A novel missense mutation in the NADPH binding domain of CYBB abolishes the NADPH oxidase activity in a male patient with increased susceptibility to infections

Khan, Taj Ali; Kalsoom, Kalsoom; Iqbal, Asif; Asif, Huma; Rahman, Hazir; Farooq, Syed Omar; Naveed, Hassan; Nasir, Umar; Amin, Muhammad Usman; Hussain, Mubashir; Tipu, Hamid Nawaz; Florea, Andrei

doi:10.1016/j.micpath.2016.09.020

Cited by 21 publications

(11 citation statements)

References 33 publications

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“…The minimal effects observed in these assays suggested that Phox may not play a protective role in TB. This conclusion contrasts with several studies indicating that human CGD patients show increased susceptibility to TB disease (Bustamante et al, 2011; Deffert et al, 2014a; Khan et al, 2016). Our dissection of disease progression in Cybb-deficient mice harmonizes these conflicting observations.…”

Section: Discussioncontrasting

confidence: 99%

“…These findings have led to the conclusion that ROS produced by Phox are not required for protection to Mtb (Nathan and Shiloh, 2000). In contrast, mutations in the Cybb gene are strongly associated with susceptibility to mycobacterial disease, including tuberculosis (Bustamante et al, 2011; Deffert et al, 2014a; Khan et al, 2016; Lee et al, 2008). Mutations that specifically reduce Cybb activity in macrophages produce a similar clinical presentation, highlighting the importance of the macrophage-derived ROS in protection from pathogenic mycobacteria (Bustamante et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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The Phagocyte Oxidase Controls Tolerance toMycobacterium tuberculosisinfection

Olive

Smith

Kiritsy

et al. 2017

Preprint

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SummaryProtection from infectious disease relies on two distinct mechanisms. “Antimicrobial resistance” directly inhibits pathogen growth, whereas “infection tolerance” controls tissue damage. A single immune-mediator can differentially contribute to these mechanisms in distinct contexts, confounding our understanding of protection to different pathogens. For example, the NADPH-dependent phagocyte oxidase complex (Phox) produces anti-microbial superoxides and protects from tuberculosis in humans. However, Phox-deficient mice do not display the expected defect in resistance to M. tuberculosis leaving the role of this complex unclear. We re-examined the mechanisms by which Phox contributes to protection from TB and found that mice lacking the Cybb subunit of Phox suffered from a specific defect in tolerance, which was due to unregulated Caspase1 activation, IL-1β production, and neutrophil influx into the lung. These studies demonstrate that Phox-derived superoxide protect against TB by promoting tolerance to persistent infection, and highlight a central role for Caspase1 in regulating TB disease progression.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Phagocyte Oxidase Controls Tolerance toMycobacterium tuberculosisinfection

Olive

Smith

Kiritsy

et al. 2017

Preprint

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“…Alterations in macrophage function, such as defects in NADPH oxidase30 and the vitamin D receptor,31 are known as risk factors for mycobacterial infection. Several studies have shown that mutations in CYBB could result in X-linked chronic granulomatous disease with much higher risk of TB,32–34 which is an immunodeficiency caused by defective activity of NADPH oxidase in phagocytes 33,35. Liu et al have also demonstrated the significant correlation between CYBB polymorphisms and decreased risk of TB, particularly among male smokers 36…”

Section: Resultsmentioning

confidence: 99%

<p>The blood transcriptional signature for active and latent tuberculosis</p>

Deng¹,

Liu²,

Fang³

et al. 2019

IDR

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BackgroundAlthough the incidence of tuberculosis (TB) has dropped substantially, it still is a serious threat to human health. And in recent years, the emergence of resistant bacilli and inadequate disease control and prevention has led to a significant rise in the global TB epidemic. It is known that the cause of TB is Mycobacterium tuberculosis infection. But it is not clear why some infected patients are active while others are latent.MethodsWe analyzed the blood gene expression profiles of 69 latent TB patients and 54 active pulmonary TB patients from GEO (Transcript Expression Omnibus) database.ResultsBy applying minimal redundancy maximal relevance and incremental feature selection, we identified 24 signature genes which can predict the TB activation. The support vector machine predictor based on these 24 genes had a sensitivity of 0.907, specificity of 0.913, and accuracy of 0.911, respectively. Although they need to be validated in a large independent dataset, the biological analysis of these 24 genes showed great promise.ConclusionWe found that cytokine production was a key process during TB activation and genes like CYBB, TSPO, CD36, and STAT1 worth further investigation.

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“…These individuals have recurrent or disseminated TB. Macrophages from patients with mutations in the gp91phox subunit of the NADPH oxidase show compromised oxidative burst upon M. bovis BCG infection, suggesting that a functional NADPH oxidase is critical for proper protection against mycobacterial diseases [ 97 , 98 , 99 ]. Further, one of the NADPH subunits, gp91phox(Cybb), is associated with TB susceptibility in humans [ 98 ].…”

Section: The Infected Neutrophil: Events Within and Its Fatementioning

confidence: 99%

Neutrophils in Tuberculosis: Cell Biology, Cellular Networking and Multitasking in Host Defense

Borkute

Woelke

Pei

et al. 2021

IJMS

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Neutrophils readily infiltrate infection foci, phagocytose and usually destroy microbes. In tuberculosis (TB), a chronic pulmonary infection caused by Mycobacterium tuberculosis (Mtb), neutrophils harbor bacilli, are abundant in tissue lesions, and their abundances in blood correlate with poor disease outcomes in patients. The biology of these innate immune cells in TB is complex. Neutrophils have been assigned host-beneficial as well as deleterious roles. The short lifespan of neutrophils purified from blood poses challenges to cell biology studies, leaving intracellular biological processes and the precise consequences of Mtb–neutrophil interactions ill-defined. The phenotypic heterogeneity of neutrophils, and their propensity to engage in cellular cross-talk and to exert various functions during homeostasis and disease, have recently been reported, and such observations are newly emerging in TB. Here, we review the interactions of neutrophils with Mtb, including subcellular events and cell fate upon infection, and summarize the cross-talks between neutrophils and lung-residing and -recruited cells. We highlight the roles of neutrophils in TB pathophysiology, discussing recent findings from distinct models of pulmonary TB, and emphasize technical advances that could facilitate the discovery of novel neutrophil-related disease mechanisms and enrich our knowledge of TB pathogenesis.

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A novel missense mutation in the NADPH binding domain of CYBB abolishes the NADPH oxidase activity in a male patient with increased susceptibility to infections

Cited by 21 publications

References 33 publications

The Phagocyte Oxidase Controls Tolerance toMycobacterium tuberculosisinfection

The Phagocyte Oxidase Controls Tolerance toMycobacterium tuberculosisinfection

<p>The blood transcriptional signature for active and latent tuberculosis</p>

Neutrophils in Tuberculosis: Cell Biology, Cellular Networking and Multitasking in Host Defense

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