[R01] Characterizing the role of LDL related receptor 1 (Lrp1) as host entry factor for multiple bunyaviruses
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2028-02-29
Importo max: 767.375 EUR
Paese: US
Descrizione
Summary:
Bunyaviruses (Order: Bunyavirales) are a growing and diverse family of animal and human pathogens with
pandemic potential. With over 300 members and an expanding distribution of mosquito and tick vectors, these
viruses are responsible for increasing outbreaks of human disease and present a significant threat to human
health. Rift Valley Fever virus (RVFV) is one of the well-studied bunyaviruses and is designated as an NIAID
Category A pathogen and included in the WHO’s Blueprint of Priority Diseases. The Coalition for Epidemic
Preparedness Innovations (CEPI) included RVFV as part of their emerging infectious diseases vaccine program,
further emphasizing the potential impact on the global health and economy. Oropouche virus (OROV) is found
in South America and has caused more than 30 large epidemics resulting in over 500,000 human cases, making
it the second most common arboviral disease in South America behind Dengue fever. However, the true case
number is likely much higher due to Oropouche fever being misdiagnosed as Chikungunya or Dengue. A third
member, La Crosse virus (LACV) is found primarily in North America and is the primary cause of pediatric viral
encephalitis in the United States. Neither OROV nor LACV have been as well studied as RVFV, and thus a
significant gap remains in our broad understanding of bunyavirus pathogenesis. Currently there are no approved
therapeutic drugs for treatment of RVFV, OROV, or LACV disease, further highlighting the need for our proposed
studies. To address this need, we conducted a genomic screen that defined several critical factors, including
Lrp1, an LDL family member. In support we provide compelling preliminary data including in vitro validation in
Lrp1 sufficient and deficient cells, transcomplementation studies, and direct interaction between RVFV
glycoprotein Gn in vitro. We also show that inhibition of Lrp1 by endogenous ligands in vitro in multiple cell lines
from evolutionarily distinct hosts, and in vivo data demonstrating the importance of Lrp1 for viral tropism and
disease in mice. Here we will characterize the importance of Lrp1 for entry of multiple bunyaviruses, define
molecular mechanisms, and validate the significance in vitro and in vivo. This work will be performed by highly
productive and collaborative investigators with expertise in every aspect of the proposed studies, including
biochemistry, viral pathogenesis, immunology, proteomics, structural biology, and virology. At completion, we
expect to validate Lrp1 as pan-bunyavirus entry factor, filling a key gap in the field and to provide novel targets
for therapeutic development.
Istituzione: WASHINGTON UNIVERSITY
PI: Gaya K. Amarasinghe, Amy L Hartman
Progetto: 5R01AI169850-04
Settori: National Institute of Allergy and Infectious Diseases
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.