Name: Analysis of 18FDG PET/CT Imaging as a Tool for Studying Mycobacterium tuberculosis Infection and Treatment in Non-human Primates (Video) | JoVE Journal
Uploaded: 2017-09-05T15:00:00.000+00:00
Duration: 10 min 4 s
Description: Learn PET/CT imaging analysis for studying Mycobacterium tuberculosis infection and treatment in non-human primates. This method enables real-time tracking of disease progression and treatment efficacy without invasive procedures.

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5 minutes

The authors wish to acknowledge Mark Rodgers for outlining the infection procedures and L. Eoin Carney and Brian Lopresti for guidance in establishing these imaging procedures. Funding for this work has been provided by The Bill and Melinda Gates Foundation (J.L.F., P.L.L.), National Institutes of Health, National Institutes of Allergy and Infectious Diseases R01 AI111871 (P.L.L.), National Heart Lung and Blood Institute R01 HL106804 (J.L.F.), R01 HL110811.

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<li>Diedrich, C. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Reactivation+of+latent+tuberculosis+in+cynomolgus+macaques+infected+with+SIV+is+associated+with+early+peripheral+T+cell+depletion+and+not+virus+load%5BTitle%5D)+AND+%22PLoS+One%22%5BJournal%5D)">Reactivation of latent tuberculosis in cynomolgus macaques infected with SIV is associated with early peripheral T cell depletion and not virus load.</a> PLoS One. 5 (3), e9611(2010).</li>
<li>Lin, P. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((The+multistage+vaccine+H56+boosts+the+effects+of+BCG+to+protect+cynomolgus+macaques+against+active+tuberculosis+and+reactivation+of+latent+Mycobacterium+tuberculosis+infection%5BTitle%5D)+AND+%22J+Clin+Invest%22%5BJournal%5D)">The multistage vaccine H56 boosts the effects of BCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection.</a> J Clin Invest. 122 (1), 303-314 (2012).</li>
<li>Lin, P. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((CD4+T+cell+depletion+exacerbates+acute+Mycobacterium+tuberculosis+while+reactivation+of+latent+infection+is+dependent+on+severity+of+tissue+depletion+in+cynomolgus+macaques%5BTitle%5D)+AND+%22AIDS+Res+Hum+Retroviruses%22%5BJournal%5D)">CD4 T cell depletion exacerbates acute Mycobacterium tuberculosis while reactivation of latent infection is dependent on severity of tissue depletion in cynomolgus macaques.</a> AIDS Res Hum Retroviruses. 28 (12), 1693-1702 (2012).</li>
<li>Mattila, J. T., Diedrich, C. R., Lin, P. L., Phuah, J., Flynn, J. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Simian+immunodeficiency+virus-induced+changes+in+T+cell+cytokine+responses+in+cynomolgus+macaques+with+latent+Mycobacterium+tuberculosis+infection+are+associated+with+timing+of+reactivation%5BTitle%5D)+AND+%22J+Immunol%22%5BJournal%5D)">Simian immunodeficiency virus-induced changes in T cell cytokine responses in cynomolgus macaques with latent Mycobacterium tuberculosis infection are associated with timing of reactivation.</a> J Immunol. 186 (6), 3527-3537 (2011).</li>
<li>Scanga, C. A., Flynn, J. A. <a target="_blank" href="http://scholar.google.com/scholar?hl=en&safe=off&q=author%3aScanga%2C+CA+%22Tuberculosis%22">Tuberculosis</a>. Kaufmann, S. H. E., Rubin, E. J., Zumla, A. , Cold Spring Harbor Laboratory Press. 243-258 (2015).</li>
<li>Kita, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Development+of+therapeutic+and+prophylactic+vaccine+against+Tuberculosis+using+monkey+and+transgenic+mice+models%5BTitle%5D)+AND+%22Hum+Vaccin%22%5BJournal%5D)">Development of therapeutic and prophylactic vaccine against Tuberculosis using monkey and transgenic mice models.</a> Hum Vaccin. , Suppl 7. 108-114 (2011).</li>
<li>Langermans, J. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Divergent+effect+of+bacillus+Calmette-Guerin+%28BCG%29+vaccination+on+Mycobacterium+tuberculosis+infection+in+highly+related+macaque+species%3A+implications+for+primate+models+in+tuberculosis+vaccine+research%5BTitle%5D)+AND+%22Proc+Natl+Acad+Sci+U+S+A%22%5BJournal%5D)">Divergent effect of bacillus Calmette-Guerin (BCG) vaccination on Mycobacterium tuberculosis infection in highly related macaque species: implications for primate models in tuberculosis vaccine research.</a> Proc Natl Acad Sci U S A. 98 (20), 11497-11502 (2001).</li>
