Cholesterol plays a larger role during Mycobacterium tuberculosis in vitro dormancy and reactivation than previously suspected

Soto-Ramirez, Maria D.; Aguilar-Ayala, Diana A.; García-Morales, Lázaro; Rodriguez-Peredo, Sofia M.; Badillo-Lopez, Claudia; Ríos-Muñiz, Diana; Meza-Segura, Mario; Rivera-Morales, Gelen Y.; Leon-Solis, Lizbel; Cerna-Cortés, Jorge F.; Rivera-Gutierrez, Sandra; Helguera-Repetto, Addy Cecilia; González-y-Merchand, Jorge A.

doi:10.1016/j.tube.2016.12.004

Cited by 32 publications

(44 citation statements)

References 61 publications

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“…As early as 1933 ( Figure 2), nutrient deprivation was indicated as able to induce the NRP state in TB [33,68]. In recent years, this work has been further developed and has shown granuloma-based bacteria that are not only nutrient starved [32,69], they are restricted to odd chain fatty acids as the sole carbon source, namely cholesterol [21,22].…”

Section: Nutrient Deprivation and Selective Carbon Sourcesmentioning

confidence: 89%

“…Conditions found within the granuloma are key to the NRP state and accurately mimicking these conditions in vitro allows for the development of new models. The environment in the granuloma has a distinct profile that includes hypoxia [17,31], nutrient deprivation [32][33][34], limited carbon sources [21,22,34] and a high concentration of Nitric Oxide (NO) [35]. Most of the above environmental conditions have been shown to induce the NRP state in mycobacteria individually.…”

Section: Conditions Within the Granulomamentioning

confidence: 99%

“…The term "latent" often refers to a dormant state with no active metabolic processes and no response to environmental stimulus. This is not true in the case of TB: its metabolism is regulated to an essential level but is still functional [20][21][22]. The phrase Non-Replicating Persistence (NRP) was first used by Wayne in 1976 and has since become adopted as the appropriate term to describe this state [17,23].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Modelling a Silent Epidemic: A Review of the <em>In Vitro </em>Models of Latent Tuberculosis

Gibson¹,

Harrison²,

Cox³

2018

Preprint

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Tuberculosis (TB) is the primary cause of death by a single infectious agent; responsible for around two million deaths in 2016. A major virulence factor of TB is the ability to enter a latent or Non-Replicating Persistent (NRP) state which is presumed untreatable. Approximately, 1.7 billion people are latently infected with TB and on reactivation many of these infections are drug resistant. As the current treatment is ineffective and diagnosis remains poor, millions of people have the potential to reactivate into active TB disease. The immune system seeks to control the TB infection by containing the bacteria in a granuloma, where it is exposed to stressful anaerobic and nutrient deprived conditions. It is thought to be these environmental conditions that trigger the NRP state. A number of in vitro models have been developed that mimic conditions within the granuloma to a lesser or greater extent. These different models have all been utilised for the research of different characteristics of NRP Mycobacterium tuberculosis, however their disparity in approach and physiological relevance often results in inconsistencies and a lack of consensus between studies. This review provides a summation of the different NRP models and a critical analysis of their respective advantages and disadvantages relating to their physiological relevance.

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Section: Nutrient Deprivation and Selective Carbon Sourcesmentioning

confidence: 89%

Section: Conditions Within the Granulomamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Modelling a Silent Epidemic: A Review of the <em>In Vitro </em>Models of Latent Tuberculosis

Gibson¹,

Harrison²,

Cox³

2018

Preprint

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“…The foamy aspect of these cells results from the accumulation of neutral lipids, typically triacylglycerides and esterified and non-esterified sterols. These foamy macrophages are nutrient-rich reservoirs for Mtb persistence [6,7].Published data support that regulating cholesterol in macrophages may affect the intracellular growth of Mtb [8,9]. However, questions remain regarding the use of hypolipidemic therapy for the treatment of Mtb infection [10].…”

mentioning

confidence: 99%

“…Published data support that regulating cholesterol in macrophages may affect the intracellular growth of Mtb [8,9]. However, questions remain regarding the use of hypolipidemic therapy for the treatment of Mtb infection [10].…”

mentioning

confidence: 99%

Fenofibrate Facilitates Post-Active Tuberculosis Infection in Macrophages and is Associated with Higher Mortality in Patients under Long-Term Treatment

