MiR-155–regulated molecular network orchestrates cell fate in the innate and adaptive immune response to
            <i>Mycobacterium tuberculosis</i>

Rothchild, Alissa C.; Sissons, James; Shafiani, Shahin; Plaisier, Christopher L.; Min, Deborah; Mai, Dat; Gilchrist, Mark; Peschon, Jacques J.; Larson, Ryan; Bergthaler, Andréas; Baliga, Nitin S.; Urdahl, Kevin B.; Aderem, Alan

doi:10.1073/pnas.1608255113

Cited by 111 publications

(100 citation statements)

References 41 publications

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“…10 minutes prior to harvest. Single-cell suspensions of lung cells were prepared by Liberase Blendzyme 3 (Roche) digestion of perfused lungs as previously described 48 . Cells from spleens were prepared as previously described (Spleen digestion protocol, Miltenyi Biotec).…”

Section: Cell Isolation Analysis and Sortingmentioning

confidence: 99%

Latent Mycobacterium tuberculosis infection provides protection for the host by changing the activation state of the innate immune system

Nemeth¹,

Rothchild³

et al. 2019

Preprint

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An efficacious vaccine against adult tuberculosis (TB) remains elusive. Progress is hampered by an incomplete understanding of the immune mechanisms that protect against infection with Mycobacterium tuberculosis (Mtb), the causative agent of TB 1 . Over 90% of people who become infected with Mtb mount an immune response that contains the bacteria indefinitely, leading to a state known as "latent TB infection" (LTBI) 2 . A significant body of epidemiologic evidence indicates that LTBI protects against active TB after re-exposure, offering an intriguing avenue to identifying protective mechanisms 3,4 . We show that in a mouse model, LTBI is highly protective against infection with Mtb for up to 100 days following aerosol challenge. LTBI mice are also protected against heterologous bacterial challenge (Listeria monocytogenes) and disseminated melanoma suggesting that protection is in part mediated by alterations in the activation state of the innate immune system. Protection is associated with elevated activation of alveolar macrophages (AM), the first cells that respond to inhaled Mtb, and accelerated recruitment of Mtb-specific T cells to the lung parenchyma upon aerosol challenge. Systems approaches, including transcriptome analysis of both naïve and infected AMs, as well as ex vivo functional assays, demonstrate that LTBI reconfigures the response of tissue resident AMs.. Furthermore, we demonstrate that both LTBI mice and latently infected humans show similar alterations in the relative proportions of circulating innate immune cells, suggesting that the same cellular changes observed in the LTBI mouse model are also occurring in humans. Therefore, we argue that under certain circumstances, LTBI could be beneficial to the host by providing protection against subsequent Mtb exposure. * * CD11b PerCPCy5.5

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Section: Cell Isolation Analysis and Sortingmentioning

confidence: 99%

Latent Mycobacterium tuberculosis infection provides protection for the host by changing the activation state of the innate immune system

Nemeth¹,

Rothchild³

et al. 2019

Preprint

Self Cite

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“…While it is not clear to what extent SHIP downregulation contributes to the oncogenic effects of miR-155, SHIP has been reported to have roles in malignancy as discussed below. Mir-155 regulation of SHIP has also been reported in the context of viral [73] and bacterial [74] infections, and may functionally impact macrophage and T-cell survival [75], DC maturation [76], and G-CSF induced mobilization of hematopoietic stem cells [77].…”

Section: Regulation Of Ship Expression Levelsmentioning

confidence: 99%

Regulation of immune cell signaling by SHIP1: A phosphatase, scaffold protein, and potential therapeutic target

