Implementation of adenovirus-mediated pulmonary expression of human ACE2 in HLA transgenic mice enables establishment of a COVID-19 murine model for assessment of immune responses to SARS-CoV-2 infection

Theodor Chitlaru, Erez Bar-Haim, Liat Bar-On, Shahar Rotem, Hila Cohen, Uri Elia, David Gur, Moshe Aftalion, Ron Alkalay, Efi Makdasi, Yentl Evgy, Reut Falach, Ma’Ayan Israeli, Adi Bercovich-Kinori, Hagit Achdout, Yfat Yahalom-Ronen, Ronit Rosenfeld, Ofer Cohen

Research output: Contribution to journalArticlepeer-review

Abstract

HLA transgenic mice are instrumental for evaluation of human-specific immune responses to viral infection. Mice do not develop COVID-19 upon infection with SARS-CoV-2 due to the strict tropism of the virus to the human ACE2 receptor. The aim of the current study was the implementation of an adenovirus-mediated infection protocol for human ACE2 expression in HLA transgenic mice. Transient pulmonary expression of the human ACE2 receptor in these mice results in their sensitisation to SARS-CoV-2 infection, consequently providing a valuable animal model for COVID-19. Infection results in a transient loss in body weight starting 3 days post-infection, reaching 20–30% loss of weight at day 7 and full recovery at days 11–13 post-infection. The evolution of the disease revealed high reproducibility and very low variability among individual mice. The method was implemented in two different strains of HLA immunized mice. Infected animals developed strong protective humoral and cellular immune responses specific to the viral spike-protein, strictly depending on the adenovirus-mediated human ACE2 expression. Convalescent animals were protected against a subsequent re-infection with SARS-CoV-2, demonstrating that the model may be applied for assessment of efficacy of anti-viral immune responses.

Original languageEnglish
Article number940
JournalPathogens
Volume10
Issue number8
DOIs
StatePublished - Aug 2021
Externally publishedYes

Keywords

  • Adenovirus vector
  • COVID-19
  • HLA transgenic mice
  • Human ACE2
  • SARS-CoV-2

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