Fig. 6.

CTSL inhibitors prevent pseudovirus infection in humanized mice. Human ACE2 transgenic mice were randomly divided into four groups and pretreated with vehicle or different drugs (E64d or amantadine) as indicated 2 days prior to virus inoculation via tail vein injection (1.5 × 10⁶ TCID₅₀ per mouse). Mice without pseudovirus inoculation were used as the healthy control group. Bioluminescence was measured 1 day post infection and visualized in pseudocolor. a The relative intensities of emitted light are presented as the photon flux values in photon/(sec/cm²/sr) and displayed as pseudocolor images, with colors ranging from blue (lowest intensity) to red (highest intensity). b Pseudovirus infection in each group as indicated by the total flux values. Statistical significance was assessed by one-way ANOVA with Tukey’s post hoc test for multiple comparisons. c Pseudovirus infection as indicated by the liver VSV-P mRNA levels in each group. Statistical significance was assessed by one-way ANOVA with Tukey’s post hoc test for multiple comparisons. d Hepatic CTSL protein levels in each group. Statistical significance was assessed by the Kruskal–Wallis test with Dunn’s post hoc test. e Hepatic CTSB protein levels in each group. Statistical significance was assessed by the Kruskal–Wallis test with Dunn’s post hoc test. f Proposed mechanism of CTSL action in SARS-CoV-2 infection. (1) CTSL cleaves the SARS-2-S protein and releases the virus from the endosome. (2) SARS-CoV-2 promotes CTSL gene transcription and enzyme activity through unknown mechanisms. (3) Upregulation of CTSL, in turn, enhances SARS-CoV-2 infection. n = 5. The data are expressed as the mean ± s.e.m. values. *P < 0.05, **P < 0.01