<li>Okada, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Novel+prophylactic+and+therapeutic+vaccine+against+tuberculosis%5BTitle%5D)+AND+%22Vaccine%22%5BJournal%5D)">Novel prophylactic and therapeutic vaccine against tuberculosis.</a> Vaccine. 27 (25-26), 3267-3270 (2009).</li>
<li>Reed, S. G., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Defined+tuberculosis+vaccine%2C+Mtb72F%2FAS02A%2C+evidence+of+protection+in+cynomolgus+monkeys%5BTitle%5D)+AND+%22Proc+Natl+Acad+Sci+U+S+A%22%5BJournal%5D)">Defined tuberculosis vaccine, Mtb72F/AS02A, evidence of protection in cynomolgus monkeys.</a> Proc Natl Acad Sci U S A. 106 (7), 2301-2306 (2009).</li>
<li>Capuano, S. V. 3rd, et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Experimental+Mycobacterium+tuberculosis+infection+of+cynomolgus+macaques+closely+resembles+the+various+manifestations+of+human+M.+tuberculosis+infection%5BTitle%5D)+AND+%22Infect+Immun%22%5BJournal%5D)">Experimental Mycobacterium tuberculosis infection of cynomolgus macaques closely resembles the various manifestations of human M. tuberculosis infection.</a> Infect Immun. 71 (10), 5831-5844 (2003).</li>
<li>Srinivas, S. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((A+recovery+coefficient+method+for+partial+volume+correction+of+PET+images%5BTitle%5D)+AND+%22Ann+Nucl+Med%22%5BJournal%5D)">A recovery coefficient method for partial volume correction of PET images.</a> Ann Nucl Med. 23 (4), 341-348 (2009).</li>
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<li>Martin, C. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Digitally+Barcoding+Mycobacterium+tuberculosis+Reveals+In+Vivo+Infection+Dynamics+in+the+Macaque+Model+of+Tuberculosis%5BTitle%5D)+AND+%22MBio%22%5BJournal%5D)">Digitally Barcoding Mycobacterium tuberculosis Reveals In Vivo Infection Dynamics in the Macaque Model of Tuberculosis.</a> MBio. 8 (3), (2017).</li>
<li>Lin, P. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Metronidazole+prevents+reactivation+of+latent+Mycobacterium+tuberculosis+infection+in+macaques%5BTitle%5D)+AND+%22Proc+Natl+Acad+Sci+U+S+A%22%5BJournal%5D)">Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques.</a> Proc Natl Acad Sci U S A. 109 (35), 14188-14193 (2012).</li>
<li>Lin, P. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Tumor+necrosis+factor+neutralization+results+in+disseminated+disease+in+acute+and+latent+Mycobacterium+tuberculosis+infection+with+normal+granuloma+structure+in+a+cynomolgus+macaque+model%5BTitle%5D)+AND+%22Arthritis+Rheum%22%5BJournal%5D)">Tumor necrosis factor neutralization results in disseminated disease in acute and latent Mycobacterium tuberculosis infection with normal granuloma structure in a cynomolgus macaque model.</a> Arthritis Rheum. 62 (2), 340-350 (2010).</li>
<li>Phuah, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Effects+of+B+Cell+Depletion+on+Early+Mycobacterium+tuberculosis+Infection+in+Cynomolgus+Macaques%5BTitle%5D)+AND+%22Infect+Immun%22%5BJournal%5D)">Effects of B Cell Depletion on Early Mycobacterium tuberculosis Infection in Cynomolgus Macaques.</a> Infect Immun. 84 (5), 1301-1311 (2016).</li>
<li>Martinez, V., Castilla-Lievre, M. A., Guillet-Caruba, C., Grenier, G., Fior, R., Desarnaud, S., Doucet-Populaire, F., Boue, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((%2818%29F-FDG+PET%2FCT+in+tuberculosis%3A+an+early+non-invasive+marker+of+therapeutic+response%5BTitle%5D)+AND+%22Int+J+Tuberc+Lung+Dis%22%5BJournal%5D)">(18)F-FDG PET/CT in tuberculosis: an early non-invasive marker of therapeutic response.</a> Int J Tuberc Lung Dis. 16 (9), 1180-1185 (2012).</li>
<li>Malherbe, S. T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Persisting+positron+emission+tomography+lesion+activity+and+Mycobacterium+tuberculosis+mRNA+after+tuberculosis+cure%5BTitle%5D)+AND+%22Nat+Med%22%5BJournal%5D)">Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure.</a> Nat Med. 22 (10), 1094-1100 (2016).</li>
<li>Chen, R. Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((PET%2FCT+imaging+correlates+with+treatment+outcome+in+patients+with+multidrug-resistant+tuberculosis%5BTitle%5D)+AND+%22Sci+Transl+Med%22%5BJournal%5D)">PET/CT imaging correlates with treatment outcome in patients with multidrug-resistant tuberculosis.</a> Sci Transl Med. 6 (265), (2014).</li>
</ol>