2017

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The phosphoinositide phosphatase SHIP is a critical regulator of immune cell activation. Despite considerable study, the mechanisms controlling SHIP activity to ensure balanced cell activation remain incompletely understood. SHIP dampens BCR signaling in part through its association with the inhibitory coreceptor Fc gamma receptor IIB, and serves as an effector for other inhibitory receptors in various immune cell types. The established paradigm emphasizes SHIP's inhibitory receptor‐dependent function in regulating phosphoinositide 3‐kinase signaling by dephosphorylating the phosphoinositide PI(3,4,5)P3; however, substantial evidence indicates that SHIP can be activated independently of inhibitory receptors and can function as an intrinsic brake on activation signaling. Here, we integrate historical and recent reports addressing the regulation and function of SHIP in immune cells, which together indicate that SHIP acts as a multifunctional protein controlled by multiple regulatory inputs, and influences downstream signaling via both phosphatase‐dependent and ‐independent means. We further summarize accumulated evidence regarding the functions of SHIP in B cells, T cells, NK cells, dendritic cells, mast cells, and macrophages, and data suggesting defective expression or activity of SHIP in autoimmune and malignant disorders. Lastly, we discuss the biological activities, therapeutic promise, and limitations of small molecule modulators of SHIP enzymatic activity.

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“…Our data suggest that the initial host response to Mtb infection is relatively anti-inflammatory and may contribute to the extended time required for antigen transport to the draining lymph node and subsequent T cell activation and adaptive immune control ( 2 ). Previous studies, including our own, have described Mtb-infected macrophages in vitro up-regulating pro-inflammatory genes primarily driven by NF-κB or type I IFN signaling ( 16, 18, 33, 35 ). Here we describe a unique Nrf2-driven transcriptional signature expressed in Mtb-infected AMs in vivo .…”

Section: Discussionmentioning

confidence: 76%

“…We isolated AMs by BAL from naïve WT mice, allowed them to adhere for 18 hours, infected them with H37Rv, and measured their transcriptional response and ability to control bacterial growth. In parallel, we performed identical experiments with bone-marrow-derived macrophages (BMDMs), which have been used extensively, including by our group, to investigate how macrophages respond to Mtb ( 35 ). Similar to their response to Mtb infection in vivo , AMs displayed little to no increase in pro-inflammatory gene expression (including Il1b, Il6 and Nos2 ) after infection in vitro , while BMDMs greatly up-regulated these genes ( Fig 6A ).…”

Section: Resultsmentioning

confidence: 99%

Alveolar macrophages up-regulate a non-classical innate response toMycobacterium tuberculosisinfectionin vivo

Nemeth

et al. 2019

Preprint

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Alveolar macrophages (AMs) are the first cells to be infected during Mycobacterium tuberculosis (Mtb) infection. Thus the AM response to infection is the first of many steps leading to initiation of the adaptive immune response, which is required for efficient control of infection. A hallmark of Mtb infection is the delay of the adaptive response, yet the mechanisms responsible for this delay are largely unknown. We developed a system to identify, sort and analyze Mtb-infected AMs from the lung within the first 10 days of infection. In contrast to what has been previously described using in vitro systems, we find that Mtb-infected AMs up-regulate a cell-protective antioxidant transcriptional signature that is dependent on the lung environment and not dependent on bacterial virulence. Computational approaches including pathway analysis and transcription factor binding motif enrichment analysis identify Nrf2 as a master regulator of the response of AMs to Mtb infection. Using knock-out mouse models, we demonstrate that Nrf2 drives the expression of the cell protective transcriptional program and impairs the ability of the host to control bacterial growth over the first 10 days of infection. Mtb-infected AMs exhibit a highly delayed pro-inflammatory response, and comparisons with uninfected AMs from the same infected animals demonstrate that inflammatory signals in the lung environment are blocked in the Mtb-infected cells. Thus, we have identified a novel lung-specific transcriptional response to Mtb infection that impedes AMs from responding rapidly to intracellular infection and thereby hinders the overall immune response.One Sentence SummaryIn response to Mtb infection in vivo, alveolar macrophages fail to up-regulate the canonical pro-inflammatory innate response and instead induce an Nrf2-dependent cell protective transcriptional program, which in turn impairs the host’s control of bacterial growth.

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MiR-155–regulated molecular network orchestrates cell fate in the innate and adaptive immune response to Mycobacterium tuberculosis

Cited by 111 publications

References 41 publications

Latent Mycobacterium tuberculosis infection provides protection for the host by changing the activation state of the innate immune system

Latent Mycobacterium tuberculosis infection provides protection for the host by changing the activation state of the innate immune system

Regulation of immune cell signaling by SHIP1: A phosphatase, scaffold protein, and potential therapeutic target

Alveolar macrophages up-regulate a non-classical innate response toMycobacterium tuberculosisinfectionin vivo

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