Anti-vascular endothelial growth factor treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery

Datta, Meenal; Via, Laura E.; Kamoun, Walid S.; Liu, Chong; Chen, Wei; Seano, Giorgio; Weiner, Danielle M.; Schimel, Daniel; England, Kathleen; Martin, John D.; Gao, Xing; Xu, Lei; Barry, Clifton E.; Jain, Rakesh K.

doi:10.1073/pnas.1424563112

Cited by 178 publications

(206 citation statements)

References 35 publications

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“…Various animal studies suggest that anti‐VEGF treatment, such as the widely prescribed anti‐VEGF antibody bevacizumab, can resolve vascular leakiness and improve outcome of TB (Datta et al, 2015; Oehlers et al, 2014; Oehlers et al, 2016). With the rising awareness that host‐directed therapy could be a valuable addition to antibiotics, VEGF seems to be an interesting target.…”

Section: Discussionmentioning

confidence: 99%

Mycobacteria employ two different mechanisms to cross the blood-brain barrier

Leeuwen

Boot

Kuijl

et al. 2018

Cellular Microbiology

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Central nervous system (CNS) infection by Mycobacterium tuberculosis is one of the most devastating complications of tuberculosis, in particular in early childhood. In order to induce CNS infection, M. tuberculosis needs to cross specialised barriers protecting the brain. How M. tuberculosis crosses the blood–brain barrier (BBB) and enters the CNS is not well understood. Here, we use transparent zebrafish larvae and the closely related pathogen Mycobacterium marinum to answer this question. We show that in the early stages of development, mycobacteria rapidly infect brain tissue, either as free mycobacteria or within circulating macrophages. After the formation of a functionally intact BBB, the infiltration of brain tissue by infected macrophages is delayed, but not blocked, suggesting that crossing the BBB via phagocytic cells is one of the mechanisms used by mycobacteria to invade the CNS. Interestingly, depletion of phagocytic cells did not prevent M. marinum from infecting the brain tissue, indicating that free mycobacteria can independently cause brain infection. Detailed analysis showed that mycobacteria are able to cause vasculitis by extracellular outgrowth in the smaller blood vessels and by infecting endothelial cells. Importantly, we could show that this second mechanism is an active process that depends on an intact ESX‐1 secretion system, which extends the role of ESX‐1 secretion beyond the macrophage infection cycle.

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Section: Discussionmentioning

confidence: 99%

Mycobacteria employ two different mechanisms to cross the blood-brain barrier

Leeuwen

Boot

Kuijl

et al. 2018

Cellular Microbiology

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“…Datta et al [61] shown that TB-infected rabbits have impaired small molecule distribution into these disease sites due to a functionally abnormal vasculature, with a low-molecularweight tracer accumulating only in peripheral regions of granulomatous lesions. Granuloma-associated vessels are morphologically and spatially heterogeneous, with poor vessel pericyte coverage in both human and experimental rabbit TB granulomas.…”

Section: Granuloma Structurementioning

confidence: 99%

Host Directed Therapies for Tuberculosis: Futures Strategies for an Ancient Disease

Palucci

Delogu

2018

Chemotherapy

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The emergence and spread of drug-resistant strains of Mycobacterium tuberculosis is worsening the global threat of tuberculosis (TB). There is a need and urgency for the development of new treatments for TB, for the management of drug resistant TB (MDR-TB) and for improved regimens against drug-susceptible TB, with the goal of reducing toxicity and length of therapy that will boost patience compliance. The paucity of new drugs is a major obstacle to design new regimens while host-directed therapies (HDTs) are emerging as a promising area of research and are opening new avenues to fight TB. In this review, we discuss examples of potentially promising strategies aimed at improving the host response to M. tuberculosis, and argue how a better understanding of TB pathogenesis, with the fine characterization of the immunological mediators involved, may pave the way for the design of new therapies, the identification of new drugs or the repurposing of some already in use for other diseases. We emphasize that any HDTs shall be included as adjunct therapy to the drug-combination regimens already in use for TB, with the goal to reduce tissue damage and immunopathology and enhance bacterial clearance. We anticipate that the benefits of HDTs against TB will be highest against MDR-TB, where the activity of current regimens is poor and the cost high.