The authors have nothing to disclose.

Data acquired from PET/CT can be used as surrogate measurements for many aspects of M. tuberculosis infection that would be unobservable without such technology. PET/CT is much more sensitive than X-ray technology, which is often used in macaques studies. PET/CT provides structural, spatial and functional information. The analyses described above have many practical applications such as monitoring disease progression, assessing effectiveness of drug treatment, and providing risk factors for reactivation<sup clas...

Mycobacterium tuberculosis has plagued humans for millennia and causes more mortality than any other single infectious agent in the world today. In 2015, there were 10.5 million reported new cases of tuberculosis (TB) globally1 with the majority of cases emanating from India, Indonesia, China, Nigeria, Pakistan, and South Africa. Estimates place the global death toll from TB at 1.4 million people during that same time period. This value is nearly 25% lower than the death rate 100 years ago. Although drug sensitive TB is treatable, the regimen is lengthy requiring multiple medications and compliance is a concern. The emergence of multi drug-resistant (MDR) strains accounted for ~580,000 of the new TB cases in 2015. The successful treatment rate of patients with MDR strains of M. tuberculosis is only estimated to be around 50%. Even more alarming is the emergence of extensively resistant (XDR) strains of M. tuberculosis, which are resistant to nearly every available drug. Thus, new techniques are needed within the TB research field that enhance the ability to diagnose TB, increase the immunological understanding of the disease process, and allow for the screening of novel treatments and prevention strategies including antibiotic regimens and vaccine efficacy studies.
M. tuberculosis is an aerobic acid-fast bacillus that is physically characterized by its very complex outer cell wall and slow growth kinetics. Infection generally occurs through inhalation of individual bacteria contained in aerosolized droplets that are expelled from a symptomatic, infected individual while coughing, sneezing, or singing. Of the exposed individuals that develop infection, only 5 - 10% of people develop active clinical TB. The remaining 90% have a varying spectrum of asymptomatic infections that ranges from subclinical infection to no disease at all, all of which is classified clinically as latent TB infection (LTBI)2,3. Of the population that has this asymptomatic infection, approximately 10% will develop active TB by reactivation of the contained infection in their lifetime. The risk of reactivation dramatically increases if a person with asymptomatic infection contracts HIV or undergoes treatment with an immunosuppressive drug, such as TNF inhibitors4,5,6. Active TB disease also presents as a spectrum, with most people having pulmonary TB, which affects the lungs and thoracic lymph nodes. However, M. tuberculosis can infect any organ, so that the infection can also present in extrapulmonary sites of involvement.
The pathologic hallmark of M. tuberculosis infection is an organized spherical structure of host cells, called the granuloma. Macrophages, T cells and B cells are major components of the granuloma, with variable numbers of neutrophils7. The center of the granuloma is often necrotic. Thus, granulomas function as an immune microenvironment to kill or contain the bacilli, preventing spread to other parts of the lungs. However, M. tuberculosis can subvert killing by the granuloma, and persist within these structures for decades. Consistent and regular monitoring for the development of active TB disease after new infection or reactivation of LTBI is impractical, scientifically challenging and time consuming. Techniques that study these processes longitudinally, in humans and human-like animal models, are extremely useful to the scientific community in furthering the understanding of the many complexities of M. tuberculosis infection and disease.