Liu

Tsai

et al. 2020

JCM

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Background: Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that infects and persists in macrophages. This study aimed to investigate the effects of long-term fenofibrate treatment in patients with tuberculosis (TB), and the intracellular viability of Mtb in human macrophages. Methods: Epidemiological data from the National Health Insurance Research Database of Taiwan were used to present outcomes of TB patients treated with fenofibrate. In the laboratory, we assessed Mtb infection in macrophages treated with or without fenofibrate. Mtb growth, lipid accumulation in macrophages, and expression of transcriptional genes were examined. Results: During 11 years of follow-up, TB patients treated with fenofibrate presented a higher risk of mortality. Longer duration of fenofibrate use was associated with a significantly higher risk of mortality. Treatment with fenofibrate significantly increased the number of bacilli in human macrophages in vitro. Fenofibrate did not reduce, but induced an increasing trend in the intracellular lipid content of macrophages. In addition, dormant genes of Mtb, icl1, tgs1, and devR, were markedly upregulated in response to fenofibrate treatment. Our results suggest that fenofibrate may facilitate intracellular Mtb persistence. Conclusions: Our data shows that long-term treatment with fenofibrate in TB patients is associated with a higher mortality. The underlying mechanisms may partly be explained by the upregulation of Mtb genes involved in lipid metabolism, enhanced intracellular growth of Mtb, and the ability of Mtb to sustain a nutrient-rich reservoir in human macrophages, observed during treatment with fenofibrate. people, it still presents the highest incidence and mortality rate [2]. This disease is transmitted via inhalation of aerosolized bacilli, which then replicate within alveolar macrophages in lung tissue. In the host, immune cells can be recruited to the affected sites, and encase the invading mycobacteria, forming a structure known as the granuloma [3,4]. A granuloma is composed of infected alveolar macrophages, monocytes, multinucleated giant cells, epithelioid cells, and most notably, foamy macrophages [4,5]. The foamy aspect of these cells results from the accumulation of neutral lipids, typically triacylglycerides and esterified and non-esterified sterols. These foamy macrophages are nutrient-rich reservoirs for Mtb persistence [6,7].Published data support that regulating cholesterol in macrophages may affect the intracellular growth of Mtb [8,9]. However, questions remain regarding the use of hypolipidemic therapy for the treatment of Mtb infection [10]. By the activation of peroxisome proliferator activated receptor α (PPARα), mainly expressed in the liver, heart, monocytes, and macrophages, fenofibrate increases lipolysis and elimination of lipids from plasma [11][12][13]. It is commonly prescribed for the treatment of hypertriglyceridemia or mixed hyperlipidemia [13][14][15]. This study aimed to investigate epidemiological data to obtain outcomes of TB...

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Biochemical characterization of acyl-coenzyme A synthetases involved in mycobacterial steroid side-chain catabolism and molecular design: synthesis of an anti-mycobacterial agent

Yang

et al. 2019

3 Biotech

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The metabolism of host cholesterol by Mycobacterium tuberculosis is an important factor for both its virulence and pathogenesis. However, the rationale for this cholesterol metabolism has not been fully understood yet. In the present study, we characterized several previously undescribed acyl-CoA synthetases that are involved in the steroid side-chain degradation in Mycobacterium smegmatis, and an analogue of intermediate from steroid degradation, 5′-O-(lithocholoyl sulfamoyl) adenosine (LCA-AMS), was successfully designed and synthesized to be used as a specific anti-mycobacterial agent. The acyl-CoA synthetases exhibited strong preferences for the length of side chain. FadD19 homologs, including FadD19 (MSMEG_5914), FadD19-2 (MSMEG_2241), and FadD19-4 (MSMEG_3687), are unanimously favorable cholesterol with a C8 alkanoate side chain. FadD17 (MSMEG_5908) and FadD1 (MSMEG_4952) showed high preferences for steroids, containing a C5 alkanoate side chain. FadD8 (MSMEG_1098) exhibited specific activity toward cholestenoate with a C8 alkanoate side chain. An acylsulfamoyl analogue of lithocholate, 5′-O-(lithocholoyl sulfamoyl) adenosine (LCA-AMS), was designed and synthesized. As expected, the intermediate analogue not only specifically inhibited those steroid-activated acyl-CoA synthetases, but also selectively inhibited the growth of mycobacterial species, including M. tuberculosis, M. smegmatis, and Mycobacterium neoaurum. Overall, our research advanced our understanding of mycobacterial steroid degradation and provided new insights to develop novel mechanism-based anti-mycobacterial agents.

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Cholesterol plays a larger role during Mycobacterium tuberculosis in vitro dormancy and reactivation than previously suspected

Cited by 32 publications

References 61 publications

Modelling a Silent Epidemic: A Review of the <em>In Vitro </em>Models of Latent Tuberculosis

Modelling a Silent Epidemic: A Review of the <em>In Vitro </em>Models of Latent Tuberculosis

Fenofibrate Facilitates Post-Active Tuberculosis Infection in Macrophages and is Associated with Higher Mortality in Patients under Long-Term Treatment

Biochemical characterization of acyl-coenzyme A synthetases involved in mycobacterial steroid side-chain catabolism and molecular design: synthesis of an anti-mycobacterial agent

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