Dying to Live: How the Death Modality of the Infected Macrophage Affects Immunity to Tuberculosis

Divangahi, Maziar; Behar, Samuel M.; Remold, Heinz G.

doi:10.1007/978-1-4614-6111-1_6

Cited by 107 publications

(94 citation statements)

References 69 publications

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“…Some groups have previously attributed delayed T-cell priming to a lack of sufficient antigenic load during the early phase of M.tb infection [8,30], which in turn has been suggested to be due to the virulence of M.tb itself [16,31]. This notion is based on the observation that while the cells infected with attenuated M.tbH37Ra undergo apoptotic cell death pathways, virulent M.tbH37Rv infection tends to promote necrotic cell death, thus preventing the efficient generation of mycobacterial antigen and subsequently, delaying T-cell priming [15,16,32].…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, our current study has identified the delayed activation of early innate DC responses in the lung and draining lymph nodes to be an important mechanism accounting for delayed protective Th1-type immunity. Thus, the lung deposition of a selected innate TLR ligand (FimH) particularly adept at APC activation is able to accelerate protective Th1-type immunity by facilitating DC migration to the lung and draining lymph nodes, thus enhancing DC antigen presentation and Th1-cell priming.Some groups have previously attributed delayed T-cell priming to a lack of sufficient antigenic load during the early phase of M.tb infection [8,30], which in turn has been suggested to be due to the virulence of M.tb itself [16,31]. This notion is based on the observation that while the cells infected with attenuated M.tbH37Ra undergo apoptotic cell death pathways, virulent M.tbH37Rv infection tends to promote necrotic cell death, thus preventing the efficient generation of mycobacterial antigen and subsequently, delaying T-cell priming [15,16,32].…”

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confidence: 99%

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Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

et al. 2014

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The immune mechanisms underlying delayed induction of Th1-type immunity in the lungs following pulmonary mycobacterial infection remain poorly understood. We have herein investigated the underlying immune mechanisms for such delayed responses and whether a selected innate immune-modulating strategy can accelerate Th1-type responses. We have found that, in the early stage of pulmonary infection with attenuated Mycobacterium tuberculosis (M.tb H37Ra), the levels of infection in the lung continue to increase logarithmically until days 14 and 21 postinfection in C57BL/6 mice. The activation of innate immune responses, particularly DCs, in the lung is delayed. This results in a delay in the subsequent downstream immune responses including the migration of antigen-bearing DCs to the draining lymph node (dLN), the Th1-cell priming in dLN, and the recruitment of Th1 cells to the lung. However, single lung mucosal exposure to the TLR agonist FimH postinfection is able to accelerate protective Th1-type immunity via facilitating DC migration to the lung and draining lymph nodes, enhancing DC antigen presentation and Th1-cell priming. These findings hold implications for the development of immunotherapeutic and vaccination strategies and suggest that enhancement of early innate immune activation is a viable option for improving Th1-type immunity against pulmonary mycobacterial diseases.Keywords: DCs r Delayed Th1 immunity r FimH r Mycobacterium r Tuberculosis Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPulmonary mycobacterial infection is mainly caused by Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), and by other slow growing less virulent nontuberculous Correspondence: Dr. Zhou Xing e-mail: xingz@mcmaster.ca mycobacterial (NTM) species including M. avium and M. kasasii. The continuing high global incidence of and death due to tuberculosis infections [1] and the dramatic increase in pulmonary NTM disease globally over the past three decades [2] underscores the need to further understand the complex host immune responses to mycobacterial exposure in order to develop effective prophylactic and therapeutic strategies.Protective immunity against mycobacterial infection requires the presence of a robust adaptive Th1-type response at the site of Eur. J. Immunol. 2014Immunol. . 44: 1375Immunol. -1386 infection. Upon exposure to the bacterium, mycobacteria is taken up by sentinel APCs such as DCs and delivered to the draining lymph node (dLN) [3,4]. On arrival, these APCs present mycobacterial antigen to naive T cells within the dLN, thereby priming the antigen-specific T cells to a Th1 phenotype and stimulating their expansion [5]. The Th1 cells are then recruited back to the site of infection, and the secretion of Th1 cytokines such as IFN-γ by these cells is critical to activation of infected APCs to control bacterial growth [6]. However, one of the defining characteristics of host defense toward mycobacterial patho...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

