A multiple comorbidities mouse lung infection model in ApoE‑deficient mice

Benjamin Bartlett; Silvia Lee; Herbert P Ludewick; Teck Siew; Shipra Verma; Grant Waterer; Vicente F Corrales-Medina; Girish Dwivedi

doi:10.3892/br.2023.1603

A multiple comorbidities mouse lung infection model in ApoE‑deficient mice

Biomed Rep. 2023 Feb 6;18(3):21. doi: 10.3892/br.2023.1603. eCollection 2023 Mar.

Authors

Benjamin Bartlett^{1

2}, Silvia Lee^{1

3}, Herbert P Ludewick^{1

4}, Teck Siew^{5

6}, Shipra Verma^{5

7}, Grant Waterer^{2

6}, Vicente F Corrales-Medina^{8

9}, Girish Dwivedi^{1

2

10}

Affiliations

¹ Department of Advanced Clinical and Translational Cardiovascular Imaging, Harry Perkins Institute of Medical Research, Perth, Western Australia 6150, Australia.
² School of Medicine, The University of Western Australia, Perth, Western Australia 6009, Australia.
³ Department of Microbiology, Pathwest Laboratory Medicine, Perth, Western Australia 6000, Australia.
⁴ Heart and Lung Research Institute, Harry Perkins Institute of Medical Research, Perth, Western Australia 6150, Australia.
⁵ Department of Nuclear Medicine, Fiona Stanley Hospital, Perth, Western Australia 6150, Australia.
⁶ Royal Perth Hospital, Perth, Western Australia 6000, Australia.
⁷ Department of Geriatric Medicine, Fiona Stanley Hospital, Perth, Western Australia 6150, Australia.
⁸ Department of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
⁹ Clinical Epidemiology Program, The Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
¹⁰ Department of Cardiology, Fiona Stanley Hospital, Perth, Western Australia 6150, Australia.

Abstract

Acute pneumonia is characterised by a period of intense inflammation. Inflammation is now considered to be a key step in atherosclerosis progression. In addition, pre-existing atherosclerotic inflammation is considered to play a role in pneumonia progression and risk. In the present study, a multiple comorbidities murine model was used to study respiratory and systemic inflammation that results from pneumonia in the setting of atherosclerosis. Firstly, a minimal infectious dose of Streptococcus pneumoniae (TIGR4 strain) to produce clinical pneumonia with a low mortality rate (20%) was established. C57Bl/6 ApoE ^-/- mice were fed a high-fat diet prior to administering intranasally 10⁵ colony forming units of TIGR4 or phosphate-buffered saline (PBS). At days 2, 7 and 28 post inoculation (PI), the lungs of mice were imaged by magnetic resonance imaging (MRI) and positron emission tomography (PET). Mice were euthanised and investigated for changes in lung morphology and changes in systemic inflammation using ELISA, Luminex assay and real-time PCR. TIGR4-inoculated mice presented with varying degrees of lung infiltrate, pleural effusion and consolidation on MRI at all time points up to 28 days PI. Moreover, PET scans identified significantly higher FDG uptake in the lungs of TIGR4-inoculated mice up to 28 days PI. The majority (90%) TIGR4-inoculated mice developed pneumococcal-specific IgG antibody response at 28 days PI. Consistent with these observations, TIGR4-inoculated mice displayed significantly increased inflammatory gene expression [interleukin (IL)-1β and IL-6] in the lungs and significantly increased levels of circulating inflammatory protein (CCL3) at 7 and 28 days PI respectively. The mouse model developed by the authors presents a discovery tool to understand the link between inflammation related to acute infection such as pneumonia and increased risk of cardiovascular disease observed in humans.

Keywords: ApoE-deficient mice; animal model; atherosclerosis; cardiovascular disease; pneumonia.

Grants and funding

Funding: The present study was funded by the Harry Perkins Institute of Medical Research. BB received funding from the Australia-India Strategic Research Fund (AISRF; grant no. AIRXIIICO000068) held by GD.