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“…These nonreplicating bacteria can reenter the replicating state when hypoxia is relieved, as a granuloma shrinks. Reducing hypoxia in granulomas has been suggested as a strategy to resensitize bacteria to antibiotics (100). The dynamics between bacterial load, granuloma size, and bacterial growth clusters are also evident if we examine multiple granulomas at multiple time points between 200 and 1,000 dpi ( tuberculosis's ability to slow its growth, i.e., its ability to enter growth cluster 4 (but not its ability to accumulate lipid inclusions), leads to lower bacterial loads and higher sterilization rates (Fig.…”

Section: Resultsmentioning

confidence: 99%

Multiscale Model of Mycobacterium tuberculosis Infection Maps Metabolite and Gene Perturbations to Granuloma Sterilization Predictions

et al. 2016

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cGranulomas are a hallmark of tuberculosis. Inside granulomas, the pathogen Mycobacterium tuberculosis may enter a metabolically inactive state that is less susceptible to antibiotics. Understanding M. tuberculosis metabolism within granulomas could contribute to reducing the lengthy treatment required for tuberculosis and provide additional targets for new drugs. Two key adaptations of M. tuberculosis are a nonreplicating phenotype and accumulation of lipid inclusions in response to hypoxic conditions. To explore how these adaptations influence granuloma-scale outcomes in vivo, we present a multiscale in silico model of granuloma formation in tuberculosis. The model comprises host immunity, M. tuberculosis metabolism, M. tuberculosis growth adaptation to hypoxia, and nutrient diffusion. We calibrated our model to in vivo data from nonhuman primates and rabbits and apply the model to predict M. tuberculosis population dynamics and heterogeneity within granulomas. We found that bacterial populations are highly dynamic throughout infection in response to changing oxygen levels and host immunity pressures. Our results indicate that a nonreplicating phenotype, but not lipid inclusion formation, is important for long-term M. tuberculosis survival in granulomas. We used virtual M. tuberculosis knockouts to predict the impact of both metabolic enzyme inhibitors and metabolic pathways exploited to overcome inhibition. Results indicate that knockouts whose growth rates are below ϳ66% of the wild-type growth rate in a culture medium featuring lipid as the only carbon source are unable to sustain infections in granulomas. By mapping metabolite-and gene-scale perturbations to granuloma-scale outcomes and predicting mechanisms of sterilization, our method provides a powerful tool for hypothesis testing and guiding experimental searches for novel antituberculosis interventions.T uberculosis (TB), caused by inhalation of the pathogen Mycobacterium tuberculosis, is a leading cause of death worldwide (1, 2). The main sites of infection during TB are lung granulomas, dense collections of immune cells and bacteria that develop following infection (3). Understanding M. tuberculosis dynamics within granulomas could aid in development of new antibiotic therapies, since M. tuberculosis growth rates, heterogeneity, and dynamics can affect antibiotic efficacy (3-7).Two in vitro-observed adaptations of M. tuberculosis, suspected to be important in the ability of M. tuberculosis to persist in the host lung, are (i) the adoption of a nonreplicating phenotype and (ii) the accumulation of lipid inclusions, aggregates of neutral lipids inside bacteria (8-13). Hypoxia is known to be a trigger for the transition to a nonreplicating phenotype and the formation of lipid inclusions (9,12,14,15).The in vivo role of the nonreplicating phenotype remains controversial. It has been suggested that M. tuberculosis acquires the nonreplicating phenotype in response to stresses present in the host (such as hypoxia) and that this phenotype allows M. tubercul...

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Anti-vascular endothelial growth factor treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery

Cited by 178 publications

References 35 publications

Mycobacteria employ two different mechanisms to cross the blood-brain barrier

Mycobacteria employ two different mechanisms to cross the blood-brain barrier

Host Directed Therapies for Tuberculosis: Futures Strategies for an Ancient Disease

Multiscale Model of Mycobacterium tuberculosis Infection Maps Metabolite and Gene Perturbations to Granuloma Sterilization Predictions

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