PET/CT is an extremely useful imaging technique that has been employed to study a vast range of disease states in humans and animal models8. PET is a functional technique that uses positron-emitting radioactive compounds as a reporter. These radioisotopes are typically functionalized to a metabolic compound, such as glucose, or to a targeting group that is designed to bind to a receptor of interest. Since the radiation emitted from PET isotopes is powerful enough to penetrate tissue, very low concentrations can be used which allows for study below saturation levels in receptor-targeting compounds and at a low enough concentration to have no impact on metabolic processes when using agents such as 2-deoxy-2-(18F)Fluoro-D-glucose (FDG). CT is a three-dimensional x-ray imaging technique that uses varying levels of x-ray attenuation to identify physical characteristics of organs within the body9. When paired with PET, CT is used as a map to determine specific locations and structures that show uptake of a PET radiotracer. PET/CT is a powerful tool for in vivo imaging of both humans and animal models infected with M. tuberculosis infection that has led to many important insights into pathogenesis, response to drug treatment, disease spectrum, etc6,10,11,12. This work describes specific PET/CT analytical methods to study TB in non-human primate models longitudinally using parameters such as granuloma size, FDG uptake in individual lesions, whole lung and lymph node FDG avidity, and detection of extrapulmonary disease6,10,11,12.
This manuscript describes methodologies of imaging analysis in non-human primates (NHPs), specifically cynomolgus macaques, which are used to longitudinally evaluate disease progression and drug treatment following infection with M. tuberculosis. NHPs are a valuable animal model because when inoculated with a low dose of M. tuberculosis Erdman strain, animals show a variety of disease outcomes with ~50% developing active TB and the remaining animals having asymptomatic infection (i.e. controlling the infection, LTBI), providing the closest model to the clinical disease spectrum seen in humans3,13,14,15,16. Reactivation of LTBI in macaques is triggered by the same agents that cause reactivation in humans, examples of which include human immunodeficiency virus (HIV, using simian immunodeficiency virus (SIV) as the macaque version of HIV), CD4 depletion or tumor necrosis factor (TNF) neutralization13,16. In addition, macaques present with pathology that is extremely similar to that seen in humans, including the organized granulomas that form in lungs or other organs17. Thus, this model has provided important insights into the basic host-pathogen interactions in M. tuberculosis infection, as well as valuable knowledge about drug regimens and vaccines for tuberculosis14,18,19,20,21.
PET/CT imaging provides the ability to follow the appearance, distribution, and progression of individual granulomas. This work has primarily used FDG as a probe, which, as a glucose analogue, incorporates into metabolically active host cells, such as macrophages, neutrophils, and lymphocytes8, all of which are in granulomas. Thus, FDG is a proxy for host inflammation. The analysis procedures detailed herein uses OsiriX, a widely used DICOM viewer available for purchase and use. The image analysis methods described track the shape, size, and metabolic activity (via FDG uptake) of individual granulomas over time and uses imaging as a map for identifying specific lesions upon animal necropsy. Additionally, a separate method has been developed that quantifies the summation of FDG uptake in the lung above a specific threshold (SUV &#8805; 2.3) and uses this value to evaluate differences between control and experimental groups across studies ranging from vaccine trials to co-infection models. These data support that this overall measure of FDG uptake in lungs is correlated with bacterial burden, thus providing information about the disease status. Similar analyses can be performed on the FDG uptake of thoracic lymph nodes to study progression of disease as well. The following protocol describes the experimental process from animal infection through image analysis.

