ABSTRACT
Rift Valley fever virus (RVFV) is a zoonotic pathogen with pandemic potential. RVFV entry is mediated by the viral glycoprotein (Gn), but host entry factors remain poorly defined. Our genome-wide CRISPR screen identified low-density lipoprotein receptor-related protein 1 (mouse Lrp1/human LRP1), heat shock protein (Grp94), and receptor-associated protein (RAP) as critical host factors for RVFV infection. RVFV Gn directly binds to specific Lrp1 clusters and is glycosylation independent. Exogenous addition of murine RAP domain 3 (mRAPD3) and anti-Lrp1 antibodies neutralizes RVFV infection in taxonomically diverse cell lines. Mice treated with mRAPD3 and infected with pathogenic RVFV are protected from disease and death. A mutant mRAPD3 that binds Lrp1 weakly failed to protect from RVFV infection. Together, these data support Lrp1 as a host entry factor for RVFV infection and define a new target to limit RVFV infections.
Subject(s)
Host-Pathogen Interactions , Low Density Lipoprotein Receptor-Related Protein-1/metabolism , Rift Valley fever virus/physiology , Virus Internalization , Animals , Antibody Specificity/immunology , Base Sequence , Brain/pathology , Brain/virology , CRISPR-Cas Systems/genetics , Cell Membrane/metabolism , Cells, Cultured , Glycoproteins/metabolism , Glycosaminoglycans/metabolism , Glycosylation , Humans , LDL-Receptor Related Protein-Associated Protein/metabolism , Ligands , Low Density Lipoprotein Receptor-Related Protein-1/deficiency , Membrane Glycoproteins/metabolism , Mice , Protein Binding , Protein Denaturation , Rift Valley Fever/pathology , Rift Valley Fever/prevention & control , Rift Valley Fever/virology , Rift Valley fever virus/immunologyABSTRACT
Teams of scientists representing diverse disciplines are often brought together for purposes of better understanding and, ultimately, resolving urgent public health and environmental problems. Likewise, the emerging field of the science of team science draws on diverse disciplinary perspectives to better understand and enhance the processes and outcomes of scientific collaboration. In this supplement to the American Journal of Preventive Medicine, leading scholars in the nascent field of team science have come together with a common goal of advancing the field with new models, methods, and measures. This summary article highlights key themes reflected in the supplement and identifies several promising directions for future research organized around the following broad challenges: (1) operationalizing cross-disciplinary team science and training more clearly; (2) conceptualizing the multiple dimensions of readiness for team science; (3) ensuring the sustainability of transdisciplinary team science; (4) developing more effective models and strategies for training transdisciplinary scientists; (5) creating and validating improved models, methods, and measures for evaluating team science; and (6) fostering transdisciplinary cross-sector partnerships. A call to action is made to leaders from the research, funding, and practice sectors to embrace strategies of creativity and innovation in a collective effort to move the field forward, which may not only advance the science of team science but, ultimately, public health science and practice.
