Analysis of &lt;sup&gt;18&lt;/sup&gt;FDG PET/CT Imaging as a Tool for Studying &lt;em&gt;Mycobacterium tuberculosis&lt;/em&gt; Infection and Treatment in Non-human Primates

White, Alexander G.; Maiello, Pauline; Coleman, M. Teresa; Tomko, Jaime; Frye, L. James; Scanga, Charles A.; Lin, Philana Ling; Flynn, JoAnne L.

doi:10.3791/56375

Cited by 78 publications

(105 citation statements)

References 28 publications

(18 reference statements)

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…Lung inflammation was quantified by total FDG activity in the lungs before and during treatment (Fig. 4A-B and Supplementary Table 1)(19). In LZD treated macaques, there was no significant decrease in total lung FDG activity after 4 weeks (p=0.2876), although there was a trend for an initial reduction in inflammation after 2 weeks of treatment (p=0.0857)(Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We assessed changes in granulomas during treatment by measuring physical size (CT) and metabolic activity (measured as the standard uptake value of FDG per granuloma, SUVR) (Fig. 4C-D)(19). During treatment, the majority of granulomas decreased in size with no differences between LZD and LZD+IL1-Rn treated animals.…”

Section: Resultsmentioning

confidence: 99%

“…We used multiple strains of mice to model distinct disease states and dissect the relative importance of the inflammasome and IL-1 signaling in HDT efficacy. As a translational model, we used cynomolgus macaques in combination with [ 18 F] FDG PET/CT serial imaging to track TB disease progression, including inflammation, before and during drug regimens (19). Cynomolgus macaques present with a similar spectrum of Mtb infection as humans, with pathology, including granuloma structure and diversity, that recapitulates human TB (20-22).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Evaluation of IL-1 blockade as an adjunct to linezolid therapy for tuberculosis in mice and macaques

Winchell

Mishra

Phuah

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

AbstractIn 2017 over 550,000 estimated new cases of multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) occurred, emphasizing a need for new treatment strategies. Linezolid (LZD) is a potent antibiotic for drug-resistant Gram-positive infections and is an effective treatment for TB. However, extended LZD use can lead to LZD-associated host toxicities, most commonly bone marrow suppression. LZD toxicities may be mediated by IL-1, an inflammatory pathway important for early immunity during M. tuberculosis infection. However, IL-1 can contribute to pathology and disease severity late in TB progression. Since IL-1 may contribute to LZD toxicity and does influence TB pathology, we targeted this pathway with a potential host-directed therapy (HDT). We hypothesized LZD efficacy could be enhanced by modulation of IL-1 pathway to reduce bone marrow toxicity and TB associated-inflammation. We used two animal models of TB to test our hypothesis, a TB-susceptible mouse model and clinically relevant cynomolgus macaques. Antagonizing IL-1 in mice with established infection reduced lung neutrophil numbers and partially restored the erythroid progenitor populations that are depleted by LZD. In macaques, we found no conclusive evidence of bone marrow suppression associated with LZD, indicating our treatment time may have been short enough to avoid the toxicities observed in humans. Though treatment was only 4 weeks (the FDA approved regimen at the time of study), we observed sterilization of the majority of granulomas regardless of co-administration of the FDA-approved IL-1 receptor antagonist (IL-1Rn), also known as Anakinra. However total lung inflammation was significantly reduced in macaques treated with IL-1Rn and LZD compared to LZD alone. Importantly, IL-1Rn administration did not impair the host response against Mtb or LZD efficacy in either animal model. Together, our data support that inhibition of IL-1 in combination with LZD has potential to be an effective HDT for TB and the need for further research in this area.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Evaluation of IL-1 blockade as an adjunct to linezolid therapy for tuberculosis in mice and macaques

Winchell

Mishra

Phuah

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The maximum standard uptake value (SUV) of each mediastinal lymph node was identified and recorded as described in reference 46. Lymph nodes with SUVR (SUV with muscle ratio) greater than or equal to 5 were then counted (46). Total lung FDG activity is a cumulative measurement of SUV values, where the SUV of every "hot" voxel (all voxels with a SUV greater than 2.3) is added up within the lung cavity (46).…”

