IP-10 contributes to the inhibition of mycobacterial growth in an ex vivo whole blood assay

Palucci, Ivana; Battah, Basem; Salustri, Alessandro; Maio, Flavio De; Petrone, Linda; Ciccosanti, Fabiola; Sali, Michela; Bondet, Vincent; Duffy, Darragh; Fimia, Gian María; Goletti, Delia; Delogu, Giovanni

doi:10.1016/j.ijmm.2019.05.005

Cited by 14 publications

(8 citation statements)

References 59 publications

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“…IP-10 functions as a chemoattractant for activated T cells and monocytes and has also been correlated to autophagy induction (Chu et al, 2017). Importantly, a role for IP-10 in restricting Mtb growth has been reported (Palucci et al, 2019). Consistent with this, Mtb-infected THP-PKR macrophages also produced higher levels of IFNγ compared to THP-Ø macrophages (Supplementary Figure S2A).…”

Section: Pkr Expression Alters the Immunological Profile Of Macrophages During Mycobacterium Tuberculosis Infectionmentioning

confidence: 52%

Protein Kinase R Restricts the Intracellular Survival of Mycobacterium tuberculosis by Promoting Selective Autophagy

et al. 2021

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Tuberculosis (TB) is a deadly infectious lung disease caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb). The identification of macrophage signaling proteins exploited by Mtb during infection will enable the development of alternative host-directed therapies (HDT) for TB. HDT strategies will boost host immunity to restrict the intracellular replication of Mtb and therefore hold promise to overcome antimicrobial resistance, a growing crisis in TB therapy. Protein Kinase R (PKR) is a key host sensor that functions in the cellular antiviral response. However, its role in defense against intracellular bacterial pathogens is not clearly defined. Herein, we demonstrate that expression and activation of PKR is upregulated in macrophages infected with Mtb. Immunological profiling of human THP-1 macrophages that overexpress PKR (THP-PKR) showed increased production of IP-10 and reduced production of IL-6, two cytokines that are reported to activate and inhibit IFNγ-dependent autophagy, respectively. Indeed, sustained expression and activation of PKR reduced the intracellular survival of Mtb, an effect that could be enhanced by IFNγ treatment. We further demonstrate that the enhanced anti-mycobacterial activity of THP-PKR macrophages is mediated by a mechanism dependent on selective autophagy, as indicated by increased levels of LC3B-II that colocalize with intracellular Mtb. Consistent with this mechanism, inhibition of autophagolysosome maturation with bafilomycin A1 abrogated the ability of THP-PKR macrophages to limit replication of Mtb, whereas pharmacological activation of autophagy enhanced the anti-mycobacterial effect of PKR overexpression. As such, PKR represents a novel and attractive host target for development of HDT for TB, and our data suggest value in the design of more specific and potent activators of PKR.

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Section: Pkr Expression Alters the Immunological Profile Of Macrophages During Mycobacterium Tuberculosis Infectionmentioning

confidence: 52%

Protein Kinase R Restricts the Intracellular Survival of Mycobacterium tuberculosis by Promoting Selective Autophagy

et al. 2021

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“…VEGF and CXCL10 are produced by activated macrophages and antigen-presenting cells and regulate cell growth and chemotaxis and may be the driving forces for stimulated angiogenesis as observed in ATB lesions (56)(57)(58). CXCL10 may also limit Mtb replication, as recently observed (59,60). CRP is synthesized in the liver and is secreted following interleukin (IL)-6 stimulation by macrophages and T lymphocytes (61).…”

Section: Discussionmentioning

confidence: 93%

Serum Biomarker Profile Including CCL1, CXCL10, VEGF, and Adenosine Deaminase Activity Distinguishes Active From Remotely Acquired Latent Tuberculosis

et al. 2021

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IntroductionThere is an urgent medical need to differentiate active tuberculosis (ATB) from latent tuberculosis infection (LTBI) and prevent undertreatment and overtreatment. The aim of this study was to identify biomarker profiles that may support the differentiation between ATB and LTBI and to validate these signatures.Materials and MethodsThe discovery cohort included adult individuals classified in four groups: ATB (n = 20), LTBI without prophylaxis (untreated LTBI; n = 20), LTBI after completion of prophylaxis (treated LTBI; n = 20), and healthy controls (HC; n = 20). Their sera were analyzed for 40 cytokines/chemokines and activity of adenosine deaminase (ADA) isozymes. A prediction model was designed to differentiate ATB from untreated LTBI using sparse partial least squares (sPLS) and logistic regression analyses. Serum samples of two independent cohorts (national and international) were used for validation.ResultssPLS regression analyses identified C-C motif chemokine ligand 1 (CCL1), C-reactive protein (CRP), C-X-C motif chemokine ligand 10 (CXCL10), and vascular endothelial growth factor (VEGF) as the most discriminating biomarkers. These markers and ADA(2) activity were significantly increased in ATB compared to untreated LTBI (p ≤ 0.007). Combining CCL1, CXCL10, VEGF, and ADA2 activity yielded a sensitivity and specificity of 95% and 90%, respectively, in differentiating ATB from untreated LTBI. These findings were confirmed in the validation cohort including remotely acquired untreated LTBI participants.ConclusionThe biomarker signature of CCL1, CXCL10, VEGF, and ADA2 activity provides a promising tool for differentiating patients with ATB from non-treated LTBI individuals.

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“…CXCLl0 is one of the chemokines in the CXC non-ELR subfamily. The cells stimulated by IFN-γ can secrete CXCLl0, directly, and CXCLl0 may then selectively activate and enhance the expression of IFN-γ gene in antigen-activated T cells (24), therefore positive feedback may recruit more T cells, participating in cell growth, differentiation, apoptosis and inflammation. In the present study, the expression of IFN-γ and CXCL10 in patients with ST was increased, which was consistent with the expression trend of CXCL9.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic value of CXCR3 and its ligands in spinal tuberculosis

et al. 2020

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The present study aimed to investigate whether C-X-C motif chemokine receptor 3 (CXCR3) and its ligands may aid in diagnosing spinal tuberculosis (ST). A total of 36 patients with ST and 20 healthy controls were enrolled in the present study. The morphology of tuberculous granuloma in spinal tissue was observed by hematoxylin and eosin staining. The presence and distribution of acid-fast bacilli (AFB) were observed by Ziehl-Neelsen (ZN) staining. The protein expression of Ag85B, IFN-γ, and CXCR3 and its ligands (CXCL9 and CXCL10) were detected by immunohistochemistry. The levels of IFN-γ, CXCR3, CXCL9 and CXCL10 in peripheral blood of patients with ST and healthy controls were detected by reverse transcription-quantitative polymerase chain reaction and ELISA. Typical tuberculous granuloma was observed in the ST close tissue. AFB was observed by ZN staining. Positive expression of Ag85B was found in the surrounding caseous necrotic tissue of the tuberculous granuloma. IFN-γ, CXCR3, CXCL9 and CXCL10 were expressed in the tissue surrounding the tuberculous granuloma and their expression levels were markedly higher than those in the distant tissues. The levels of IFN-γ, CXCR3, CXCL9 and CXCL10 in peripheral blood of patients with ST were significantly higher than those in the healthy controls. Receiver operating characteristic curve analysis demonstrated that IFN-γ, CXCR3 and CXCL10 were more reliable diagnostic markers in terms of sensitivity and specificity. IFN-γ, CXCR3, CXCL9 and CXCL10 were highly expressed in the lesion tissue and peripheral blood samples of patients with ST, and IFN-γ, CXCR3 and its ligands aided in diagnosing ST.

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IP-10 contributes to the inhibition of mycobacterial growth in an ex vivo whole blood assay

Cited by 14 publications

References 59 publications

Protein Kinase R Restricts the Intracellular Survival of Mycobacterium tuberculosis by Promoting Selective Autophagy

Protein Kinase R Restricts the Intracellular Survival of Mycobacterium tuberculosis by Promoting Selective Autophagy

Serum Biomarker Profile Including CCL1, CXCL10, VEGF, and Adenosine Deaminase Activity Distinguishes Active From Remotely Acquired Latent Tuberculosis

Diagnostic value of CXCR3 and its ligands in spinal tuberculosis

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