanced animal and human organ explant models of viral pathogenesis (Lim) to address a potential global health threat posed by pararubulaviruses (PRubVs), a genus of emerging bat-derived paramyxoviruses related to but distinct from human-specific orthorubulaviruses exemplified by mumps virus, and human parainfluenza virus 2 and 4. PRubVs such as Menangle virus (MenV) and Sosuga virus (SosV) cause severe disease when spilled over into humans, and MenV infection of pregnant sows has resulted in fetal demise and a myriad of fetal abnormalities. Despite their known risk, critical aspects of PRubVs' interaction with human hosts, such as cellular tropism, receptor usage, and pathogenesis mechanisms, remain elusive, hindering the development of effective medical countermeasures (MCMs). The overarching goal of this project is to elucidate these unknowns through three interrelated Specific Aims: (1) to define the cellular tropism of Menangle and Sosuga viruses in human cells, employing innovative organ explant techniques and cutting-edge molecular biology tools; (2) to characterize the receptor usage pathways of these viruses, leveraging state-of-the-art reverse genetics systems; and (3) to develop a pathogenic animal model that reflects human disease, facilitating the study of viral pathogenesis in vivo. These aims are designed not only to fill critical knowledge gaps but also to establish foundational insights that can guide the development of targeted medical countermeasures, which are lacking for this group of understudied viruses. By synergizing the distinct but complementary scientific approaches and expertise of the MPIs, this project promises to advance our understanding of PRubVs significantly. Through a combination of reverse genetics, organ explant models, and animal studies, it aims to uncover the molecular and cellular mechanisms underlying PRubV infection and pathogenesis. This research will provide critical insights into how these viruses cross species barriers and interact with human cells, laying the groundwork for novel therapeutic and preventive strategies against PRubVs and enhancing our preparedness for future zoonotic outbreaks.
