124I-Iodo-DPA-713 Positron Emission Tomography in a Hamster Model of SARS-CoV-2 Infection

doi:10.1007/s11307-021-01638-5

. 2022 Feb;24(1):135-143.

doi: 10.1007/s11307-021-01638-5. Epub 2021 Aug 23.

¹²⁴I-Iodo-DPA-713 Positron Emission Tomography in a Hamster Model of SARS-CoV-2 Infection

Camilo A Ruiz-Bedoya^#^{1

2

3}, Filipa Mota^#^{1

2

3}, Alvaro A Ordonez^{1

2

3}, Catherine A Foss^{1

4}, Alok K Singh³, Monali Praharaj⁵, Farina J Mahmud^{1

2

3}, Ali Ghayoor⁶, Kelly Flavahan^{1

2

3}, Patricia De Jesus^{1

2

3}, Melissa Bahr^{1

2

3}, Santosh Dhakal⁷, Ruifeng Zhou⁷, Clarisse V Solis⁸, Kathleen R Mulka⁸, William R Bishai³, Andrew Pekosz^{7

8}, Joseph L Mankowski⁸, Jason Villano⁸, Sabra L Klein^#⁷, Sanjay K Jain^{9

10

11

12}

Affiliations

¹ Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Pediatrics, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB-II Room 109, Baltimore, MD, USA.
³ Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Bloomberg-Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Invicro, Boston, MA, USA.
⁷ W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁸ Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sjain5@jhu.edu.
¹⁰ Department of Pediatrics, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB-II Room 109, Baltimore, MD, USA. sjain5@jhu.edu.
¹¹ Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sjain5@jhu.edu.
¹² Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sjain5@jhu.edu.

^# Contributed equally.

PMID: 34424479
PMCID: PMC8381721
DOI: 10.1007/s11307-021-01638-5

¹²⁴I-Iodo-DPA-713 Positron Emission Tomography in a Hamster Model of SARS-CoV-2 Infection

Camilo A Ruiz-Bedoya et al. Mol Imaging Biol. 2022 Feb.

. 2022 Feb;24(1):135-143.

doi: 10.1007/s11307-021-01638-5. Epub 2021 Aug 23.

Authors

Affiliations

¹ Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Pediatrics, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB-II Room 109, Baltimore, MD, USA.
³ Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁵ Bloomberg-Kimmel Institute for Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Invicro, Boston, MA, USA.
⁷ W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁸ Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁹ Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sjain5@jhu.edu.
¹⁰ Department of Pediatrics, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB-II Room 109, Baltimore, MD, USA. sjain5@jhu.edu.
¹¹ Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sjain5@jhu.edu.
¹² Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. sjain5@jhu.edu.

^# Contributed equally.

PMID: 34424479
PMCID: PMC8381721
DOI: 10.1007/s11307-021-01638-5

Abstract

Purpose: Molecular imaging has provided unparalleled opportunities to monitor disease processes, although tools for evaluating infection remain limited. Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by lung injury that we sought to model. Activated macrophages/phagocytes have an important role in lung injury, which is responsible for subsequent respiratory failure and death. We performed pulmonary PET/CT with ¹²⁴I-iodo-DPA-713, a low-molecular-weight pyrazolopyrimidine ligand selectively trapped by activated macrophages cells, to evaluate the local immune response in a hamster model of SARS-CoV-2 infection.

Procedures: Pulmonary ¹²⁴I-iodo-DPA-713 PET/CT was performed in SARS-CoV-2-infected golden Syrian hamsters. CT images were quantified using a custom-built lung segmentation tool. Studies with DPA-713-IRDye680LT and a fluorescent analog of DPA-713 as well as histopathology and flow cytometry were performed on post-mortem tissues.

Results: Infected hamsters were imaged at the peak of inflammatory lung disease (7 days post-infection). Quantitative CT analysis was successful for all scans and demonstrated worse pulmonary disease in male versus female animals (P < 0.01). Increased ¹²⁴I-iodo-DPA-713 PET activity co-localized with the pneumonic lesions. Additionally, higher pulmonary ¹²⁴I-iodo-DPA-713 PET activity was noted in male versus female hamsters (P = 0.02). DPA-713-IRDye680LT also localized to the pneumonic lesions. Flow cytometry demonstrated a higher percentage of myeloid and CD11b + cells (macrophages, phagocytes) in male versus female lung tissues (P = 0.02).

Conclusion: ¹²⁴I-Iodo-DPA-713 accumulates within pneumonic lesions in a hamster model of SARS-CoV-2 infection. As a novel molecular imaging tool, ¹²⁴I-Iodo-DPA-713 PET could serve as a noninvasive, clinically translatable approach to monitor SARS-CoV-2-associated pulmonary inflammation and expedite the development of novel therapeutics for COVID-19.

