Publications by authors named "Alvaro A Ordonez"

52 Publications

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

Mol Imaging Biol 2021 Aug 23. Epub 2021 Aug 23.

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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 I-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 I-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 I-iodo-DPA-713 PET activity co-localized with the pneumonic lesions. Additionally, higher pulmonary I-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: I-Iodo-DPA-713 accumulates within pneumonic lesions in a hamster model of SARS-CoV-2 infection. As a novel molecular imaging tool, I-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.
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http://dx.doi.org/10.1007/s11307-021-01638-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381721PMC
August 2021

Sex Differences in Lung Imaging and SARS-CoV-2 Antibody Responses in a COVID-19 Golden Syrian Hamster Model.

mBio 2021 08 13;12(4):e0097421. Epub 2021 Jul 13.

W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.

In the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more severe outcomes are reported in males than in females, including hospitalizations and deaths. Animal models can provide an opportunity to mechanistically interrogate causes of sex differences in the pathogenesis of SARS-CoV-2. Adult male and female golden Syrian hamsters (8 to 10 weeks of age) were inoculated intranasally with 10 50% tissue culture infective dose (TCID) of SARS-CoV-2/USA-WA1/2020 and euthanized at several time points during the acute (i.e., virus actively replicating) and recovery (i.e., after the infectious virus has been cleared) phases of infection. There was no mortality, but infected male hamsters experienced greater morbidity, losing a greater percentage of body mass, developed more extensive pneumonia as noted on chest computed tomography, and recovered more slowly than females. Treatment of male hamsters with estradiol did not alter pulmonary damage. Virus titers in respiratory tissues, including nasal turbinates, trachea, and lungs, and pulmonary cytokine concentrations, including interferon-β (IFN-β) and tumor necrosis factor-α (TNF-α), were comparable between the sexes. However, during the recovery phase of infection, females mounted 2-fold greater IgM, IgG, and IgA responses against the receptor-binding domain of the spike protein (S-RBD) in both plasma and respiratory tissues. Female hamsters also had significantly greater IgG antibodies against whole-inactivated SARS-CoV-2 and mutant S-RBDs as well as virus-neutralizing antibodies in plasma. The development of an animal model to study COVID-19 sex differences will allow for a greater mechanistic understanding of the SARS-CoV-2-associated sex differences seen in the human population. Men experience more severe outcomes from coronavirus disease 2019 (COVID-19) than women. Golden Syrian hamsters were used to explore sex differences in the pathogenesis of a human isolate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After inoculation, male hamsters experienced greater sickness, developed more severe lung pathology, and recovered more slowly than females. Sex differences in disease could not be reversed by estradiol treatment in males and were not explained by either virus replication kinetics or the concentrations of inflammatory cytokines in the lungs. During the recovery period, antiviral antibody responses in the respiratory tract and plasma, including to newly emerging SARS-CoV-2 variants, were greater in female than in male hamsters. Greater lung pathology during the acute phase combined with lower antiviral antibody responses during the recovery phase of infection in males than in females illustrate the utility of golden Syrian hamsters as a model to explore sex differences in the pathogenesis of SARS-CoV-2 and vaccine-induced immunity and protection.
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http://dx.doi.org/10.1128/mBio.00974-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406232PMC
August 2021

Chemiluminescent Protease Probe for Rapid, Sensitive, and Inexpensive Detection of Live .

ACS Cent Sci 2021 May 14;7(5):803-814. Epub 2021 Apr 14.

Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, United States.

Tuberculosis (TB) is a top-ten cause of death worldwide. Successful treatment is often limited by insufficient diagnostic capabilities, especially at the point of care in low-resource settings. The ideal diagnostic must be fast, be cheap, and require minimal clinical resources while providing high sensitivity, selectivity, and the ability to differentiate live from dead bacteria. We describe here the development of a fast, luminescent, and affordable sensor of Hip1 (FLASH) for detecting and monitoring drug susceptibility of (). FLASH is a selective chemiluminescent substrate for the protease Hip1 that, when processed, produces visible light that can be measured with a high signal-to-noise ratio using inexpensive sensors. FLASH is sensitive to fmol of recombinant Hip1 enzyme and can detect as few as thousands of cells in culture or in human sputum samples within minutes. The probe is highly selective for compared to other nontuberculous mycobacteria and can distinguish live from dead cells. Importantly, FLASH can be used to measure antibiotic killing of in culture with greatly accelerated timelines compared to traditional protocols. Overall, FLASH has the potential to enhance both TB diagnostics and drug resistance monitoring in resource-limited settings.
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http://dx.doi.org/10.1021/acscentsci.0c01345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161474PMC
May 2021

Rapid detection of SARS-CoV-2 using a radiolabeled antibody.

Nucl Med Biol 2021 Jul-Aug;98-99:69-75. Epub 2021 May 25.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Radiology, Weill Cornell Medical College, New York, NY, USA. Electronic address:

Purpose: Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus 2019 disease (COVID-19), poses a serious risk to humanity and represents a huge challenge for healthcare systems worldwide. Since the early days of the COVID-19 pandemic, it has been evident that adequate testing is an essential step in limiting and controlling the spread of SARS-CoV-2. Here, we present an accurate, inexpensive, scalable, portable, and rapid detection kit to directly detect SARS-CoV-2 in biological samples that could even be translated for population testing. We have demonstrated that our method can reliably identify viral load and could be used to reach those fractions of the population with limited access to more sophisticated and expensive tests.

