We report the use of high-throughput quantitative phase imaging (QPI) flow cytometry (based on multiplexed asymmetric-detection time-stretch optical microscopy (multi-ATOM)) to investigate biophysical profiles of single cells infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This technique reveals the subtle biophysical heterogeneity of SARS-CoV-2 infection under the same multiplicity of infection. Furthermore, analyzing the label-free high-dimensional single-cell biophysical profiles (derived from multi-ATOM images) based on an unsupervised trajectory inference algorithm accurately recovers the infection progression over time. This study could offer biophysical insight of cellular morphogenesis of SARS-CoV-2 and shows the potential of label-free morphological profiling as a complementary drug discovery strategy for SARS-CoV-2.
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