<table><tbody><tr><td>Ketamine</td><td>Henry Schein</td><td>23061</td><td>Henry Schein</td></tr><tr><td>Telazol</td><td>Zoetis</td><td>4866</td><td>Henry Schein</td></tr><tr><td>Cetacaine</td><td>Patterson Vet Generics</td><td>07-892-6862</td><td>Patterson</td></tr><tr><td>Sterile saline</td><td>Hospira</td><td>07-800-9721</td><td>Patterson</td></tr><tr><td>7H11 agar</td><td>BD</td><td>283810</td><td>BD Biosciences</td></tr><tr><td>IV catheter</td><td>Surflash</td><td>07-806-7659</td><td>Patterson</td></tr><tr><td>18F-FDG</td><td>Zevacor</td><td>N/A</td><td></td></tr><tr><td>Endotracheal tube</td><td>Jorgensen Labs Inc</td><td>07-887-0284</td><td>Patterson</td></tr><tr><td>Artificial tears</td><td>Patterson Vet Generics</td><td>07-888-1663</td><td>Patterson</td></tr><tr><td>Isoflurane</td><td>Zoetis</td><td>07-806-3204</td><td>Patterson</td></tr><tr><td>Neurologica Ceretom CT</td><td>Samsung Neurologica</td><td>N/A</td><td></td></tr><tr><td>Siemens Focus 220 microPET</td><td>Siemens Molecular Imaging Systems</td><td>N/A</td><td></td></tr><tr><td>Inveon Research Software</td><td>Siemens Molecular Imaging Systems</td><td>N/A</td><td></td></tr><tr><td>OsiriX</td><td>Pixmeo</td><td>N/A</td><td></td></tr></tbody></table>

analysis of 18fdg pet/ct imaging as a tool for studying mycobacterium tuberculosis infection and treatment in non-human primates

Analysis of 18FDG PET/CT Imaging as a Tool for Studying Mycobacterium tuberculosis Infection and Treatment in Non-human Primates

Mycobacterium tuberculosis remains the number one infectious agent in the world today. With the emergence of antibiotic resistant strains, new clinically relevant methods are needed that evaluate the disease process and screen for potential antibiotic and vaccine treatments. Positron Emission Tomography/Computed Tomography (PET/CT) has been established as a valuable tool for studying a number of afflictions such as cancer, Alzheimer&#39;s disease, and inflammation/infection. Outlined here are a number of strategies that have been employed to evaluate PET/CT images in cynomolgus macaques that are infected intrabronchially with low doses of M. tuberculosis. Through evaluation of lesion size on CT and uptake of 18F-fluorodeoxyglucose (FDG) in lesions and lymph nodes in PET images, these described methods show that PET/CT imaging can predict future development of active versus latent disease and the propensity for reactivation from a latent state of infection. Additionally, by analyzing the overall level of lung inflammation, these methods determine antibiotic efficacy of drugs against M. tuberculosis in the most clinically relevant existing animal model. These image analysis methods are some of the most powerful tools in the arsenal against this disease as not only can they evaluate a number of characteristics of infection and drug treatment, but they are also directly translatable to a clinical setting for use in human studies.

