R01AI169850

Characterizing the Role of LDL Related Receptor 1 (LRP1) as Host Entry Factor for Multiple Bunyaviruses - Project Summary/Abstract

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 due to climate change, 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 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 a pan-bunyavirus entry factor, filling a key gap in the field and to provide novel targets for therapeutic development.

Washington University

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS; TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Saint Louis, Missouri 631101010 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 97% from $1,567,112 to $3,085,681.