Antibody-Based Inhibition of Pathogenic New World Hemorrhagic Fever Mammarenaviruses by Steric Occlusion of the Human Transferrin Receptor 1 Apical Domain.

Pathogenic clade B New World mammarenaviruses (NWM) can cause Argentine, Venezuelan, Brazilian, and Bolivian hemorrhagic fevers. Sequence variability among NWM glycoproteins (GP) poses a challenge to the development of broadly neutralizing therapeutics against the entire clade of viruses. However, blockade of their shared binding site on the apical domain of human transferrin receptor 1 (hTfR1/CD71) presents an opportunity for the development of effective and broadly neutralizing therapeutics. Here, we demonstrate that the murine monoclonal antibody OKT9, which targets the apical domain of hTfR1, can sterically block cellular entry by viral particles presenting clade B NWM glycoproteins (GP1-GP2). OKT9 blockade is also effective against viral particles pseudotyped with glycoproteins of a recently identified pathogenic Sabia-like virus. With nanomolar affinity for hTfR1, the OKT9 antigen binding fragment (OKT9-Fab) sterically blocks clade B NWM-GP1s and reduces infectivity of an attenuated strain of Junin virus. Binding of OKT9 to the hTfR1 ectodomain in its soluble, dimeric state produces stable assemblies that are observable by negative-stain electron microscopy. A model of the OKT9-sTfR1 complex, informed by the known crystallographic structure of sTfR1 and a newly determined structure of the OKT9 antigen binding fragment (Fab), suggests that OKT9 and the Machupo virus GP1 share a binding site on the hTfR1 apical domain. The structural basis for this interaction presents a framework for the design and development of high-affinity, broadly acting agents targeting clade B NWMs. IMPORTANCE Pathogenic clade B NWMs cause grave infectious diseases, the South American hemorrhagic fevers. Their etiological agents are Junin (JUNV), Guanarito (GTOV), Sabiá (SABV), Machupo (MACV), Chapare (CHAV), and a new Sabiá-like (SABV-L) virus recently identified in Brazil. These are priority A pathogens due to their high infectivity and mortality, their potential for person-to-person transmission, and the limited availability of effective therapeutics and vaccines to curb their effects. While low homology between surface glycoproteins of NWMs foils efforts to develop broadly neutralizing therapies targeting NWMs, this work provides structural evidence that OKT9, a monoclonal antibody targeting a single NWM glycoprotein binding site on hTfR1, can efficiently prevent their entry into cells.

The effect of meniscal tears on cartilage loss of the knee: findings on serial MRIs.

BACKGROUND: The relationship between meniscal tears and progressive loss of hyaline cartilage and osteoarthritis of the knee has been reported in the literature. The current treatment protocols for meniscal tears include conservative treatment, meniscal repair, and meniscectomy. Treatment plans are based on factors such as tear pattern, patient age, and associated pathology. The mechanism, pattern, and treatment of meniscal tears vary with age and activity level. Younger, more active patients often sustain more acute tears, which are more amenable to repair due to increased propensity for healing compared with older patients. It is unclear which patients or types of meniscal tears will go on to sustain cartilage loss or osteoarthritis. OBJECTIVE: In our study, we aimed to determine magnetic resonance imaging (MRI) findings in patients with meniscal tears that may be predictive as a risk factor for future cartilage loss. METHODS: A database was retrospectively searched for patients with ≥ 2 MRIs of the same knee over a 7-year period, with the initial report containing the keyword "meniscal tear." Follow-up examinations were then evaluated for cartilage loss. RESULTS: Seventy-six meniscal tears were evaluated. Initial MRI findings associated with cartilage loss included subchondral bone marrow edema (P < 0.0001), meniscal extrusion (P < 0.001), radial meniscal tear (P = 0.017), and posterior horn meniscal tear (P = 0.031). In patients without meniscectomy, cartilage loss was observed in 38% (15/39) compared with 76% (28/37) in patients with meniscectomy, (P = 0.0001). CONCLUSION: Subchondral bone marrow edema and meniscal extrusion were the strongest MRI predictors for cartilage loss in an untreated knee with a meniscal tear. There was significantly greater cartilage loss in patients post-meniscectomy at follow-up than in those who did not undergo meniscectomy.

Cryo-EM structure of a human prion fibril with a hydrophobic, protease-resistant core.

Self-templating assemblies of the human prion protein are clinically associated with transmissible spongiform encephalopathies. Here we present the cryo-EM structure of a denaturant- and protease-resistant fibril formed in vitro spontaneously by a 9.7-kDa unglycosylated fragment of the human prion protein. This human prion fibril contains two protofilaments intertwined with screw symmetry and linked by a tightly packed hydrophobic interface. Each protofilament consists of an extended beta arch formed by residues 106 to 145 of the prion protein, a hydrophobic and highly fibrillogenic disease-associated segment. Such structures of prion polymorphs serve as blueprints on which to evaluate the potential impact of sequence variants on prion disease.