The immune landscape in tuberculosis reveals populations linked to disease and latency

Esaulova, Ekaterina; Das, Shibali; Singh, Dhiraj Kumar; Choreño-Parra, José Alberto; Swain, Amanda; Arthur, Laura L.; Rangel-Moreno, Javier; Ahmed, Mushtaq; Singh, Bindu; Gupta, Ananya; Fernández-López, Luis Alejandro; García-Hernández, María de la Luz; Bucşan, Allison N.; Moodley, Chivonne; Mehra, Smriti; Garcı́a-Latorre, Ethel; Zúñiga, Joaquı́n; Atkinson, Jeffrey J.; Kaushal, Deepak; Artyomov, Maxim N.; Khader, Shabaana A.

doi:10.1016/j.chom.2020.11.013

Cited by 138 publications

(166 citation statements)

References 64 publications

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“…In-depth and unbiased pro ling of pulmonary immune cell populations led us to discover that CXCL9/10 expression in pulmonary macrophages is enhanced upon coinfection but not after type I IFN receptor blockade, which was also validated with multiplex immuno uorescence analysis and ELISA. Consistent with our ndings, Esaulova et al also suggested that both type I and II IFN signals accumulate in pulmonary active disease, but they could not identify the events thereafter 70 . In comparison, we further tracked the next events after increased CXCL9/10 expression.…”

Section: Discussionsupporting

confidence: 83%

“…Indeed, Cai et al performed scRNA-seq using human PBMCs from healthy controls and individuals with latent or active tuberculosis 69 . Additionally, Esaulova et al recently described the immune landscape of TB latency and disease in the lungs of nonhuman primates, de ning the features of pulmonary active TB, such as the accumulation of IFN producers and responders in the lung 70 . Here, single-cell analysis played a key role in providing clues to discover the mechanism by which viral infection disrupts immune responses and exacerbates Mtb-mediated pathology.…”

Section: Discussionmentioning

confidence: 99%

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Viral coinfection promotes tuberculosis immunopathogenesis by type I IFN signaling-dependent impediment of Th1 pulmonary influx

Shin

Kang

Kwon

et al. 2021

Preprint

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is often exacerbated upon coinfection, but the underlying immunological mechanisms remain unclear. Here, to elucidate these mechanisms, we used a Mtb and lymphocytic choriomeningitis virus coinfection model. Viral coinfection significantly suppressed Mtb-specific IFN-γ production, with elevated bacterial loads and hyperinflammation in the lungs. Type I IFN signaling blockade rescued the Mtb-specific IFN-γ response and ameliorated lung immunopathology. Single-cell sequencing, tissue immunofluorescence staining, and adoptive transfer experiments revealed that type I IFN signaling produced in response to viral infection inhibited CXCL9/10 production in myeloid cells, resulting in impaired pulmonary migration of Mtb-specific CD4+ T cells from lymph nodes. Thus, virus coinfection-induced type I IFN signaling prior to the pulmonary localization of Mtb-specific Th1 cells exacerbates TB immunopathogenesis by impeding the Mtb-specific Th1 cell influx. Our study highlights another novel negative role of viral coinfection and/or type I IFNs in delaying Mtb-specific Th1 responses in the lung.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Viral coinfection promotes tuberculosis immunopathogenesis by type I IFN signaling-dependent impediment of Th1 pulmonary influx

Shin

Kang

Kwon

et al. 2021

Preprint

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“…IFNγ-expressing NK cells have been described to accumulate in the pleural fluid of patients with TB pleurisy [112]. Individuals with LTBI exhibited increased numbers of circulating NK cells in peripheral blood and these cells exhibited increased cytotoxic capacity associated with high expression of granzyme B and perforin [113], and accumulation of CD27 + NK cells in the lung has also been associated with LTBI in nonhuman primates [114]. In contrast, circulating NK cells were markedly decreased in peripheral blood of patients with active TB [113].…”