et al. 2014

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“…Death of M. tuberculosisinfected macrophages is caused by two processes: necrosis and apoptosis. Necrosis is characterized by metabolic collapse and loss of membrane integrity and is used by M. tuberculosis to exit destroyed cells, evade host defenses, and disseminate to other tissues and eventually to new hosts (10). By contrast, apoptosis of the infected macrophages helps the host to control the bacterial infection (11).…”

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confidence: 99%

An outer membrane channel protein of Mycobacterium tuberculosis with exotoxin activity

Danilchanka¹,

Sun²,

Pavlenok³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

109

136

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The ability to control the timing and mode of host cell death plays a pivotal role in microbial infections. Many bacteria use toxins to kill host cells and evade immune responses. Such toxins are unknown in Mycobacterium tuberculosis. Virulent M. tuberculosis strains induce necrotic cell death in macrophages by an obscure molecular mechanism. Here we show that the M. tuberculosis protein Rv3903c (channel protein with necrosis-inducing toxin, CpnT) consists of an N-terminal channel domain that is used for uptake of nutrients across the outer membrane and a secreted toxic C-terminal domain. Infection experiments revealed that CpnT is required for survival and cytotoxicity of M. tuberculosis in macrophages. Furthermore, we demonstrate that the C-terminal domain of CpnT causes necrotic cell death in eukaryotic cells. Thus, CpnT has a dual function in uptake of nutrients and induction of host cell death by M. tuberculosis.transport | pore | secretion

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“…MTB infection mainly results in necrosis, while attenuated mutant strains including BCG and H37Ra primarily induce apoptosis [113]. Most of the factors that have been described as anti-apoptotic molecules play roles in the bacterial redox homeostasis (katG, sodA, secA2 and pknE) because phagosome ROS promotes the apoptosis.…”

Section: Inhibition Of Apoptosismentioning

confidence: 99%

“…Apoptosis reduces the viability of different mycobacterial species, including MTB; in fact many attenuated strains of mycobacteria induce more apoptosis than their wild type counterparts and exists a reciprocal relationship between virulence and apoptosis [113]. MTB infection mainly results in necrosis, while attenuated mutant strains including BCG and H37Ra primarily induce apoptosis [113].…”

Section: Inhibition Of Apoptosismentioning

confidence: 99%

Virulence Factors and Pathogenicity of Mycobacterium

Echeverría-Valencia¹,

Flores-Villalva²,

Espitia³

2018

Mycobacterium - Research and Development

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Virulence, is referred as the ability of a pathogen to cause disease, and for mycobacteria it depends on their ability to reside within host cells and evade the microbicidal mechanisms of macrophages. The outcome of tuberculosis (TB) infection is highly variable and it seems that the closest relationship between the Mycobacterium genre and humans has shaped the mycobacterial genome to encode bacterial factors that reflects a highly evolved and coordinated program of immune evasion strategies that interfere with both innate and adaptive immunity causing disease even in fully immunocompetent host. Although Mycobacterium tuberculosis (MTB) does not have classical virulence factors, it has described many virulence-associated genes and virulence lifestyle genes from Mycobacterium tuberculosis complex (MTBC). In this chapter, we describe the most important gene/molecule involved in the host defense modulation response, also the plethora of strategies to evade immune mechanisms of macrophage. We review the main genes whose inactivation in the mycobacterial genome leads to a measurable loss in virulence in the different validated TB models.

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Dying to Live: How the Death Modality of the Infected Macrophage Affects Immunity to Tuberculosis

Cited by 107 publications

References 69 publications

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

Restoration of innate immune activation accelerates Th1‐cell priming and protection following pulmonary mycobacterial infection

An outer membrane channel protein of Mycobacterium tuberculosis with exotoxin activity

Virulence Factors and Pathogenicity of Mycobacterium

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