Identification and Analysis of Individual Lesions
Individual granulomas can be visualized for number, size, and FDG uptake qualitatively to understand the general scope of the infection process (Figure 1). Using these images, counting granulomas over time is a quantitative measure of disease spread. Figure 2 depicts individual granuloma counts over time in a gr...

Here, we present a protocol to describe the analysis of 18F-FDG PET/CT imaging in non-human primates that have been infected with M. tuberculosis to study disease process, drug treatment, and disease reactivation.

Mycobacterium tuberculosis remains the number one infectious agent in the world today. With the emergence of antibiotic resistant strains, new clinically ...

analysis-18fdg-petct-imaging-as-tool-for-studying-mycobacterium

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We describe the optical imaging of mice infected with Mycobacterium tuberculosis (M. tuberculosis) using reporter enzyme fluorescence (REF). This protocol facilitates the sensitive and specific detection of M. tuberculosis in pre-clinical animal models for pathogenesis, therapeutics and vaccine research.

Imaging Mycobacterium tuberculosis in Mice with Reporter Enzyme Fluorescence

In this protocol, we describe how to utilize [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (18F-FDG PET/CT) imaging to measure the tumor metabolic response to the targeted therapy MLN0128 in a Kras/Lkb1 mutant mouse model of lung cancer and coupled imaging with high resolution ex vivo autoradiography and quantitative histology.

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

This article describes the generation of an orthotopic mouse model of human pleural mesothelioma by implantation of H2052/484 mesothelioma cells into the pleural cavity of immunocompromised athymic mice. The longitudinal monitoring of the development of intrapleural tumors was assessed by non-invasive multimodal [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography imaging.

Implantation and Monitoring by PET/CT of an Orthotopic Model of Human Pleural Mesothelioma in Athymic Mice

This paper details methodology for radiolabeling a human-specific anti-CD19 monoclonal antibody and how to use it to quantify B cells in the central nervous system and peripheral tissues of a mouse model of multiple sclerosis using in vivo PET imaging, ex vivo gamma counting, and autoradiography approaches.

Imaging CD19+ B Cells in an Experimental Autoimmune Encephalomyelitis Mouse Model using Positron Emission Tomography

This protocol describes the procedure for performing in vivo PET imaging on mice using Body Conforming Animal Molds (BCAMs) in the G8 PET/CT scanner. Technical details on mouse preparation, including proper tumor implantation, optimal positioning, BCAM-assisted PET/CT image acquisition, and data analysis, are provided.

Preclinical Positron Emission Tomography with Body Conforming Animal Molds for Cloud-Based Automated Image Analysis in Mice

Here, we present a protocol for intravital imaging of an attenuated BSL-2-approved Mycobacterium tuberculosis. strain in the murine lung using a permanent lung window. This approach enables longitudinal, single-cell-resolution analysis of early host-pathogen interactions, including bacillary localization, vascular dynamics, and macrophage uptake within the same lung microenvironment.

Intravital Imaging of Attenuated Auxotrophic Mycobacterium tuberculosis in Murine Lung during Early Intravascular Infection

Learn PET/CT imaging analysis for studying Mycobacterium tuberculosis infection and treatment in non-human primates. This method enables real-time tracking of disease progression and treatment efficacy without invasive procedures.

Analysis of 18FDG PET/CT Imaging as a Tool for Studying Mycobacterium tuberculosis Infection and Treatment in Non-human Primates (Video) | JoVE Journal

Analysis of ¹⁸FDG PET/CT Imaging as a Tool for Studying Mycobacterium tuberculosis Infection and Treatment in Non-human Primates

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