Section: Epithelial Barriers and Innate Immunitymentioning

confidence: 99%

Microbiome-immune interactions in tuberculosis

2021

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Tuberculosis (TB) remains an infectious disease of global significance and a leading cause of death in low- and middle-income countries. Significant effort has been directed towards understanding Mycobacterium tuberculosis genomics, virulence, and pathophysiology within the framework of Koch postulates. More recently, the advent of “-omics” approaches has broadened our appreciation of how “commensal” microbes have coevolved with their host and have a central role in shaping health and susceptibility to disease. It is now clear that there is a diverse repertoire of interactions between the microbiota and host immune responses that can either sustain or disrupt homeostasis. In the context of the global efforts to combatting TB, such findings and knowledge have raised important questions: Does microbiome composition indicate or determine susceptibility or resistance to M. tuberculosis infection? Is the development of active disease or latent infection upon M. tuberculosis exposure influenced by the microbiome? Does microbiome composition influence TB therapy outcome and risk of reinfection with M. tuberculosis? Can the microbiome be actively managed to reduce risk of M. tuberculosis infection or recurrence of TB? Here, we explore these questions with a particular focus on microbiome-immune interactions that may affect TB susceptibility, manifestation and progression, the long-term implications of anti-TB therapy, as well as the potential of the host microbiome as target for clinical manipulation.

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“…Conversely, TBM patients displayed a higher amount of cytotoxic CD56 dim CD16 + NK cells in the circulation. Cytotoxicity mediated by NK cells is protective for some neurological complications of infections [ 51 , 52 ], and increased numbers of cytotoxic NK cells in the lung are a hallmark that defines latency over active disease in macaques infected with Mtb [ 28 ]. Thus, the increased abundance of CD56 dim CD16 + NK cells in TBM patients' blood might reflect an active mobilization of these cells to the CNS as an attempt to control the local infection.…”

Section: Discussionmentioning

confidence: 99%

“…Several phenotypical and functional deficiencies are displayed by peripheral NK cells from PTB patients compared to LTBI individuals, supporting a role for NK cells in defenses against pulmonary Mtb [ 15 , 20 – 24 ]. Strikingly, NK cell subsets with adaptive properties expand in mice, primates, and humans with TB, making them potential targets for vaccines [ 25 – 28 ]. However, the phenotype and function of NK cells in TB patients that develop extrapulmonary disease manifestations, including TBM, has not been extensively addressed.…”

Section: Introductionmentioning

confidence: 99%

Phenotype of Peripheral NK Cells in Latent, Active, and Meningeal Tuberculosis

Choreño-Parra

Jiménez-Álvarez

Maldonado-Díaz

et al. 2021

Journal of Immunology Research

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The mechanisms underlying the immunopathology of tuberculous meningitis (TBM), the most severe clinical form of extrapulmonary tuberculosis (TB), are not understood. It is currently believed that the spread of Mycobacterium tuberculosis (Mtb) from the lung is an early event that occurs before the establishment of adaptive immunity. Hence, several innate immune mechanisms may participate in the containment of Mtb infection and prevent extrapulmonary disease manifestations. Natural killer (NK) cells participate in defensive processes that distinguish latent TB infection (LTBI) from active pulmonary TB (PTB). However, their role in TBM is unknown. Here, we performed a cross-sectional analysis of circulating NK cellCID="C008" value="s" phenotype in a prospective cohort of TBM patients ( n = 10 ) using flow cytometry. Also, we addressed the responses of memory-like NK cell subpopulations to the contact with Mtb antigens in vitro. Finally, we determined plasma levels of soluble NKG2D receptor ligands in our cohort of TBM patients by enzyme-linked immunosorbent assay (ELISA). Our comparative groups consisted of individuals with LTBI ( n = 11 ) and PTB ( n = 27 ) patients. We found that NK cells from TBM patients showed lower absolute frequencies, higher CD69 expression, and poor expansion of the CD45RO+ memory-like subpopulation upon Mtb exposure in vitro compared to LTBI individuals. In addition, a reduction in the frequency of CD56brightCD16- NK cells characterized TBM patients but not LTBI or PTB subjects. Our study expands on earlier reports about the role of NK cells in TBM showing a reduced frequency of cytokine-producing cells compared to LTBI and PTB.

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The immune landscape in tuberculosis reveals populations linked to disease and latency

Cited by 138 publications

References 64 publications

Viral coinfection promotes tuberculosis immunopathogenesis by type I IFN signaling-dependent impediment of Th1 pulmonary influx

Viral coinfection promotes tuberculosis immunopathogenesis by type I IFN signaling-dependent impediment of Th1 pulmonary influx

Microbiome-immune interactions in tuberculosis

Phenotype of Peripheral NK Cells in Latent, Active, and Meningeal Tuberculosis

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