Section: Methodsmentioning

confidence: 99%

Rhesus Macaques Are More Susceptible to Progressive Tuberculosis than Cynomolgus Macaques: a Quantitative Comparison

et al. 2018

Self Cite

View full text Add to dashboard Cite

In the past 2 decades, it has become increasingly clear that nonhuman primates, specifically macaques, are useful models for human tuberculosis (TB). Several macaque species have been used for TB studies, and questions remain about the similarities and differences in TB pathogenesis among macaque species, which can complicate decisions about the best species for a specific experiment. Here we provide a quantitative assessment, using serial positron emission tomography and computed tomography (PET-CT) imaging and precise quantitative determination of bacterial burdens of low-dose Mycobacterium tuberculosis infection in cynomolgus macaques of Chinese origin, rhesus macaques of Chinese origin, and Mauritian cynomolgus macaques. This comprehensive study demonstrates that there is substantial variability in the outcome of infection within and among species. Overall, rhesus macaques have higher rates of disease progression, more lung, lymph node, and extrapulmonary involvement, and higher bacterial burdens than Chinese cynomolgus macaques. The small cohort of Mauritian cynomolgus macaques assessed here indicates that this species is more similar to rhesus macaques than to Chinese cynomolgus macaques in terms of M. tuberculosis infection outcome. These data provide insights into the differences among species, providing valuable data to the field for assessing macaque studies of TB.KEYWORDS Mycobacterium, PET CT, macaque, nonhuman primate, tuberculosis N ovel therapeutics for tuberculosis (TB) are greatly needed to curb the 10.4 million new cases and 1.8 million deaths that occur due to this global pandemic (1). Drugs have aided the fight against TB by saving an estimated 49 million lives between 2000 and 2015 (1). However, the current drug regimen is lengthy and cumbersome, and about 480,000 people developed multidrug-resistant TB in 2015 alone (1), so there is much room for improvement. The only licensed vaccine for TB, Mycobacterium bovis bacillus Calmette-Guérin (BCG), protects infants from severe manifestations of TB but does not provide long-lasting immunity against pulmonary TB (2). The urgent need for new therapeutics for TB has driven the development of novel drugs and vaccines that require preclinical evaluation in animal models. Many animal models are used in TB research, including mice, zebra fish, cattle, rabbits, guinea pigs, and nonhuman primates (NHPs) (3, 4). Mice and NHPs are the two animal models that are the most useful, as the other models suffer from a lack of resources available for immunologic studies. Mice have their shortcomings too, as their TB pathology is not fully representative of the pathology observed in humans, and they do not develop human-like latent TB infection (LTBI). NHPs recapitulate the full spectrum of Mycobacterium tuberculosis

show abstract

“…Three core CTVD primate facilities will have the same custom-configured PET-CT imagers (Mediso Ltd.), and the data from each imager will be analyzed at a core facility at the University of Pittsburgh. Guidelines for imaging and image analysis have recently been published (11). PET-CT of NHPs can be aligned with PET-CT imaging of M. tuberculosis-infected humans.…”

mentioning

confidence: 99%

Toward Tuberculosis Vaccine Development: Recommendations for Nonhuman Primate Study Design

et al. 2018

View full text Add to dashboard Cite

Clinical trials of novel tuberculosis (TB) vaccines are expensive, while global resources for TB vaccine development are limited. Therefore, there is a need for robust and predictive preclinical data to support advancement of candidate vaccines into clinical trials. Here, we provide a rationale for using the nonhuman primate as an essential component of these efforts, as well as guidance to the TB community for standardizing experimental design and aligning endpoints to facilitate development of new TB vaccines.

show abstract

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

Cited by 78 publications

References 28 publications

Evaluation of IL-1 blockade as an adjunct to linezolid therapy for tuberculosis in mice and macaques

Evaluation of IL-1 blockade as an adjunct to linezolid therapy for tuberculosis in mice and macaques

Rhesus Macaques Are More Susceptible to Progressive Tuberculosis than Cynomolgus Macaques: a Quantitative Comparison

Toward Tuberculosis Vaccine Development: Recommendations for Nonhuman Primate Study Design

Contact Info

Product

Resources

About