Clinical MedicineInfectious disease Open Access | 10.1172/JCI156679

Iris K. Lee,1,2 Daniel A. Jacome,1 Joshua K. Cho,1 Vincent Tu,3 Anthony J. Young,1 Tiffany Dominguez,1 Justin D. Northrup,1 Jean M. Etersque,1,4 Hsiaoju S. Lee,1 Andrew Ruff,1 Ouniol Aklilu,1 Kyle Bittinger,3 Laurel J. Glaser,5 Daniel Dorgan,6 Denis Hadjiliadis,6 Rahul M. Kohli,4,7 Robert H. Mach,1 David A. Mankoff,1 Robert K. Doot,1 and Mark A. Sellmyer1,4

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Lee, I. in: JCI | PubMed | Google Scholar |

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Jacome, D. in: JCI | PubMed | Google Scholar

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Cho, J. in: JCI | PubMed | Google Scholar

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Tu, V. in: JCI | PubMed | Google Scholar

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Young, A. in: JCI | PubMed | Google Scholar

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Dominguez, T. in: JCI | PubMed | Google Scholar

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

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1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

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1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Lee, H. in: JCI | PubMed | Google Scholar

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Ruff, A. in: JCI | PubMed | Google Scholar

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Aklilu, O. in: JCI | PubMed | Google Scholar

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Bittinger, K. in: JCI | PubMed | Google Scholar |

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

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1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Dorgan, D. in: JCI | PubMed | Google Scholar

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Hadjiliadis, D. in: JCI | PubMed | Google Scholar

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Kohli, R. in: JCI | PubMed | Google Scholar |

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Mach, R. in: JCI | PubMed | Google Scholar

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Mankoff, D. in: JCI | PubMed | Google Scholar

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Doot, R. in: JCI | PubMed | Google Scholar |

1Department of Radiology and

2Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

3Department of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

4Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

5Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

6Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, and

7Department of Medicine, Division of Infectious Disease, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Address correspondence to: Mark A. Sellmyer, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 813A Stellar-Chance Labs, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA. Phone: 215.573.3212; Email: mark.sellmyer@pennmedicine.upenn.edu.

Authorship note: IKL and DAJ are co–first authors.

Find articles by Sellmyer, M. in: JCI | PubMed | Google Scholar |

Authorship note: IKL and DAJ are co–first authors.

Published September 15, 2022 - More info

Published in Volume 132, Issue 18 on September 15, 2022
J Clin Invest. 2022;132(18):e156679. https://doi.org/10.1172/JCI156679.
© 2022 Lee et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published September 15, 2022 - Version history
Received: November 22, 2021; Accepted: July 19, 2022 View PDF Abstract

BACKGROUND. Several molecular imaging strategies can identify bacterial infections in humans. PET affords the potential for sensitive infection detection deep within the body. Among PET-based approaches, antibiotic-based radiotracers, which often target key bacterial-specific enzymes, have considerable promise. One question for antibiotic radiotracers is whether antimicrobial resistance (AMR) reduces specific accumulation within bacteria, diminishing the predictive value of the diagnostic test.

METHODS. Using a PET radiotracer based on the antibiotic trimethoprim (TMP), [11C]-TMP, we performed in vitro uptake studies in susceptible and drug-resistant bacterial strains and whole-genome sequencing (WGS) in selected strains to identify TMP resistance mechanisms. Next, we queried the NCBI database of annotated bacterial genomes for WT and resistant dihydrofolate reductase (DHFR) genes. Finally, we initiated a first-in-human protocol of [11C]-TMP in patients infected with both TMP-sensitive and TMP-resistant organisms to demonstrate the clinical feasibility of the tool.

RESULTS. We observed robust [11C]-TMP uptake in our panel of TMP-sensitive and -resistant bacteria, noting relatively variable and decreased uptake in a few strains of P. aeruginosa and E. coli. WGS showed that the vast majority of clinically relevant bacteria harbor a WT copy of DHFR, targetable by [11C]-TMP, and that despite the AMR, these strains should be “imageable.” Clinical imaging of patients with [11C]-TMP demonstrated focal radiotracer uptake in areas of infectious lesions.

CONCLUSION. This work highlights an approach to imaging bacterial infection in patients, which could affect our understanding of bacterial pathogenesis as well as our ability to better diagnose infections and monitor response to therapy.

TRIAL REGISTRATION. ClinicalTrials.gov NCT03424525.

FUNDING. Institute for Translational Medicine and Therapeutics, Burroughs Wellcome Fund, NIH Office of the Director Early Independence Award (DP5-OD26386), and University of Pennsylvania NIH T32 Radiology Research Training Grant (5T32EB004311-12).