Procedures: The proposed SARS-CoV-2 detection kit is based on the combination of a SARS-CoV-2-targeted antibody (CR3022) that targets spike protein S1 domain on the viral surface. This antibody was radiolabeled with a long-lived isotope (Iodine-125) to allow us to detect bound antibody in samples with SARS-CoV-2. We used a series of in vitro assays to determine sensitivity and specificity and facilitate automation of the testing kit. Bound antibody was extracted from saliva samples via a centrifugation step and a semi-permeable membrane. Our kit was further validated using SARS-CoV-2 virions.

Results: We were able to accomplish radiosynthesis of [I]I-CR3022 reliably without loss of binding. The SARS-CoV-2-sensing antibody was shown to maintain its spike S1 affinity and to bind to as low as 2.5-5 ng of spike protein. We then used beads-bound spike S1 to develop a separation kit which proved to be both easy to use and inexpensive. The kit made it possible to extract bound antibody from the saliva-like sample. We were able to validate the separation kit using intact SARS-CoV-2 virions and showed that our kit can detect a viral concentration as low as 19,700 PFU/mL (~ 9.22%TBF) and as high as 1,970,000 PFU/mL (45.04%TBF).

Conclusion: Here we report the development and validation of a SARS-CoV-2 detection system based on the combination of a specific radiolabeled antibody and a separation membrane. We demonstrate our system to be comparable to other SARS-CoV-2 detection kits already approved by the FDA and believe this technology could be easily deployed to countries with limited resources for the diagnosis of COVID-19. Furthermore, workflows could be easily adapted to target other antigens and therefore other types of diseases.
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http://dx.doi.org/10.1016/j.nucmedbio.2021.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144098PMC
June 2021

Current and future perspectives on functional molecular imaging in nephro-urology: theranostics on the horizon.

Theranostics 2021 7;11(12):6105-6119. Epub 2021 Apr 7.

Department of Nuclear Medicine, University Hospital Wuerzburg, Wuerzburg, Germany.

In recent years, a paradigm shift from single-photon-emitting radionuclide radiotracers toward positron-emission tomography (PET) radiotracers has occurred in nuclear oncology. Although PET-based molecular imaging of the kidneys is still in its infancy, such a trend has emerged in the field of functional renal radionuclide imaging. Potentially allowing for precise and thorough evaluation of renal radiotracer urodynamics, PET radionuclide imaging has numerous advantages including precise anatomical co-registration with CT images and dynamic three-dimensional imaging capability. In addition, relative to scintigraphic approaches, PET can allow for significantly reduced scan time enabling high-throughput in a busy PET practice and further reduces radiation exposure, which may have a clinical impact in pediatric populations. In recent years, multiple renal PET radiotracers labeled with C, Ga, and F have been utilized in clinical studies. Beyond providing a precise non-invasive read-out of renal function, such radiotracers may also be used to assess renal inflammation. This manuscript will provide an overview of renal molecular PET imaging and will highlight the transformation of conventional scintigraphy of the kidneys toward novel, high-resolution PET imaging for assessing renal function. In addition, future applications will be introduced, e.g. by transferring the concept of molecular image-guided diagnostics and therapy (theranostics) to the field of nephrology.
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http://dx.doi.org/10.7150/thno.58682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058716PMC
July 2021

Imaging infections in patients using pathogen-specific positron emission tomography.

Sci Transl Med 2021 04;13(589)

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

represent the largest group of bacterial pathogens in humans and are responsible for severe, deep-seated infections, often resulting in sepsis or death. They are also a prominent cause of multidrug-resistant (MDR) infections, and some species are recognized as biothreat pathogens. Tools for noninvasive, whole-body analysis that can localize a pathogen with specificity are needed, but no such technology currently exists. We previously demonstrated that positron emission tomography (PET) with 2-deoxy-2-[F]fluoro-d-sorbitol (F-FDS) can selectively detect infections in murine models. Here, we demonstrate that uptake of F-FDS by bacteria occurs via a metabolically conserved sorbitol-specific pathway with rapid in vitro F-FDS uptake noted in clinical strains, including MDR isolates. Whole-body F-FDS PET/computerized tomography (CT) in 26 prospectively enrolled patients with either microbiologically confirmed infection or other pathologies demonstrated that F-FDS PET/CT was safe, could rapidly detect and localize infections due to drug-susceptible or MDR strains, and differentiated them from sterile inflammation or cancerous lesions. Repeat imaging in the same patients monitored antibiotic efficacy with decreases in PET signal correlating with clinical improvement. To facilitate the use of F-FDS, we developed a self-contained, solid-phase cartridge to rapidly (<10 min) formulate ready-to-use F-FDS from commercially available 2-deoxy-2-[F]fluoro-d-glucose (F-FDG) at room temperature. In a hamster model, F-FDS PET/CT also differentiated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia from secondary pneumonia-a leading cause of complications in hospitalized patients with COVID-19. These data support F-FDS as an innovative and readily available, pathogen-specific PET technology with clinical applications.
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http://dx.doi.org/10.1126/scitranslmed.abe9805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120649PMC
April 2021

Functional characterization of CD4+ T cell receptors crossreactive for SARS-CoV-2 and endemic coronaviruses.

