Visualizing the dynamics of tuberculosis pathology using molecular imaging

Ordoñez, Alvaro A.; Tucker, Elizabeth W.; Anderson, Carolyn J.; Carter, Claire L.; Ganatra, Shashank; Kaushal, Deepak; Kramnik, Igor; Lin, Philana Ling; Madigan, Cressida A.; Méndez, Susana; Rao, Jianghong; Savic, Rada; Tobin, David M.; Walzl, Gerhard; Wilkinson, Robert J.; Lacourciere, Karen A.; Via, Laura E.; Jain, Sanjay

doi:10.1172/jci145107

Cited by 15 publications

(14 citation statements)

References 126 publications

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“…Our data suggest that animal models of TB meningitis can be used to evaluate and prioritize promising treatments prior to their evaluation in clinical trials. State-of-the-art, clinically translatable imaging approaches can also expedite unbiased, cross-species studies and validation of animal data in relevant human populations (10,49,50). Finally, while rifampin is a key first-line TB drug, it is widely used to treat serious infections due to other pathogens, e.g.…”

Section: Discussionmentioning

confidence: 99%

High-dose rifampin improves bactericidal activity without increased intracerebral inflammation in animal models of tuberculous meningitis

Ruiz-Bedoya¹,

Mota²,

Tucker³

et al. 2022

Journal of Clinical Investigation

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Tuberculous (TB) meningitis is the most severe form of TB, requiring 12 months of multidrug treatment for cure, and is associated with high morbidity and mortality. High-dose rifampin (35 mg/kg/day) is safe and improves the bactericidal activity of the standard-dose (10 mg/kg/day) rifampin-containing TB regimen in pulmonary TB. However, there are conflicting clinical data regarding its benefit for TB meningitis, where outcomes may also be associated with intracerebral inflammation. In this study, we conducted cross-species studies in mice and rabbits, demonstrating that an intensified high-dose rifampin-containing regimen has significantly improved bactericidal activity for TB meningitis over the first-line, standard-dose rifampin regimen, without an increase in intracerebral inflammation. Positron emission tomography in live animals demonstrated spatially compartmentalized, lesion-specific pathology, with post-mortem analyses showing discordant brain tissue and cerebrospinal fluid rifampin levels and inflammatory markers. Longitudinal multimodal imaging in the same cohort of animals during TB treatment as well as imaging studies in two cohorts of TB patients demonstrated that spatiotemporal changes in localized blood-brain barrier disruption in TB meningitis are an important driver of rifampin brain exposure. These data provide unique insights into the mechanisms underlying high-dose rifampin in TB meningitis with important implications for developing new antibiotic treatments for infections.

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Section: Discussionmentioning

confidence: 99%

High-dose rifampin improves bactericidal activity without increased intracerebral inflammation in animal models of tuberculous meningitis

Ruiz-Bedoya¹,

Mota²,

Tucker³

et al. 2022

Journal of Clinical Investigation

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“…MIT visualizes molecules of relevance to a disease at both microscopic levels and in living subjects. For the latter, it provides 3D spatial characterization (often using existing imaging modalities) and non-invasive, temporal monitoring within the same subject[ 32 ]. MIT may augment TB research by advancing fundamental knowledge and accelerating the development of novel diagnostics, biomarkers, and therapeutics[ 32 ].…”

Section: Imaging Methods In Tuberculosismentioning

confidence: 99%

“…, single-cell resolution) live imaging in small animal models and has provided very valuable insights into various biological processes ( e.g. , TB granuloma formation)[ 32 , 88 ]. It is performed with highly sensitive fluorescent or bioluminescent agents.…”

Section: Imaging Methods In Tuberculosismentioning

confidence: 99%

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Tuberculosis conundrum - current and future scenarios: A proposed comprehensive approach combining laboratory, imaging, and computing advances