Keywords: COVID-19; Immune response; Macrophage; Molecular imaging; PET/CT; SARS-CoV-2; Sex difference.

PubMed Disclaimer

Conflict of interest statement

Ali Ghayoor works at Invicro, Boston, MA, USA. A. A. O. receives consulting fees from Cubresa Inc. S. K. J. is a Senior Editor for Molecular Imaging and Biology.

Figures

**Fig. 1**
Experimental scheme. a Golden Syrian hamsters were intranasally challenged with SARS-CoV-2 and imaging performed as outlined. b In-house developed, transparent, and sealed biocontainment cells with 0.02-µm filters attached to the inlet and outlet for O₂ and anesthesia and compliant with BSL-3 containment. c SARS-CoV-2-infected hamster inside a biocontainment bed being imaged at Ci3R imaging facility (Johns Hopkins University).

**Fig. 2**
Lung pathology in SARS-CoV-2-infected hamsters. a, Gross pathology, histopathology (H&E, 40 × , scales bars of 50 µm), and CT findings at 7 days post-infection. Ground glass opacities (GGO) and consolidations were detected by CT scan (pink arrows indicates affected area). b Automated lung segmentation of CT images from a SARS-CoV-2-infected hamster is shown. c Maximum intensity projection of SARS-CoV-2-infected hamster demonstrating the lung (blue) and pneumonic areas (pink). d Whole lung, lung volume above threshold, and CT score for male (n = 15) and female (n = 11) hamsters. While no differences are noted in the whole lung volumes, the lung disease (CT score) was substantially worse in male compared to female animals. Data represented as median ± interquartile range.

**Fig. 3**
Pulmonary ¹²⁴I-iodo-DPA-713 PET/CT of SARS-CoV-2-infected hamsters. a Transverse lung sections of a representative hamster imaged with ¹²⁴I-iodo-DPA-713 showing higher uptake within the GGO and pneumonic areas. b ¹²⁴I-iodo-DPA-713 PET activity is higher in pneumonic regions compared to unaffected lung. c DPA-713-IRDye680LT fluorescence co-localizes with the diseased lung. d ¹²⁴I-iodo-DPA-713 PET signal is higher in male versus female hamsters. A VOI was created for each lung lesion (GGO and consolidations) in males (n = 11), females (n = 11) and unnaffected lung (n = 19). Data represented as median ± interquartile range.

**Fig. 4**
Iba-1 staining and flow cytometry. a Immunohistochemistry demonstrates clusters of Iba-positive cells within pneumonic tissues. b Flow cytometry demonstrates a higher percentage of myeloid cells and CD11b + cells (macrophages, phagocytes) in males (n = 5), than females (n = 5). Data represented as median ± interquartile range.

See this image and copyright information in PMC

Cited by

The SARS-CoV-2 spike protein binds and modulates estrogen receptors.
Solis O, Beccari AR, Iaconis D, Talarico C, Ruiz-Bedoya CA, Nwachukwu JC, Cimini A, Castelli V, Bertini R, Montopoli M, Cocetta V, Borocci S, Prandi IG, Flavahan K, Bahr M, Napiorkowski A, Chillemi G, Ooka M, Yang X, Zhang S, Xia M, Zheng W, Bonaventura J, Pomper MG, Hooper JE, Morales M, Rosenberg AZ, Nettles KW, Jain SK, Allegretti M, Michaelides M. Solis O, et al. Sci Adv. 2022 Dec 2;8(48):eadd4150. doi: 10.1126/sciadv.add4150. Epub 2022 Nov 30. Sci Adv. 2022. PMID: 36449624 Free PMC article.
Medical imaging of pulmonary disease in SARS-CoV-2-exposed non-human primates.
Stammes MA, Lee JH, Meijer L, Naninck T, Doyle-Meyers LA, White AG, Borish HJ, Hartman AL, Alvarez X, Ganatra S, Kaushal D, Bohm RP, le Grand R, Scanga CA, Langermans JAM, Bontrop RE, Finch CL, Flynn JL, Calcagno C, Crozier I, Kuhn JH. Stammes MA, et al. Trends Mol Med. 2022 Feb;28(2):123-142. doi: 10.1016/j.molmed.2021.12.001. Epub 2021 Dec 7. Trends Mol Med. 2022. PMID: 34955425 Free PMC article. Review.
Intravenous BCG vaccination reduces SARS-CoV-2 severity and promotes extensive reprogramming of lung immune cells.
Singh AK, Wang R, Lombardo KA, Praharaj M, Bullen CK, Um P, Gupta M, Srikrishna G, Davis S, Komm O, Illei PB, Ordonez AA, Bahr M, Huang J, Gupta A, Psoter KJ, Creisher PS, Li M, Pekosz A, Klein SL, Jain SK, Bivalacqua TJ, Yegnasubramanian S, Bishai WR. Singh AK, et al. iScience. 2023 Aug 24;26(10):107733. doi: 10.1016/j.isci.2023.107733. eCollection 2023 Oct 20. iScience. 2023. PMID: 37674985 Free PMC article.
Radiotracers for Imaging of Inflammatory Biomarkers TSPO and COX-2 in the Brain and in the Periphery.
Uzuegbunam BC, Rummel C, Librizzi D, Culmsee C, Hooshyar Yousefi B. Uzuegbunam BC, et al. Int J Mol Sci. 2023 Dec 13;24(24):17419. doi: 10.3390/ijms242417419. Int J Mol Sci. 2023. PMID: 38139248 Free PMC article. Review.
Molecular Imaging of Infections: Advancing the Search for the Hidden Enemy.
Hammoud DA, Clifford Lane H, Jain SK. Hammoud DA, et al. J Infect Dis. 2023 Oct 3;228(Suppl 4):S233-S236. doi: 10.1093/infdis/jiad079. J Infect Dis. 2023. PMID: 37788496 Free PMC article.