J Clin Invest 2021 05;131(10)

Bloomberg~Kimmel Institute for Cancer Immunotherapy.

BACKGROUNDRecent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to crossrecognition by T cells specific for common cold coronaviruses (CCCs). True T cell crossreactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2.METHODSWe used the viral functional expansion of specific T cells (ViraFEST) platform to identify T cell responses crossreactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC crossreactivity and assessments of functional avidity were performed using a TCR cloning and transfection system.RESULTSMemory CD4+ T cell clonotypes that crossrecognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Crossreactive T cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to monospecific CD4+ T cells, which was consistent with lower functional avidity of their TCRs for SARS-CoV-2 relative to CCC.CONCLUSIONSOur data confirm, for what we believe is the first time, the existence of unique memory CD4+ T cell clonotypes crossrecognizing SARS-CoV-2 and CCCs. The lower avidity of crossreactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that preexisting CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these crossreactive T cell responses affect clinical outcomes in COVID-19 patients.FUNDINGNIH funding (U54CA260492, P30CA006973, P41EB028239, R01AI153349, R01AI145435-A1, R21AI149760, and U19A1088791) was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, and the National Institute of Biomedical Imaging and Bioengineering. The Bloomberg~Kimmel Institute for Cancer Immunotherapy, The Johns Hopkins University Provost, and The Bill and Melinda Gates Foundation provided funding for this study.
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http://dx.doi.org/10.1172/JCI146922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121515PMC
May 2021

Sulforaphane exhibits in vitro and in vivo antiviral activity against pandemic SARS-CoV-2 and seasonal HCoV-OC43 coronaviruses.

bioRxiv 2021 Mar 25. Epub 2021 Mar 25.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has incited a global health crisis. Currently, there are no orally available medications for prophylaxis for those exposed to SARS-CoV-2 and limited therapeutic options for those who develop COVID-19. We evaluated the antiviral activity of sulforaphane (SFN), a naturally occurring, orally available, well-tolerated, nutritional supplement present in high concentrations in cruciferous vegetables with limited side effects. SFN inhibited in vitro replication of four strains of SARS-CoV-2 as well as that of the seasonal coronavirus HCoV-OC43. Further, SFN and remdesivir interacted synergistically to inhibit coronavirus infection in vitro. Prophylactic administration of SFN to K18-hACE2 mice prior to intranasal SARS-CoV-2 infection significantly decreased the viral load in the lungs and upper respiratory tract and reduced lung injury and pulmonary pathology compared to untreated infected mice. SFN treatment diminished immune cell activation in the lungs, including significantly lower recruitment of myeloid cells and a reduction in T cell activation and cytokine production. Our results suggest that SFN is a promising treatment for prevention of coronavirus infection or treatment of early disease.
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http://dx.doi.org/10.1101/2021.03.25.437060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010735PMC
March 2021

Metabolic programs define dysfunctional immune responses in severe COVID-19 patients.

Cell Rep 2021 03 26;34(11):108863. Epub 2021 Feb 26.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address:

It is unclear why some SARS-CoV-2 patients readily resolve infection while others develop severe disease. By interrogating metabolic programs of immune cells in severe and recovered coronavirus disease 2019 (COVID-19) patients compared with other viral infections, we identify a unique population of T cells. These T cells express increased Voltage-Dependent Anion Channel 1 (VDAC1), accompanied by gene programs and functional characteristics linked to mitochondrial dysfunction and apoptosis. The percentage of these cells increases in elderly patients and correlates with lymphopenia. Importantly, T cell apoptosis is inhibited in vitro by targeting the oligomerization of VDAC1 or blocking caspase activity. We also observe an expansion of myeloid-derived suppressor cells with unique metabolic phenotypes specific to COVID-19, and their presence distinguishes severe from mild disease. Overall, the identification of these metabolic phenotypes provides insight into the dysfunctional immune response in acutely ill COVID-19 patients and provides a means to predict and track disease severity and/or design metabolic therapeutic regimens.
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http://dx.doi.org/10.1016/j.celrep.2021.108863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908880PMC
March 2021

Visualizing the dynamics of tuberculosis pathology using molecular imaging.

J Clin Invest 2021 03;131(5)

Center for Infection and Inflammation Imaging Research.