Graphical Abstract Introduction

The ability to specifically detect and characterize a bacterial infection in a patient has been a long-sought goal for molecular imaging (1). The implications of such a technique are wide-ranging and could improve diagnosis of bacterial infection as well as allow quantitative monitoring of the effects of antimicrobial treatment. The current standards of biopsy and ex vivo microbial culture are hampered by contaminations, sampling limitations, variable sensitivity, potential for procedural complications, and delayed results (2). Thus, bacterial-specific radiotracers could have a positive effect on clinical practice and move the field of infection imaging beyond the current practices, which generally rely on nonspecific nuclear imaging approaches, such as radionuclide-tagged white blood cell, [67Ga]-citrate, and 2-deoxy-2-[18F]fluoro-D-glucose (FDG) scans (3, 4).

Several approaches have been pursued to develop bacterial-specific radiotracers. One method is targeting biochemical/metabolic transformations that are unique to bacterial biology. For example, promising advancements have been made in preclinical models using radiotracers, including [18F]-fluorodeoxy-sorbitol (FDS), [11C]-para-aminobenzoic acid, D-amino acids, and probes targeting the maltose transporter in bacteria (5–9). Only [18F]-FDS and [11C]-para-aminobenzoic acid have been reported in humans at this time (10, 11). Another strategy is to use radiolabeled antibiotics that can inhibit metabolic processes that are essential to the bacterial life cycle. We previously reported the development of [11C]- and [18F]-labeled trimethoprim-based (TMP-based) radiotracers and have demonstrated specificity for bacterial infection over other pathologies such as sterile inflammation (turpentine) and neoplasm (breast carcinoma) in rodent models (12, 13). TMP is generally thought to be a biologically inert and non-toxic in human cells at low concentrations. It affects nucleotide metabolism via competitive binding of bacterial dihydrofolate reductase (DHFR), with 10,000-fold selectivity over the mammalian enzyme (14). However, antibiotic radiotracers, such as TMP, have raised concerns that imaging antibiotic-resistant bacteria may be challenging. Furthermore, bacterial infection radiotracers need to maintain high uptake across a broad spectrum of bacterial species (e.g., targeting both Gram-positive and Gram-negative species) to produce favorable positive and negative predictive test characteristics when the causative organism is unknown (15).

Here, using previously tested laboratory bacterial strains and newly acquired, drug-resistant clinical isolates, we performed dose-response assays with TMP. We then tested uptake of [11C]-TMP in these pathogenic species to determine whether TMP resistance by itself is a critical factor for the “imageability” of the bacterial species. In addition, we performed whole-genome sequencing (WGS) of a subset of the clinical isolates to identify the number of DHFR genes and to probe for other resistance mechanisms present in these strains. To extend our WGS results, we used the NCBI database of annotated bacterial whole genomes and assessed the top 19 pathogenic bacterial species for the presence of WT and mutant DHFR enzymes. With evidence of the ability to image both TMP-susceptible and -resistant strains, we report the first-in-human feasibility study of bacterial infection imaging with [11C]-TMP, with a focus on lung and bone infections. We discuss cases demonstrating the biodistribution and specificity of [11C]-TMP uptake in humans and include instances when antibiotic treatments were administered to highlight the potential of [11C]-TMP to add diagnostic information in different clinical scenarios of bacterial infection.

Results

[11C]-TMP was synthesized as previously reported (Figure 1A; ref. 13). We have tested TMP-sensitive bacterial strains in animal models (12), and thus, TMP-resistant clinical isolates of the same species were acquired (details included in Table 1). All strains were classified as susceptible or resistant by their TMP minimum inhibitory concentration (MIC) (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/JCI156679DS1). MIC cutoffs were based on CLSI M100 break points (see MIC assays in Methods). To further characterize the susceptibility or resistance of our bacterial panel to TMP, we performed dose-response assays. Each bacterial strain was incubated with varying concentrations of TMP (0–50 μM) for 6 hours, and growth endpoints were recorded (Figure 1B and Supplemental Figure 1B for luminescence data). IC50 values are summarized in Supplemental Figure 1C.

Figure 1

Structure of [11C]-TMP and in vitro TMP dose-response assays of different bacterial strains. (A) Structures of trimethoprim (TMP) and [11C]-TMP. (B) TMP dose-response assay on bacterial strains. OD600 measurement was taken following a 6-hour incubation of different bacterial strains with TMP. The susceptibility or resistance of a bacterial strain to TMP is color-coded based on the IC50 and minimum inhibitory concentration (MIC). Blue indicates susceptible bacteria, and red indicates resistant bacteria. n = 3; data represent mean ± SD. (C) Representative [11C]-TMP uptake in bacterial cultures after a 30-minute incubation at 37°C. n = 3–5; data represent mean ± SD. The experiment was repeated a total of 2–3 times for biological replicates.

