Innate immunity in tuberculosis: how the sensing of mycobacteria and tissue damage modulates macrophage death

Amaral, Eduardo Pinheiro; Lassounskaia, Elena; Lima, Maria Regina D'Império

doi:10.1016/j.micinf.2015.09.005

Cited by 49 publications

(39 citation statements)

References 121 publications

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“…In our previous studies, we demonstrated that the ability of hypervirulent clinical isolates to induce necrotic cell death in macrophage cultures was significantly higher, when compared with laboratory strains [17,10,11]. Additionally, massive liberation of intracellular danger signals, such as ATP, from dying phagocytes triggers the activation of pro-inflammatory mechanisms contributing to death of lung cells in vivo [18]. Recently, we demonstrated the role of the purinergic P2X7 receptor, a sensor of extracellular ATP, in the promotion of necrotic pulmonary pathology in C57BL/6 mice, presumably through NLRP3 inflammasome-dependent induction of vicious cycles of leukocyte recruitment, cell death and production of pro-inflammatory cytokines, including IL-1β [11].…”

Section: Discussionmentioning

confidence: 99%

Hypervirulent Mycobacterium tuberculosis strain triggers necrotic lung pathology associated with enhanced recruitment of neutrophils in resistant C57BL/6 mice

et al. 2017

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Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb) that in most cases induces irreversible necrosis of lung tissue as a result of excessive inflammatory reactions. The murine model of TB in resistant C57BL/6 mice infected with reference Mtb strains is widely used in TB studies; however, these mice do not show a necrotic pathology, which restricts their use in studies of irreversible tissue damage. Recently, we demonstrated that necrotic lung lesions could be induced in the C57BL/6 mice by highly virulent Mtb strains belonging to the modern Beijing sublineage. However, the pathogenic mechanisms leading to necrosis in this model were not elucidated. In this study, we investigated the dynamics of lung lesions in mice infected with highly virulent Beijing Mtb strain M299, compared with those infected with laboratory Mtb strain H37Rv. The data demonstrate that necrotic lung lesions in mice infected by the strain M299 were associated with enhanced recruitment of myeloid cells, especially neutrophils, and increased levels of proinflammatory cytokines, consistent with exacerbated inflammation. High levels of IFN-γ production contributed to the control of bacterial growth. Further progression to chronic disease was associated with a reduction in the levels of inflammatory mediators in the lungs, the accumulation of foamy macrophages and partial healing of the necrotic tissue by fibrosis. At a late stage of disease, degradation of foamy cells resulted in the liberation of accumulated lipids and persisting bacilli and further activation of inflammation, which promoted lung consolidation. Overall, our studies show that C57BL/6 mice infected with highly virulent Mtb strain may serve as a TB model reproducing an exacerbated inflammatory response in a resistant host to hypervirulent mycobacteria, leading to irreversible necrotic lung lesions.

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Section: Discussionmentioning

confidence: 99%

Hypervirulent Mycobacterium tuberculosis strain triggers necrotic lung pathology associated with enhanced recruitment of neutrophils in resistant C57BL/6 mice

et al. 2017

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“…In this HTS system, human macrophages of THP-1 cells and lung epithelial cells of A549 serve as mycobacterium-infected cells since primary types of these cells are the main host targets for MTB bacilli infection181920. We utilized MSL for infection and reporting of these host cells in the cell-based HTS, so that HTS assay could be done in BSL2 (Biosafety Shelter Laboratory, Level 2) lab without a special need for BSL3 operation.…”

Section: Discussionmentioning

confidence: 99%

Bis-biguanide dihydrochloride inhibits intracellular replication of M. tuberculosis and controls infection in mice

Shen

Wang

Zeng

et al. 2016

Sci Rep

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While there is an urgent need to develop new and effective drugs for treatment of tuberculosis (TB) and multi-drug resistant TB (MDR-TB), repurposing FDA (U.S. Food and Drug Administration) -approved drugs for development of anti-TB agents may decrease time and effort from bench to bedside. Here, we employed host cell-based high throughput screening (HTS) assay to screen and characterize FDA-approved, off-patent library drugs for anti-Mycobacterium tuberculosis (MTB) activities. The cell-based HTS allowed us to identify an anti-cancer drug of bis-biguanide dihydrochloride (BBD) as potent anti-mycobacteria agent. Further characterization showed that BBD could inhibit intracellular and extracellular growth of M. smegmatis and slow-growing M. bovis BCG. BBD also potently inhibited replication of clinically-isolated MTB and MDR-TB strains. The proof-of-concept study showed that BBD treatment of MTB-infected mice could significantly decrease CFU counts in the lung and spleen. Notably, comparative evaluation showed that MTB CFU counts in BBD-treated mice were lower than those in rifampicin-treated mice. No apparent BBD side effects were found in BBD-treated mice. Thus, our findings support further studies to develop BBD as a new and effective drug against TB and MDR-TB.

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“…140 Shree and colleagues 141 reported that Rv3042c (also known as MtSerB2), a bacterial haloacid dehalogenase phosphatase, interacts with HSP90, HSP70, and HSP27 and inhibits apoptotic pathways in host cells, which in turn has been shown to be required for mycobacterial elimination. 142 Indeed, MtSerB2 dephosphorylates NF-κB and MAPK-p38, which results in cell deactivation and failure of host resistance against M. tuberculosis. Pharmacologic inhibition of MtSerB2 with clofazimine, a drug used for the treatment of extensively drug resistant and multidrug resistant TB cases, is thought to successfully restore antimycobacterial cellular response, 141 reinforcing the idea that M. tuberculosis directly dampens NF-κB activation to suppress host resistance.…”

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confidence: 99%

Nuclear Factor κB Activation Pathways During Infection

Andrade¹,

Amaral²

2017

CCI

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ABSTRACT:The interactions between pathogens and host cells and the way by which the immune response is modulated during this process ultimately dictate the fate of infection. Host phagocytes exposed to Mycobacterium tuberculosis (M. tuberculosis) sense microbial-associated molecular patterns and activate a series of signaling pathways. In this setting, activation of the nuclear factor κB (NF-κB) initiates transcription of several key genes involved in orchestration of antimycobacterial effector functions. This review describes these major pathways that govern the outcome of host phagocytes infected with M. tuberculosis. Furthermore, we highlight evidence of how M. tuberculosis modulates activation of NF-κB pathways to evade the host antimycobacterial defense.

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Innate immunity in tuberculosis: how the sensing of mycobacteria and tissue damage modulates macrophage death

Cited by 49 publications

References 121 publications

Hypervirulent Mycobacterium tuberculosis strain triggers necrotic lung pathology associated with enhanced recruitment of neutrophils in resistant C57BL/6 mice

Hypervirulent Mycobacterium tuberculosis strain triggers necrotic lung pathology associated with enhanced recruitment of neutrophils in resistant C57BL/6 mice

Bis-biguanide dihydrochloride inhibits intracellular replication of M. tuberculosis and controls infection in mice

Nuclear Factor κB Activation Pathways During Infection

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