Nearly 140 years after Robert Koch discovered Mycobacterium tuberculosis, tuberculosis (TB) remains a global threat and a deadly human pathogen. M. tuberculosis is notable for complex host-pathogen interactions that lead to poorly understood disease states ranging from latent infection to active disease. Additionally, multiple pathologies with a distinct local milieu (bacterial burden, antibiotic exposure, and host response) can coexist simultaneously within the same subject and change independently over time. Current tools cannot optimally measure these distinct pathologies or the spatiotemporal changes. Next-generation molecular imaging affords unparalleled opportunities to visualize infection by providing holistic, 3D spatial characterization and noninvasive, temporal monitoring within the same subject. This rapidly evolving technology could powerfully augment TB research by advancing fundamental knowledge and accelerating the development of novel diagnostics, biomarkers, and therapeutics.
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http://dx.doi.org/10.1172/JCI145107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919721PMC
March 2021

Metabolic programs define dysfunctional immune responses in severe COVID-19 patients.

medRxiv 2020 Oct 5. Epub 2020 Oct 5.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

It remains unclear why some patients infected with SARS-CoV-2 readily resolve infection while others develop severe disease. To address this question, we employed a novel assay to interrogate immune-metabolic programs of T cells and myeloid cells in severe and recovered COVID-19 patients. Using this approach, we identified a unique population of T cells expressing high H3K27me3 and the mitochondrial membrane protein voltage-dependent anion channel (VDAC), which were expanded in acutely ill COVID-19 patients and distinct from T cells found in patients infected with hepatitis c or influenza and in recovered COVID-19. Increased VDAC was associated with gene programs linked to mitochondrial dysfunction and apoptosis. High-resolution fluorescence and electron microscopy imaging of the cells revealed dysmorphic mitochondria and release of cytochrome into the cytoplasm, indicative of apoptosis activation. The percentage of these cells was markedly increased in elderly patients and correlated with lymphopenia. Importantly, T cell apoptosis could be inhibited by targeting the oligomerization of VDAC or blocking caspase activity. In addition to these T cell findings, we also observed a robust population of Hexokinase II polymorphonuclear-myeloid derived suppressor cells (PMN-MDSC), exclusively found in the acutely ill COVID-19 patients and not the other viral diseases. Finally, we revealed a unique population of monocytic MDSC (M-MDSC) expressing high levels of carnitine palmitoyltransferase 1a (CPT1a) and VDAC. The metabolic phenotype of these cells was not only highly specific to COVID-19 patients but the presence of these cells was able to distinguish severe from mild disease. Overall, the identification of these novel metabolic phenotypes not only provides insight into the dysfunctional immune response in acutely ill COVID-19 patients but also provide a means to predict and track disease severity as well as an opportunity to design and evaluate novel metabolic therapeutic regimens.
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http://dx.doi.org/10.1101/2020.09.10.20186064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491535PMC
October 2020

Advanced imaging tools for childhood tuberculosis: potential applications and research needs.

Lancet Infect Dis 2020 11 23;20(11):e289-e297. Epub 2020 Jun 23.

Tuberculosis Clinic, Pima County Health Department, Tucson, AZ, USA; Division of Infectious Diseases, University of Arizona College of Medicine, Tucson, AZ, USA.

Tuberculosis is the leading cause of death globally that is due to a single pathogen, and up to a fifth of patients with tuberculosis in high-incidence countries are children younger than 16 years. Unfortunately, the diagnosis of childhood tuberculosis is challenging because the disease is often paucibacillary and it is difficult to obtain suitable specimens, causing poor sensitivity of currently available pathogen-based tests. Chest radiography is important for diagnostic evaluations because it detects abnormalities consistent with childhood tuberculosis, but several limitations exist in the interpretation of such results. Therefore, other imaging methods need to be systematically evaluated in children with tuberculosis, although current data suggest that when available, cross-sectional imaging, such as CT, should be considered in the diagnostic evaluation for tuberculosis in a symptomatic child. Additionally, much of the understanding of childhood tuberculosis stems from clinical specimens that might not accurately represent the lesional biology at infection sites. By providing non-invasive measures of lesional biology, advanced imaging tools could enhance the understanding of basic biology and improve on the poor sensitivity of current pathogen detection systems. Finally, there are key knowledge gaps regarding the use of imaging tools for childhood tuberculosis that we outlined in this Personal View, in conjunction with a proposed roadmap for future research.
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http://dx.doi.org/10.1016/S1473-3099(20)30177-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606757PMC
November 2020

Rabbit model of implant-associated spinal infection.

Dis Model Mech 2020 07 28;13(7). Epub 2020 Jul 28.

Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

Post-surgical implant-associated spinal infection is a devastating complication commonly caused by Biofilm formation is thought to reduce penetration of antibiotics and immune cells, contributing to chronic and difficult-to-treat infections. A rabbit model of a posterior-approach spinal surgery was created, in which bilateral titanium pedicle screws were interconnected by a plate at the level of lumbar vertebra L6 and inoculated with a methicillin-resistant (MRSA) bioluminescent strain. whole-animal bioluminescence imaging (BLI) and bacterial cultures demonstrated a peak in bacterial burden by day 14, when wound dehiscence occurred. Structures suggestive of biofilm, visualized by scanning electron microscopy, were evident up to 56 days following infection. Infection-induced inflammation and bone remodeling were also monitored using F-fluorodeoxyglucose (F-FDG) positron emission tomography (PET) and computed tomography (CT). PET imaging signals were noted in the soft tissue and bone surrounding the implanted materials. CT imaging demonstrated marked bone remodeling and a decrease in dense bone at the infection sites. This rabbit model of implant-associated spinal infection provides a valuable preclinical approach to investigate the pathogenesis of implant-associated spinal infections and to evaluate novel therapeutics.
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http://dx.doi.org/10.1242/dmm.045385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406311PMC
July 2020

Cavitary tuberculosis: the gateway of disease transmission.

