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bioRxiv · 10.1101/2022.03.23.485412

A multiple comorbidities mouse model to assess atherosclerosis progression following lung infection in ApoE deficient mice

Bartlett, B.·Lee, S.·Ludewick, H. P.·Siew, T.·Verma, S.·Waterer, G.·Corrales-Medina, V.·Dwivedi, G.
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Abstract

BackgroundInflammation is a risk factor for atherosclerosis progression. Hospitalisation for pneumonia is associated with increased risk of cardiovascular disease. Herein, we describe a multiple comorbidities murine model to study the impact of bacterial pneumonia on atherosclerosis. MethodsFirstly, 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 MRI and PET. Mice were euthanised and investigated for changes in systemic inflammation and changes in lung morphology using ELISA, Luminex assay and real-time PCR. ResultsTIGR4 inoculated mice presented with varying degreess of lung infiltrate, pleural effusion and consolidation on MRI at all timepoints 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. 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 (IL-1{beta} & IL6) in the lungs and significantly increased levels of circulating inflammatory protein (CCL3) at 7- and 28-days PI respectively. ConclusionsOur mouse model presents a discovery tool to understand the link between acute infections, including pneumonia, and increased cardiovascular disease risk in humans with inflammation as the mechanistic catalyst. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/485412v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@e76491org.highwire.dtl.DTLVardef@17b712eorg.highwire.dtl.DTLVardef@143b2f4org.highwire.dtl.DTLVardef@199dbe1_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Bartlett, B., Lee, S., Ludewick, H. P., Siew, T., Verma, S., Waterer, G., Corrales-Medina, V., Dwivedi, G.. 2022-03-23. A multiple comorbidities mouse model to assess atherosclerosis progression following lung infection in ApoE deficient mice. https://doi.org/10.1101/2022.03.23.485412

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