Chemokines in tuberculosis: The good, the bad and the ugly

Monin, Leticia; Khader, Shabaana A.

doi:10.1016/j.smim.2014.09.004

Cited by 102 publications

(77 citation statements)

References 80 publications

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“…The pyogranulomatous lesion may be surrounded by a layer of endothelial macrophages that may be secreting the same inflammatory cytokines. Support for parts of the model of the pyogranulomatous lesion was also from previous reported animal model studies of melioidosis [29][30][31][33][34][35] and tuberculosis [70][71][72]. There are some similarities between the pyogranulomatous lesions seen in the chronic murine model and lesions reported in humans with chronic melioidosis [30,73].…”

Section: Discussionmentioning

confidence: 63%

Dysregulation of TNF-α and IFN-γ expression is a common host immune response in a chronically infected mouse model of melioidosis when comparing multiple human strains of Burkholderia pseudomallei

et al. 2020

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Background: Melioidosis is endemic in Southeast Asia and Northern Australia and is caused by the Gram-negative, facultative intracellular pathogen Burkholderia pseudomallei. Diagnosis of melioidosis is often difficult because of the protean clinical presentation of the disease, and it may mimic other diseases, such as tuberculosis. There are many different strains of B. pseudomallei that have been isolated from patients with melioidosis, but it was not clear if they could cause a similar disease in a chronic BALB/c murine model of melioidosis. Hence, we wanted to examine chronically infected mice exposed to different strains of B. pseudomallei to determine if there were differences in the host immune response to the pathogen. Results:We identified common host immune responses exhibited in chronically infected BALB/c mice, although there was some heterogeneity in the host response in chronically infected mice after exposure to different strains of B. pseudomallei. They all displayed pyogranulomatous lesions in their spleens with a large influx of monocytes/ macrophages, NK cells, and neutrophils identified by flow cytometry. Sera from chronically infected mice by ELISA exhibited elevated IgG titers to the pathogen, and we detected by Luminex micro-bead array technology a significant increase in the expression of inflammatory cytokines/chemokines, such as IFN-γ, IL-1α, IL-1β, KC, and MIG. By immunohistochemical and in situ RNA hybridization analysis we found that the increased expression of proinflammatory cytokines (IL-1α, IL-1β, TNF-α, IFN-γ) was confined primarily to the area with the pathogen within pyogranulomatous lesions. We also found that cultured splenocytes from chronically infected mice could express IFN-γ, TNF-α, and MIP-1α ex vivo without the need for additional exogenous stimulation. In addition by flow cytometry, we detected significant amounts of intracellular expression of TNF-α and IFN-γ without a protein transport blocker in monocytes/macrophages, NK cells, and neutrophils but not in CD4 + or CD8 + T cells in splenocytes from chronically infected mice.

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Section: Discussionmentioning

confidence: 63%

Dysregulation of TNF-α and IFN-γ expression is a common host immune response in a chronically infected mouse model of melioidosis when comparing multiple human strains of Burkholderia pseudomallei

et al. 2020

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“…These studies also indicate that a better understanding of this aspect of immunity could improve vaccine development and drug treatment. 5,208,209 Cytokines embody both good and bad roles in TB, because they can have context-dependent protective and pathologic consequences. 5 Monin and Khader 208 similarly suggested that chemokine responses can be both good and bad, and that protection in TB is a trade-off between immune control and bacterial replication mediated by appropriately calibrated responses.…”

Section: Discussionmentioning

confidence: 99%

Dynamic balance of pro‐ and anti‐inflammatory signals controls disease and limits pathology

Cicchese

Evans

Hult

et al. 2018

Immunological Reviews

235

171

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Immune responses to pathogens are complex and not well understood in many diseases, and this is especially true for infections by persistent pathogens. One mechanism that allows for long-term control of infection while also preventing an over-zealous inflammatory response from causing extensive tissue damage is for the immune system to balance pro- and anti-inflammatory cells and signals. This balance is dynamic and the immune system responds to cues from both host and pathogen, maintaining a steady state across multiple scales through continuous feedback. Identifying the signals, cells, cytokines, and other immune response factors that mediate this balance over time has been difficult using traditional research strategies. Computational modeling studies based on data from traditional systems can identify how this balance contributes to immunity. Here we provide evidence from both experimental and mathematical/computational studies to support the concept of a dynamic balance operating during persistent and other infection scenarios. We focus mainly on tuberculosis, currently the leading cause of death due to infectious disease in the world, and also provide evidence for other infections. A better understanding of the dynamically balanced immune response can help shape treatment strategies that utilize both drugs and host-directed therapies.

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“…Macrophages, the sentinels of innate immune system serve as the primary niche to the pathogen and mediate the early retaliation3. In this regard, chemokines produced by immune cells have been implicated in controlling key processes during mycobacterial infection and in defining the concerted recruitment of various other immune cells like neutrophils, T- and B-lymphocytes to curtail the spread of the pathogen45678.…”

mentioning

confidence: 99%

Mycobacterium tuberculosis-triggered Hippo pathway orchestrates CXCL1/2 expression to modulate host immune responses

Boro

Singh

Balaji

2016

Sci Rep

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Mycobacterium tuberculosis (Mtb) pathogenesis encompasses a plethora of finely regulated alterations within the host which eventually coin the outcome of infection. Chemokines are important components in directing immune cell recruitment to the site of infection, and shaping the disease progression. Here, we demonstrate that Hippo (mammalian sterile 20–like 1 and 2 kinases, MST1/2, in mammals), is activated during mycobacterial infection in a toll-like receptor (TLR) 2-interleukin receptor-1 associated kinases (IRAK1/4)-dependent manner. Mtb-triggered Hippo signaling modulates the expression and secretion of chemokines (CXCL1 and CXCL2); as silencing MST1/2 compromised the ability of Mtb to furnish the same. Further insight into the mechanism of Hippo-mediated regulation of chemokines revealed the role for a non-canonical Hippo effector interferon (IFN) regulatory factor (IRF) 3 in the process and marked the effect to be independent of LATS1. Alongside their ability to guide directed recruitment of immune cells, we have uncovered a paracrine role for Hippo-mediated secretion of CXCL1 and CXCL2 in the production of anti-microbial peptides (beta-defensins), iNOS, NOX2 and pro-inflammatory molecules during mycobacterial infection of the host. This study highlights the involvement of TLR2-IRAK1/4-MST1/2-IRF3 axis in Mtb-triggered modulation of chemokines and identifies Hippo signaling as a novel regulator of host-mycobacterial interactions.

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Chemokines in tuberculosis: The good, the bad and the ugly

Cited by 102 publications

References 80 publications

Dysregulation of TNF-α and IFN-γ expression is a common host immune response in a chronically infected mouse model of melioidosis when comparing multiple human strains of Burkholderia pseudomallei

Dysregulation of TNF-α and IFN-γ expression is a common host immune response in a chronically infected mouse model of melioidosis when comparing multiple human strains of Burkholderia pseudomallei

Dynamic balance of pro‐ and anti‐inflammatory signals controls disease and limits pathology

Mycobacterium tuberculosis-triggered Hippo pathway orchestrates CXCL1/2 expression to modulate host immune responses

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