Lancet Infect Dis 2020 06 5;20(6):e117-e128. Epub 2020 May 5.

Center for Tuberculosis Research, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Center for Infection and Inflammation Imaging Research, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Tuberculosis continues to be a major threat to global health. Cavitation is a dangerous consequence of pulmonary tuberculosis associated with poor outcomes, treatment relapse, higher transmission rates, and development of drug resistance. However, in the antibiotic era, cavities are often identified as the most extreme outcome of treatment failure and are one of the least-studied aspects of tuberculosis. We review the epidemiology, clinical features, and concurrent standards of care for individuals with cavitary tuberculosis. We also discuss developments in the understanding of tuberculosis cavities as dynamic physical and biochemical structures that interface the host response with a unique mycobacterial niche to drive tuberculosis-associated morbidity and transmission. Advances in preclinical models and non-invasive imaging can provide valuable insights into the drivers of cavitation. These insights will guide the development of specific pharmacological interventions to prevent cavitation and improve lung function for individuals with tuberculosis.
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http://dx.doi.org/10.1016/S1473-3099(20)30148-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357333PMC
June 2020

Radiosynthesis and Biodistribution of F-Linezolid in -Infected Mice Using Positron Emission Tomography.

ACS Infect Dis 2020 05 9;6(5):916-921. Epub 2020 Apr 9.

Department of Pharmacology, Physiology, and Neuroscience, Rutgers University-New Jersey Medical School, Newark, New Jersey 07103, United States.

Oxazolidinones are a novel class of antibacterials with excellent activity against resistant Gram-positive bacteria including strains causing multidrug-resistant tuberculosis (TB). Despite their excellent efficacy, optimal dosing strategies to limit their toxicities are still under development. Here, we developed a novel synthetic strategy for fluorine-18-radiolabeled oxazolidinones. As proof-of-concept, we performed whole-body F-linezolid positron emission tomography (PET) in a mouse model of pulmonary TB for noninvasive measurements of time-activity curves in multiple compartments with subsequent confirmation by tissue gamma counting. After intravenous injection, F-linezolid rapidly distributed to all organs with excellent penetration into -infected lungs. Drug biodistribution studies with PET can provide unbiased, drug measurements, which could boost efforts to optimize antibiotic dosing strategies.
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http://dx.doi.org/10.1021/acsinfecdis.9b00473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212803PMC
May 2020

Caspase-Based PET for Evaluating Pro-Apoptotic Treatments in a Tuberculosis Mouse Model.

Mol Imaging Biol 2020 12;22(6):1489-1494

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Purpose: Despite recent advances in antimicrobial treatments, tuberculosis (TB) remains a major global health threat. Mycobacterium tuberculosis proliferates in macrophages, preventing apoptosis by inducing anti-apoptotic proteins leading to necrosis of the infected cells. Necrosis then leads to increased tissue destruction, reducing the penetration of antimicrobials and immune cells to the areas where they are needed most. Pro-apoptotic drugs could be used as host-directed therapies in TB to improve antimicrobial treatments and patient outcomes.

Procedure: We evaluated [F]-ICMT-11, a caspase-3/7-specific positron emission tomography (PET) radiotracer, in macrophage cell cultures and in an animal model of pulmonary TB that closely resembles human disease.

Results: Cells infected with M. tuberculosis and treated with cisplatin accumulated [F]-ICMT-11 at significantly higher levels compared with that of controls, which correlated with levels of caspase-3/7 activity. Infected mice treated with cisplatin with increased caspase-3/7 activity also had a higher [F]-ICMT-11 PET signal compared with that of untreated infected animals.

Conclusions: [F]-ICMT-11 PET could be used as a noninvasive approach to measure intralesional pro-apoptotic responses in situ in pulmonary TB models and support the development of pro-apoptotic host-directed therapies for TB.
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http://dx.doi.org/10.1007/s11307-020-01494-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529691PMC
December 2020

C-PABA as a PET Radiotracer for Functional Renal Imaging: Preclinical and First-in-Human Study.

J Nucl Med 2020 11 20;61(11):1665-1671. Epub 2020 Mar 20.

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland

Aminobenzoic acid (PABA) has been previously used as an exogenous marker to verify completion of 24-h urine sampling. Therefore, we hypothesized that PABA radiolabeled with C might allow high-quality dynamic PET of the kidneys with less radiation exposure than other agents because of its shorter biologic and physical half-life. We evaluated if C-PABA can visualize renal anatomy and quantify function in healthy rats and rabbits and in a first-in-humans study on healthy volunteers. Healthy rats and rabbits were injected with C-PABA intravenously. Subsequently, dynamic PET was performed, followed by postmortem tissue-biodistribution studies. C-PABA PET was directly compared with the current standard, Tc-mercaptoacetyltriglycin, in rats. Three healthy human subjects also underwent dynamic PET after intravenous injection of C-PABA. In healthy rats and rabbits, dynamic PET demonstrated a rapid accumulation of C-PABA in the renal cortex, followed by rapid excretion through the pelvicalyceal system. In humans, C-PABA PET was safe and well tolerated. There were no adverse or clinically detectable pharmacologic effects in any subject. The cortex was delineated on PET, and the activity gradually transited to the medulla and then pelvis with high spatiotemporal resolution. C-PABA demonstrated fast renal excretion with a very low background signal in animals and humans. These results suggest that C-PABA might be used as a novel radiotracer for functional renal imaging, providing high-quality spatiotemporal images with low radiation exposure.
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http://dx.doi.org/10.2967/jnumed.119.239806DOI Listing
November 2020

Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions.