See all "Cited by" articles

References

1. Ordonez AA, Sellmyer MA, Gowrishankar G, et al (2019) Molecular imaging of bacterial infections: overcoming the barriers to clinical translation. Sci Transl Med 11 - PMC - PubMed
1. Scully EP, Haverfield J, Ursin RL, Tannenbaum C, Klein SL (2020) Considering how biological sex impacts immune responses and COVID-19 outcomes. Nat Rev Immunol 1–6 - PMC - PubMed
1. Schulte-Schrepping J, Reusch N, Paclik D, et al. Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell. 2020;182:1419-+. doi: 10.1016/j.cell.2020.08.001. - DOI - PMC - PubMed
1. GlobalHealth5050 The sex, gender and COVID-19 Project. https://globalhealth5050.org/the-sex-gender-and-covid-19-project/ (accessed Dec 28, 2020)
1. Peckham H, de Gruijter NM, Raine C, et al. Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nat Commun. 2020;11:6317. doi: 10.1038/s41467-020-19741-6. - DOI - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- ImmPort - Shared Data - Datasets
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

[1] Ordonez AA, Sellmyer MA, Gowrishankar G, et al (2019) Molecular imaging of bacterial infections: overcoming the barriers to clinical translation. Sci Transl Med 11 - PMC - PubMed

[2] Ordonez AA, Sellmyer MA, Gowrishankar G, et al (2019) Molecular imaging of bacterial infections: overcoming the barriers to clinical translation. Sci Transl Med 11 - PMC - PubMed

[3] Scully EP, Haverfield J, Ursin RL, Tannenbaum C, Klein SL (2020) Considering how biological sex impacts immune responses and COVID-19 outcomes. Nat Rev Immunol 1–6 - PMC - PubMed

[4] Scully EP, Haverfield J, Ursin RL, Tannenbaum C, Klein SL (2020) Considering how biological sex impacts immune responses and COVID-19 outcomes. Nat Rev Immunol 1–6 - PMC - PubMed

[5] Schulte-Schrepping J, Reusch N, Paclik D, et al. Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell. 2020;182:1419-+. doi: 10.1016/j.cell.2020.08.001. - DOI - PMC - PubMed

[6] Schulte-Schrepping J, Reusch N, Paclik D, et al. Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell. 2020;182:1419-+. doi: 10.1016/j.cell.2020.08.001. - DOI - PMC - PubMed

[7] GlobalHealth5050 The sex, gender and COVID-19 Project. https://globalhealth5050.org/the-sex-gender-and-covid-19-project/ (accessed Dec 28, 2020)

[8] GlobalHealth5050 The sex, gender and COVID-19 Project. https://globalhealth5050.org/the-sex-gender-and-covid-19-project/ (accessed Dec 28, 2020)

[9] Peckham H, de Gruijter NM, Raine C, et al. Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nat Commun. 2020;11:6317. doi: 10.1038/s41467-020-19741-6. - DOI - PMC - PubMed

[10] Peckham H, de Gruijter NM, Raine C, et al. Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission. Nat Commun. 2020;11:6317. doi: 10.1038/s41467-020-19741-6. - DOI - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

¹²⁴I-Iodo-DPA-713 Positron Emission Tomography in a Hamster Model of SARS-CoV-2 Infection

Affiliations

¹²⁴I-Iodo-DPA-713 Positron Emission Tomography in a Hamster Model of SARS-CoV-2 Infection

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous