Complement pathway gene activation and rising circulating immune complexes characterize early disease in HIV-associated tuberculosis

Esmail, Hanif; Lai, Rachel; Lesosky, Maia; Wilkinson, Katalin A.; Graham, Christine M.; Horswell, Stuart; Coussens, Anna K.; Barry, Clifton E.; O’Garra, Anne; Wilkinson, Robert J.

doi:10.1073/pnas.1711853115

Cited by 89 publications

(73 citation statements)

References 34 publications

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“…of immune complexes and antibody-dependent cytotoxicity (83). Recently, it was determined that a subset of transcripts enriched for IgG receptors was present in the whole blood of symptomatic TB patients and individuals with subclinical disease, suggesting an early cellular response to antigen/antibody complexes during TB disease in HIV-infected individuals (84). Additionally, the higher expression levels of FCGR1A in TB patients regardless of HIV status or genetic background have been considered a remarkable and consistent classifier of active disease (85).…”

Section: Ams Of Tb Patients Respond To Infection With Virulent Mtb CLmentioning

confidence: 99%

Human Alveolar and Splenic Macrophage Populations Display a Distinct Transcriptomic Response to Infection With Mycobacterium tuberculosis

2020

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Mycobacterium tuberculosis (Mtb) infects alveolar macrophages (AMs), causing pulmonary tuberculosis (PTB), the most common form of the disease. Less frequently, Mtb is disseminated to many other organs and tissues, resulting in different extrapulmonary forms of TB. Nevertheless, very few studies have addressed the global mRNA response of human AMs, particularly from humans with the active form of the disease. Strikingly, almost no studies have addressed the response of human extrapulmonary macrophages to Mtb infection. In this pilot study, using microarray technology, we examined the transcriptomic ex vivo response of AMs from PTB patients (AMTBs) and AMs from control subjects (AMCTs) infected with two clinical isolates of Mtb. Furthermore, we also studied the infection response of human splenic macrophages (SMs) to Mtb isolates, as a model for extrapulmonary infection, and compared the transcriptomic response between AMs and SMs. Our results showed a striking difference in global mRNA profiles in response to infection between AMs and SMs, implicating a tissue-specific macrophage response to Mtb.

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Section: Ams Of Tb Patients Respond To Infection With Virulent Mtb CLmentioning

confidence: 99%

Human Alveolar and Splenic Macrophage Populations Display a Distinct Transcriptomic Response to Infection With Mycobacterium tuberculosis

2020

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“…In the previous studies, IFN-depended gene signatures were observed in the blood of acute phase of tuberculosis, as well as, in the patient of chronic stage of infection from UK, Indonesia and South Africa [10,11,32]. In addition, it is reported that blood transcriptional profiles of individuals in the early stage of tuberculosis were dominated by Type I IFN-inducible gene profiles, that were associated with radiographic detectable lung lesions and subsided with proper therapy [10].…”

Section: Discussionmentioning

confidence: 98%

Inhibition of Type I Interferon Signaling Abrogates Early Mycobacterium bovis Infection

Zhou

Hussain

Zhang

et al. 2019

Preprint

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Background: Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. Methods: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 hour before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and the role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR were performed to detect the expression of Type I IFNs and related genes. Lung lesions induced by M. bovis were assessed by histopathological examination.Viable bacterial count was determined by CFU assay. Results: We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell activation and recruitment in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. Conclusions: Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.

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“…[13][14][15] A blood transcriptomic study reported abundance of transcripts representing the classical compliments pathway in active TB patients in comparison to those with subclinical stages of the disease. 9 Further on analysing publicly available blood gene expression microarray data of TB patients in comparison with latent TB or other lung diseases complement gene C1QC transcripts were observed more than 2 fold higher in TB patients in 78% (7/9) of the studies. 16 C1QC encodes for Cchain polypeptide of serum complement subcomponent C1q, which associates with C1r and C1s to yield the first component of the classical complement system.…”

Section: Discussionmentioning

confidence: 99%

“…Earlier blood gene expression studies have highlighted compliment as candidate biomarker for active TB even in the presence of HIV co-infection. [7][8][9] A recent study reported increased expression of C1qC in peripheral blood during active TB and C1QC has better diagnostic value than other inflammatory markers like IL-6 and TNF-α. 10 Thus, in the present study, we evaluated the potential of serum C1qC level to discriminate active TB patients from controls comprising of healthy, latent TB and patients with respiratory diseases other than TB by Enzyme linked Immunosorbent Assay (ELISA) in Indian cohort.…”

mentioning

confidence: 99%

Evaluation of Serum Complement Component 1Q Subcomponent C (C1qC) as a Marker for Tuberculosis

Kumar¹,

Chawla²,

Madigubba³

et al. 2019

jemds

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A B S T R A C T BACKGROUNDDespite several efforts, tuberculosis (TB) continues to be a global concern. For proper management of TB, more sensitive and specific biomarkers for early and accurate diagnosis of TB are still required. Blood based host markers are more appealing as an alternate to sputum-based diagnostics. Thus, in the present study, we evaluated the potential of Serum Complement Component 1 Q Subcomponent C (C1qC) as a marker for tuberculosis. METHODSSerum samples from 84 subjects which included 39 smear positive pulmonary TB patients and 45 controls (Latent TB n=15, Healthy n= 15 and patients with respiratory diseases other than TB n= 15) were collected and Enzyme Linked Immunosorbent Assay was performed to estimate the serum C1qC levels. RESULTSThe mean (±SD) serum C1qC levels in TB, Healthy, Latent TB and patients with respiratory diseases other than TB was found to be 21.80 (±4.39), 13.64 (±1.32), 15.18(±1.29) and 17.31(±1.87) pg/ml respectively. The AUC of serum C1qC to discriminate TB patients from controls was found to be 0.924 (95% CI, 0.869-0.978). At an optimal cut-off value of 16.99 pg/ml, the sensitivity and specificity of serum C1qC to discriminate TB from controls was found to be 84.62% (95% CI, 69.47%-94.14%) and 84.44% (95% CI, 70.54%-93.51%) respectively with a likelihood ratio of 5.44. CONCLUSIONSThe levels of serum C1qC in TB patients was found to be significantly higher than controls. C1qC seems to be a promising marker for the diagnosis and therapeutic monitoring of TB, though further elaborate studies in larger cohorts are required to establish the role for C1qC in the diagnosis and therapeutic monitoring of TB.

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Complement pathway gene activation and rising circulating immune complexes characterize early disease in HIV-associated tuberculosis

Abstract: 32Understanding the events in early tuberculosis disease will facilitate the development of novel 33 tests to predict disease progression and interventions to prevent it. Blood

Cited by 89 publications

References 34 publications

Human Alveolar and Splenic Macrophage Populations Display a Distinct Transcriptomic Response to Infection With Mycobacterium tuberculosis

Human Alveolar and Splenic Macrophage Populations Display a Distinct Transcriptomic Response to Infection With Mycobacterium tuberculosis

Inhibition of Type I Interferon Signaling Abrogates Early Mycobacterium bovis Infection

Evaluation of Serum Complement Component 1Q Subcomponent C (C1qC) as a Marker for Tuberculosis

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