Nat Med 2020 04 17;26(4):529-534. Epub 2020 Feb 17.

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure. However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments. In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration-time profiles in humans. Newly identified patients with rifampin-susceptible pulmonary TB were enrolled in a first-in-human study using dynamic [C]rifampin (administered as a microdose) positron emission tomography (PET) and computed tomography (CT). [C]rifampin PET-CT was safe and demonstrated spatially compartmentalized rifampin exposures in pathologically distinct TB lesions within the same patients, with low cavity wall rifampin exposures. Repeat PET-CT measurements demonstrated independent temporal evolution of rifampin exposure trajectories in different lesions within the same patients. Similar findings were recapitulated by PET-CT in experimentally infected rabbits with cavitary TB and confirmed using postmortem mass spectrometry. Integrated modeling of the PET-captured concentration-time profiles in hollow-fiber bacterial kill curve experiments provided estimates on the rifampin dosing required to achieve cure in 4 months. These data, capturing the spatial and temporal heterogeneity of intralesional drug PK, have major implications for antimicrobial drug development.
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http://dx.doi.org/10.1038/s41591-020-0770-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160048PMC
April 2020

Radiotracer Development for Bacterial Imaging.

J Med Chem 2020 03 21;63(5):1964-1977. Epub 2020 Feb 21.

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, United States.

Bacterial infections remain a major threat to humanity and are a leading cause of death and disability. Antimicrobial resistance has been declared as one of the top ten threats to human health by the World Health Organization, and new technologies are urgently needed for the early diagnosis and monitoring of deep-seated and complicated infections in hospitalized patients. This review summarizes the radiotracers as applied to imaging of bacterial infections. We summarize the recent progress in the development of pathogen-specific imaging and the application of radiotracers in understanding drug pharmacokinetics as well as the local biology at the infection sites. We also highlight the opportunities for medicinal chemists in radiotracer development for bacterial infections, with an emphasis on target selection and radiosynthetic approaches. Imaging of infections is an emerging field. Beyond clinical applications, these technologies could provide unique insights into disease pathogenesis and expedite bench-to-bedside translation of new therapeutics.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069783PMC
March 2020

Molecular Imaging of Diabetic Foot Infections: New Tools for Old Questions.

Int J Mol Sci 2019 Nov 28;20(23). Epub 2019 Nov 28.

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Diabetic foot infections (DFIs) are a common, complex, and costly medical problem with increasing prevalence. Diagnosing DFIs is a clinical challenge due to the poor specificity of the available methods to accurately determine the presence of infection in these patients. However, failure to perform an opportune diagnosis and provide optimal antibiotic therapy can lead to higher morbidity for the patient, unnecessary amputations, and increased healthcare costs. Novel developments in bacteria-specific molecular imaging can provide a non-invasive assessment of the infection site to support diagnosis, determine the extension and location of the infection, guide the selection of antibiotics, and monitor the response to treatment. This is a review of recent research in molecular imaging of infections in the context of DFI. We summarize different clinical and preclinical methods and the translational implications aimed to improve the care of patients with DFI.
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http://dx.doi.org/10.3390/ijms20235984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928969PMC
November 2019

Molecular Imaging: a Novel Tool To Visualize Pathogenesis of Infections .

mBio 2019 10 29;10(5). Epub 2019 Oct 29.

Division of Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Molecular imaging is an emerging technology that enables the noninvasive visualization, characterization, and quantification of molecular events within living subjects. Positron emission tomography (PET) is a clinically available molecular imaging tool with significant potential to study pathogenesis of infections in humans. PET enables dynamic assessment of infectious processes within the same subject with high temporal and spatial resolution and obviates the need for invasive tissue sampling, which is difficult in patients and generally limited to a single time point, even in animal models. This review presents current state-of-the-art concepts on the application of molecular imaging for infectious diseases and details how PET imaging can facilitate novel insights into infectious processes, ongoing development of pathogen-specific imaging, and simultaneous measurements of intralesional antimicrobial pharmacokinetics in multiple compartments, including privileged sites. Finally, the potential clinical applications of this promising technology are also discussed.
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http://dx.doi.org/10.1128/mBio.00317-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819656PMC
October 2019

Molecular imaging of bacterial infections: Overcoming the barriers to clinical translation.

Sci Transl Med 2019 09;11(508)

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Clinical diagnostic tools requiring direct sample testing cannot be applied to infections deep within the body, and clinically available imaging tools lack specificity. New approaches are needed for early diagnosis and monitoring of bacterial infections and rapid detection of drug-resistant organisms. Molecular imaging allows for longitudinal, noninvasive assessments and can provide key information about infectious processes deep within the body.
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http://dx.doi.org/10.1126/scitranslmed.aax8251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743081PMC
September 2019

Radiosynthesis and PET Bioimaging of Br-Bedaquiline in a Murine Model of Tuberculosis.

