Engineering an ACE2-Derived Fragment as a Decoy for Novel SARS-CoV-2 Virus.

Entry inhibitors are an important resource in the response against emerging pathogens like the novel SARS-CoV-2, which enters human cells via interaction between the surface spike glycoprotein and the cellular membrane receptor angiotensin-converting enzyme 2 (ACE2). Using a combination of comparative structural analyses of the binding surface of the spike to ACE2, docking experiments, and molecular dynamics simulations, we identified a stable fragment of ACE2 that binds to the spike, is soluble, and is not predicted to bind to its physiological ligand angiotensin II. From this fragment we computationally designed and experimentally validated a smaller, stable peptide that disrupts ACE2-spike interaction at nanomolar concentrations, suggesting its potential use as a decoy that could interfere with viral binding by competition.

Cross-Reactive T Cell Response Exists in Chronic Lymphocytic Choriomeningitis Virus Infection upon Pichinde Virus Challenge.

Immunological memory to a previously encountered pathogen can influence the outcome of a sequential infection, which is called heterologous immunity. Lymphocytic choriomeningitis virus (LCMV) immune mice develop a NP205-specific T cell response that is cross-reactive to Pichinde virus infection (PICV). So far, limited data are available if cross-reactive T cell responses appear also during chronic infections with exhausted T cell responses. Exhaustion in chronic viral infections can be treated with checkpoint inhibitors, which might affect heterologous outcomes unexpectedly. The aim of this study was to investigate the cross-reactive immune response in chronic LCMV clone 13 (LCMVcl13) infection during primary PICV infection at phenotypic, functional, and T cell receptor (TCR) level. Moreover, the influence of checkpoint inhibitor therapy with αPD-L1 was investigated. Cross-reactive NP205-specific responses were present and functional in the chronic environment. Additionally, chronically infected mice were also protected from PICV mediated weight loss compared to naive PICV mice. An altered phenotype of NP205-specific T cells was detectable, but no major differences in the clonality and diversity of their TCR repertoire were observed. Checkpoint inhibitor treatment with αPD-L1 did alter chronic LCMV infection but had no major effect on heterologous immunity to PICV. Our study demonstrated that cross-reactive CD8+ T cells also exist in the setting of chronic infection, indicating a clinically relevant role of cross-reactive T cells in chronic infections.