Merchant¹,

Shaikh²,

Nadkarni³

2022

WJR

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Tuberculosis (TB) remains a global threat, with the rise of multiple and extensively drug resistant TB posing additional challenges. The International health community has set various 5-yearly targets for TB elimination: mathematical modelling suggests that a 2050 target is feasible with a strategy combining better diagnostics, drugs, and vaccines to detect and treat both latent and active infection. The availability of rapid and highly sensitive diagnostic tools (Gene-Xpert, TB-Quick) will vastly facilitate population-level identification of TB (including rifampicin resistance and through it, multi-drug-resistant TB). Basic-research advances have illuminated molecular mechanisms in TB, including the protective role of Vitamin D. Also, Mycobacterium tuberculosis impairs the host immune response through epigenetic mechanisms (histone-binding modulation). Imaging will continue to be key, both for initial diagnosis and follow-up. We discuss advances in multiple imaging modalities to evaluate TB tissue changes, such as molecular imaging techniques (including pathogen-specific positron emission tomography imaging agents), non-invasive temporal monitoring, and computing enhancements to improve data acquisition and reduce scan times. Big data analysis and Artificial Intelligence (AI) algorithms, notably in the AI sub-field called “Deep Learning”, can potentially increase the speed and accuracy of diagnosis. Additionally, Federated learning makes multi-institutional/multi-city AI-based collaborations possible without sharing identifiable patient data. More powerful hardware designs - e.g. , Edge and Quantum Computing- will facilitate the role of computing applications in TB. However, “Artificial Intelligence needs real Intelligence to guide it!” To have maximal impact, AI must use a holistic approach that incorporates time tested human wisdom gained over decades from the full gamut of TB, i.e. , key imaging and clinical parameters, including prognostic indicators, plus bacterial and epidemiologic data. We propose a similar holistic approach at the level of national/international policy formulation and implementation, to enable effective culmination of TB’s endgame, summarizing it with the acronym “TB - REVISITED”.

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“…The use of the radionuclide technique for studying the in vivo biodistribution of drugs allows for the noninvasive exploration of the biokinetics of the drugs in humans without relying on extrapolated data from animal studies. Radionuclide techniques can be perfectly used for drug biodistribution studies and may be cheaper and more accurate than the currently used approaches for drug development [128][129][130].…”

Section: Targeting Fungal Cell Membrane/cell Wall Synthesismentioning

confidence: 99%

Radionuclide Imaging of Invasive Fungal Disease in Immunocompromised Hosts

et al. 2021

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Invasive fungal disease (IFD) leads to increased mortality, morbidity, and costs of treatment in patients with immunosuppressive conditions. The definitive diagnosis of IFD relies on the isolation of the causative fungal agents through microscopy, culture, or nucleic acid testing in tissue samples obtained from the sites of the disease. Biopsy is not always feasible or safe to be undertaken in immunocompromised hosts at risk of IFD. Noninvasive diagnostic techniques are, therefore, needed for the diagnosis and treatment response assessment of IFD. The available techniques that identify fungal-specific antigens in biological samples for diagnosing IFD have variable sensitivity and specificity. They also have limited utility in response assessment. Imaging has, therefore, been applied for the noninvasive detection of IFD. Morphologic imaging with computed tomography (CT) and magnetic resonance imaging (MRI) is the most applied technique. These techniques are neither sufficiently sensitive nor specific for the early diagnosis of IFD. Morphologic changes evaluated by CT and MRI occur later in the disease course and during recovery after successful treatment. These modalities may, therefore, not be ideal for early diagnosis and early response to therapy determination. Radionuclide imaging allows for targeting the host response to pathogenic fungi or specific structures of the pathogen itself. This makes radionuclide imaging techniques suitable for the early diagnosis and treatment response assessment of IFD. In this review, we aimed to discuss the interplay of host immunity, immunosuppression, and the occurrence of IFD. We also discuss the currently available radionuclide probes that have been evaluated in preclinical and clinical studies for their ability to detect IFD.

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Visualizing the dynamics of tuberculosis pathology using molecular imaging

Cited by 15 publications

References 126 publications

High-dose rifampin improves bactericidal activity without increased intracerebral inflammation in animal models of tuberculous meningitis

High-dose rifampin improves bactericidal activity without increased intracerebral inflammation in animal models of tuberculous meningitis

Tuberculosis conundrum - current and future scenarios: A proposed comprehensive approach combining laboratory, imaging, and computing advances

Radionuclide Imaging of Invasive Fungal Disease in Immunocompromised Hosts

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