ACS Infect Dis 2019 12 29;5(12):1996-2002. Epub 2019 Jul 29.

Russell H. Morgan Department of Radiology and Radiological Science , Johns Hopkins University School of Medicine , Baltimore , Maryland 21287 , United States.

Bedaquiline is a promising drug against tuberculosis (TB), but limited data are available on its intralesional pharmacokinetics. Moreover, current techniques rely on invasive tissue resection, which is difficult in humans and generally limited even in animals. In this study, we developed a novel radiosynthesis for Br-bedaquiline and performed noninvasive, longitudinal whole-body positron emission tomography (PET) in live, -infected mice over 48 h. After the intravenous injection, Br-bedaquiline distributed to all organs and selectively localized to adipose tissue and liver, with excellent penetration into infected lung lesions (86%) and measurable penetration into the brain parenchyma (15%). Ex vivo high resolution, two-dimensional autoradiography, and same section hematoxylin/eosin and immunofluorescence provided detailed intralesional drug biodistribution. PET bioimaging and high-resolution autoradiography are novel techniques that can provide detailed, multicompartment, and intralesional pharmacokinetics of new and existing TB drugs. These technologies can significantly advance efforts to optimize drug dosing.
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http://dx.doi.org/10.1021/acsinfecdis.9b00207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911007PMC
December 2019

Matrix Metalloproteinases in Pulmonary and Central Nervous System Tuberculosis-A Review.

Int J Mol Sci 2019 Mar 18;20(6). Epub 2019 Mar 18.

Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town 7925, South Africa.

Tuberculosis (TB) remains the single biggest infectious cause of death globally, claiming almost two million lives and causing disease in over 10 million individuals annually. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes with various physiological roles implicated as key factors contributing to the spread of TB. They are involved in the breakdown of lung extracellular matrix and the consequent release of bacilli into the airways. Evidence demonstrates that MMPs also play a role in central nervous system (CNS) tuberculosis, as they contribute to the breakdown of the blood brain barrier and are associated with poor outcome in adults with tuberculous meningitis (TBM). However, in pediatric TBM, data indicate that MMPs may play a role in both pathology and recovery of the developing brain. MMPs also have a significant role in HIV-TB-associated immune reconstitution inflammatory syndrome in the lungs and the brain, and their modulation offers potential novel therapeutic avenues. This is a review of recent research on MMPs in pulmonary and CNS TB in adults and children and in the context of co-infection with HIV. We summarize different methods of MMP investigation and discuss the translational implications of MMP inhibition to reduce immunopathology.
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http://dx.doi.org/10.3390/ijms20061350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471445PMC
March 2019

Novel Functional Renal PET Imaging With 18F-FDS in Human Subjects.

Clin Nucl Med 2019 May;44(5):410-411

Department of Nuclear Medicine, and.

The novel PET probe 2-deoxy-2-F-fluoro-D-sorbitol (F-FDS) has demonstrated favorable renal kinetics in animals. We aimed to elucidate its imaging properties in 2 human volunteers. F-FDS was produced by a simple 1-step reduction from F-FDG. On dynamic renal PET, the cortex was delineated and activity gradually transited in the parenchyma, followed by radiotracer excretion. No adverse effects were reported. Given the higher spatiotemporal resolution of PET relative to conventional scintigraphy, F-FDS PET offers a more thorough evaluation of human renal kinetics. Due to its simple production from F-FDG, F-FDS is virtually available at any PET facility with radiochemistry infrastructure.
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http://dx.doi.org/10.1097/RLU.0000000000002494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449191PMC
May 2019

Noninvasive C-rifampin positron emission tomography reveals drug biodistribution in tuberculous meningitis.

Sci Transl Med 2018 12;10(470)

Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB), and key TB antimicrobials, including rifampin, have restricted brain penetration. A lack of reliable data on intralesional drug biodistribution in infected tissues has limited pharmacokinetic (PK) modeling efforts to optimize TBM treatments. Current methods to measure intralesional drug distribution rely on tissue resection, which is difficult in humans and generally limited to a single time point even in animals. In this study, we developed a multidrug treatment model in rabbits with experimentally induced TBM and performed serial noninvasive dynamic C-rifampin positron emission tomography (PET) over 6 weeks. Area under the curve brain/plasma ratios were calculated using PET and correlated with postmortem mass spectrometry. We demonstrate that rifampin penetration into infected brain lesions is limited, spatially heterogeneous, and decreases rapidly as early as 2 weeks into treatment. Moreover, rifampin concentrations in the cerebrospinal fluid did not correlate well with those in the brain lesions. First-in-human C-rifampin PET performed in a patient with TBM confirmed these findings. PK modeling predicted that rifampin doses (≥30 mg/kg) were required to achieve adequate intralesional concentrations in young children with TBM. These data demonstrate the proof of concept of PET as a clinically translatable tool to noninvasively measure intralesional antimicrobial distribution in infected tissues.
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http://dx.doi.org/10.1126/scitranslmed.aau0965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360528PMC
December 2018

Positron Emission Tomography Imaging with 2-[F]F- p-Aminobenzoic Acid Detects Staphylococcus aureus Infections and Monitors Drug Response.