Table 1

Bacterial strains and their sources

[11C]-TMP uptake was tested in both TMP-susceptible and TMP-resistant bacteria by incubating the strains for 30 minutes with the radiotracer. Heat-killed or excess unlabeled TMP-blocked conditions served as controls. A DHFR-knockout strain of Escherichia coli (E. coli) K549 (ΔfolA) was tested as an additional negative control. Substantial increased uptake was observed across most of the strains, regardless of their susceptibility to TMP (Figure 1C). For comparison, uptake values were also normalized to the uptake values of the corresponding strain’s blocked control for comparison across species, which showed between approximately 5- and 500-fold increased uptake (Supplemental Figure 2). E. coli no. 3 and strains of Pseudomonas aeruginosa exhibited a relatively low level of uptake, and importantly, DHFR-knockout E. coli K549 (ΔfolA) showed no radiotracer retention. This varied yet maintained [11C]-TMP uptake in resistant strains suggested that TMP resistance was not simply the mutation of the TMP binding site of the endogenous DHFR gene and that further study was warranted.

Resistance to TMP is known to be mediated by altered gene regulation, leading to increased translation of the DHFR enzyme as well as horizontal gene transfer of mutant DHFRs, to which TMP binds poorly (16). To identify the resistance mechanism(s) present in our panel of bacteria, we performed WGS on the following TMP-resistant subset of strains; they were chosen from an initial panel of bacterial strains prior to uptake studies: E. coli no. 1, Klebsiella pneumoniae 700721, Streptococcus agalactiae, P. aeruginosa no. 1, and Staphylococcus aureus no. 1. The genomes were assembled using an A-Bruijn assembler, and the completeness of the genomes was assessed using sets of single-copy genes within a phylogenetic lineage (17, 18). Quality control approaches of WGS analysis are summarized in Supplemental Figures 3 and 4. Following quality control, predicted DHFR ORFs from the assembled genomes of all 5 strains were individually investigated using the NCBI’s BLASTp database and a literature search (Table 2 and Supplemental Figure 5). Based on the analysis, S. aureus and E. coli each contained 2 different DHFR genes. In both cases, the first gene was a resistant DHFR enzyme termed DfrA, which mediates TMP resistance (19, 20). The second gene was the canonical WT DHFR for the strain that is known to bind TMP. K. pneumoniae similarly carried a WT DHFR known to bind TMP (21) as well as a DHFR gene, whose TMP binding, to our knowledge, is uncharacterized to date. However, only 1 DHFR ORF was found in P. aeruginosa. UniProt and NCBI databases suggest this is the native DHFR gene in P. aeruginosa. It has been shown that drug-resistant strains of P. aeruginosa express export pumps that confer multidrug resistance to TMP and other antibiotics (22, 23), which was apparent in our dose-response assays (Figure 1B and Supplemental Figure 1, B and C). Of note, previous reports showed that when drug-susceptible and -resistant strains of P. aeruginosa were lysed, TMP inhibited the catalytic activity of DHFR of all strains with equal potency (24), suggesting that P. aeruginosa DHFR may still bind to TMP radiotracers. For S. agalactiae, only 1 DHFR was found in the genome, with no reports on whether it confers resistance.

It has been shown that DHFR redundancy can be a common feature of clinically relevant bacteria (25). Given the potential implications for clinical imaging with TMP radiotracers and our observations from WGS of several strains that maintained TMP uptake despite resistance, we broadly surveyed the DHFR genes in the NCBI RefSeq deposited genomes of the top 19 most clinically relevant bacterial pathogens (Figure 2A). We found that there is high heterogeneity both between and within species regarding the number of DHFRs carried. For example, the 5 most common bacterial pathogens responsible for health care–associated infections are E. coli, S. aureus, K. pneumoniae, P. aeruginosa, and Enterococcus faecalis (26). These strains on average carry 1.44, 1.14, 1.84, 2.05, and 2.21 DHFRs per genome, respectively. The percentage of resistance-conferring DHFR genes was calculated using gene annotation. We found that there is almost always a nonresistant DHFR within these pathogenic species. In fact, only 0.56% of strains exclusively carried DHFRs that confer TMP resistance, a total of 742 of 132,878 strains assessed. Moreover, there is an expected pattern relating the number of total DHFR genes per genome and the proportion of those genes that are TMP resistant (Figure 2B and Supplemental Figures 6 and 7). Taking E. coli as an example, when a strain bears only 1 DHFR, that single gene is not resistant in almost all cases. Conversely, when a strain bears 2 DHFRs, typically 1 of the 2 is resistant (50%). Furthermore, when strains bear 3 DHFRs, typically either 1 or 2 DHFRs (33% and 67%) confer resistance. The pattern holds for 4 and 5 DHFRs and so on (