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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.

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.

SUBMITTER: Chitlaru T

PROVIDER: S-EPMC8398702 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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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.

Chitlaru Theodor T Bar-Haim Erez E Bar-On Liat L Rotem Shahar S Cohen Hila H Elia Uri U Gur David D Aftalion Moshe M Alkalay Ron R Makdasi Efi E Evgy Yentl Y Falach Reut R Israeli Ma'ayan M Bercovich-Kinori Adi A Achdout Hagit H Yahalom-Ronen Yfat Y Rosenfeld Ronit R Cohen Ofer O

Pathogens (Basel, Switzerland) 20210726 8

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 in ...[more]

PMID: 34451403

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Project description:Reports have shown that activation of tumor-specific CD4(+) helper T (Th) cells is crucial for effective anti-tumor immunity and identification of Th-cell epitopes is critical for peptide vaccine-based cancer immunotherapy. Although computer algorithms are available to predict peptides with high binding affinity to a specific HLA class II molecule, the ability of those peptides to induce Th-cell responses must be evaluated. We have established HLA-DR4 (HLA-DRA*01:01/HLA-DRB1*04:05) transgenic mice (Tgm), since this HLA-DR allele is most frequent (13.6%) in Japanese population, to evaluate HLA-DR4-restricted Th-cell responses to tumor-associated antigen (TAA)-derived peptides predicted to bind to HLA-DR4. To avoid weak binding between mouse CD4 and HLA-DR4, Tgm were designed to express chimeric HLA-DR4/I-E(d), where I-E(d) α1 and β1 domains were replaced with those from HLA-DR4. Th cells isolated from Tgm immunized with adjuvant and HLA-DR4-binding cytomegalovirus-derived peptide proliferated when stimulated with peptide-pulsed HLA-DR4-transduced mouse L cells, indicating chimeric HLA-DR4/I-E(d) has equivalent antigen presenting capacity to HLA-DR4. Immunization with CDCA155-78 peptide, a computer algorithm-predicted HLA-DR4-binding peptide derived from TAA CDCA1, successfully induced Th-cell responses in Tgm, while immunization of HLA-DR4-binding Wilms' tumor 1 antigen-derived peptide with identical amino acid sequence to mouse ortholog failed. This was overcome by using peptide-pulsed syngeneic bone marrow-derived dendritic cells (BM-DC) followed by immunization with peptide/CFA booster. BM-DC-based immunization of KIF20A494-517 peptide from another TAA KIF20A, with an almost identical HLA-binding core amino acid sequence to mouse ortholog, successfully induced Th-cell responses in Tgm. Notably, both CDCA155-78 and KIF20A494-517 peptides induced human Th-cell responses in PBMCs from HLA-DR4-positive donors. Finally, an HLA-DR4 binding DEPDC1191-213 peptide from a new TAA DEPDC1 overexpressed in bladder cancer induced strong Th-cell responses both in Tgm and in PBMCs from an HLA-DR4-positive donor. Thus, the HLA-DR4 Tgm combined with computer algorithm was useful for preliminary screening of candidate peptides for vaccination.

Dataset Information

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.

Publications

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.

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