ACS Infect Dis 2018 11 17;4(11):1635-1644. Epub 2018 Aug 17.

Institute for Chemical Biology & Drug Discovery, Department of Chemistry and Radiology , Stony Brook University , 100 Nicolls Road , 633 Chemistry, Stony Brook , New York 11794 , United States.

Staphylococcus aureus is the leading cause of life-threatening infections, frequently originating from unknown or deep-seated foci. Source control and institution of appropriate antibiotics remain challenges, especially with infections due to methicillin-resistant S. aureus (MRSA). In this study, we developed a radiofluorinated analog of para-aminobenzoic acid (2-[F]F-PABA) and demonstrate that it is an efficient alternative substrate for the S. aureus dihydropteroate synthase (DHPS). 2-[F]F-PABA rapidly accumulated in vitro within laboratory and clinical (including MRSA) strains of S. aureus but not in mammalian cells. Biodistribution in murine and rat models demonstrated localization at infection sites and rapid renal elimination. In a rat model, 2-[F]F-PABA positron emission tomography (PET) rapidly differentiated S. aureus infection from sterile inflammation and could also detect therapeutic failures associated with MRSA. These data suggest that 2-[F]F-PABA has the potential for translation to humans as a rapid, noninvasive diagnostic tool to identify, localize, and monitor S. aureus infections.
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http://dx.doi.org/10.1021/acsinfecdis.8b00182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226330PMC
November 2018

SPECT/CT Imaging of Mycobacterium tuberculosis Infection with [I]anti-C3d mAb.

Mol Imaging Biol 2019 06;21(3):473-481

The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, 1550 Orleans St. CRB2 493, Baltimore, MD, 21228, USA.

Purpose: Diagnosis and therapeutic monitoring of chronic bacterial infection requires methods to detect and localize sites of infection accurately. Complement C3 activation fragments are generated and covalently bound to selective bacterial pathogens during the immune response and can serve as biomarkers of ongoing bacterial infection. We have developed several probes for detecting tissue-bound C3 deposits, including a monoclonal antibody (mAb 3d29) that recognizes the tissue-bound terminal processing fragments iC3b and C3d but does not recognize native circulating C3 or tissue-bound C3b.

Procedures: To determine whether mAb 3d29 could be used to detect chronic Mycobacterium tuberculosis infection non-invasively, aerosol-infected female C3HeB/FeJ mice were injected with [I]3d29 mAb and either imaged using single-photon emission computed tomography (SPECT)/X-ray computed tomography (CT) imaging at 24 and 48 h after radiotracer injection or being subjected to biodistribution analysis.

Results: Discrete lesions were detected by SPECT/CT imaging in the lungs and spleens of infected mice, consistent with the location of granulomas in the infected animals as detected by CT. Low-level signal was seen in the spleens of uninfected mice and no signal was seen in the lungs of healthy mice. Immunofluorescence microscopy revealed that 3d29 in the lungs of infected mice co-localized with aggregates of macrophages (detected with anti-CD68 antibodies). 3d29 was detected in the cytoplasm of macrophages, consistent with the location of internalized M. tuberculosis. 3d29 was also present within alveolar epithelial cells, indicating that it detected M. tuberculosis phagocytosed by other CD68-positive cells. Healthy controls showed very little retention of fluorescent or radiolabeled antibody across tissues. Radiolabeled 3d29 compared with radiolabeled isotype control showed a 3.5:1 ratio of increased uptake in infected lungs, indicating specific uptake by 3d29.

Conclusion: 3d29 can be used to detect and localize areas of infection with M. tuberculosis non-invasively by 24 h after radiotracer injection and with high contrast.
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http://dx.doi.org/10.1007/s11307-018-1228-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329677PMC
June 2019

Imaging Pulmonary Foreign Body Reaction Using [I]iodo-DPA-713 SPECT/CT in Mice.

Mol Imaging Biol 2019 04;21(2):228-231

Center for Infection and Inflammation Imaging Research, Johns Hopkins University, 1550 Orleans Street, CRB-II, Rm 1.09, Baltimore, MD, 21287, USA.

Purpose: Foreign body reactions elicit granulomatous inflammation composed of reactive macrophages. We hypothesized that [I]iodo-DPA-713 single-photon emission computed tomography (SPECT), a low-molecular-weight pyrazolopyrimidine ligand selectively trapped by phagocytes, could be used to detect foreign body reactions in a murine model.

Procedures: C57BL/6 mice intratracheally inoculated with dextran beads, which developed foreign body lesions, were imaged after injection of [I]iodo-DPA-713 or DPA-713-IRDye800CW using SPECT and optical imaging, respectively.

Results: Foreign body lesions were clearly observed in the lungs of the dextran-treated mice on computer tomography imaging and demonstrated significantly higher [I]iodo-DPA-713 uptake compared with control animals (p < 0.01). Ex vivo studies demonstrated granulomatous reactions in the lungs of dextran-treated mice and localization of DPA-713-IRDye800CW at the diseased sites confirming the imaging findings.

Conclusion: Radioiodinated DPA-713 may be used as a noninvasive biomarker for the detection of pulmonary foreign body reactions.
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http://dx.doi.org/10.1007/s11307-018-1249-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326897PMC
April 2019
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