A Clinical Correlate of the Dysregulated Immunoendocrine Response in Human Tuberculosis

Santucci, Natalia; D’Attilio, Luciano; Besedovsky, Hugo O.; Rey, Adriana del; Bay, María Luisa

doi:10.1159/000258719

Cited by 13 publications

(13 citation statements)

References 22 publications

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“…Schwenk et al [22] suggest that leptin may not be involved in the loss of weight in TB, although in their study leptin positively correlated with body mass. To some extent, considering the already known correlation between serum leptin levels and BMI [23], and that leptin concentration is related to the adipose tissue mass [24], the reduced leptin levels found in this and in a former series of TB patients [25] may be linked to the weight loss that accompanies the disease. At the same time, it is known chronic stimulation with pro-inflammatory cytokines, as is the case of TB, suppresses leptin production [26], [27].…”

Section: Discussionmentioning

confidence: 60%

A Multifaceted Analysis of Immune-Endocrine-Metabolic Alterations in Patients with Pulmonary Tuberculosis

et al. 2011

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Our study investigated the circulating levels of factors involved in immune-inflammatory-endocrine-metabolic responses in patients with tuberculosis with the aim of uncovering a relation between certain immune and hormonal patterns, their clinical status and in vitro immune response. The concentration of leptin, adiponectin, IL-6, IL-1β, ghrelin, C-reactive protein (CRP), cortisol and dehydroepiandrosterone (DHEA), and the in vitro immune response (lymphoproliferation and IFN-γ production) was evaluated in 53 patients with active untreated tuberculosis, 27 household contacts and 25 healthy controls, without significant age- or sex-related differences. Patients had a lower body mass index (BMI), reduced levels of leptin and DHEA, and increased concentrations of CRP, IL-6, cortisol, IL-1β and nearly significant adiponectin values than household contacts and controls. Within tuberculosis patients the BMI and leptin levels were positively correlated and decreased with increasing disease severity, whereas higher concentrations of IL-6, CRP, IL-1β, cortisol, and ghrelin were seen in cases with moderate to severe tuberculosis. Household contacts had lower DHEA and higher IL-6 levels than controls. Group classification by means of discriminant analysis and the k-nearest neighbor method showed that tuberculosis patients were clearly different from the other groups, having higher levels of CRP and lower DHEA concentration and BMI. Furthermore, plasma leptin levels were positively associated with the basal in vitro IFN-γ production and the ConA-driven proliferation of cells from tuberculosis patients. Present alterations in the communication between the neuro-endocrine and immune systems in tuberculosis may contribute to disease worsening.

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Section: Discussionmentioning

confidence: 60%

A Multifaceted Analysis of Immune-Endocrine-Metabolic Alterations in Patients with Pulmonary Tuberculosis

et al. 2011

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“…In active tuberculosis (TB), emerging evidence suggests that high TNF-α level can accelerate disease progression [66]. The pro-inflammatory cytokines, including TNF-α and IL-6, present at the foci [67], are partially responsible for systemic manifestations such as cachexia and wasting in tuberculosis patients [68,69]. IL-10 is an important regulator of myeloid cells, potently inhibiting the capacity of monocytes/macrophages to secrete inflammatory cytokines as well as down-regulating their capacity to serve as accessory cells [70].…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium TuberculosisPPE Family Protein Rv1808 Manipulates Cytokines Profile via Co-Activation of MAPK and NF-κB Signaling Pathways

Deng

Zeng

et al. 2014

Cell Physiol Biochem

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Background/Aims: Mycobacterium tuberculosis is an extremely successful intracellular pathogen armed with multiple tactics to subvert host immunity. PPE (Pro-Pro-Glu) family exclusively distributed in mycobacteria might be responsible for the virulence and pathogenicity of M.tuberculosis. The up-regulation of Rv1808 (PPE32) in many conditions prompted us to define its role in host innate immune response. Methods: The Rv1808 encoding gene was expressed in nonpathogenic fast growing Mycobacterium smegmatis, mycobacteria- Escherichia coli shuttle plasmid pNITmyc served as control. RT-PCR and ELISA were used to detect the transcription and translation of host cytokines in culture supernatant from macrophage incubated with purified Rv1808 protein. Pharmacological inhibitors were applied to confirm the specificity of the effector interfering of host signaling. Results: Recombinant Ms_Rv1808 survived better than Ms_pNITmyc within macrophage, accompanied by slightly higher host cell death. Rv1808 protein is associated with the cell wall and exposed on the cell surface. Physical binding of Rv1808 to TLR2 resulted in increase in the secretion of anti-inflammatory cytokine interleukin-10 (IL-10) and pro-inflammatory cytokines tumor necrosis factor (TNF-a) and interleukin-6 (IL-6) possibly via co-activation of NF-κB and MAPK (p38MAPK, JNK and ERK) signalling. Conclusion: Cell wall associated Rv1808 protein manipulated the host cytokines via MAPK and NF-κB signaling pathways.

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“…In active tuberculosis (TB), emerging evidence suggests that a high level of TNF could accelerate disease progression (5,10,12,39,69,71). The production of proinflammatory cytokines, including TNF and IL-6, is present at the site of disease (8,18,45), and these proinflammatory cytokines are partially responsible for systemic manifestations such as cachexia and wasting in tuberculosis patients (59,74). Consistent with this view, we observed more extensive tissue damage and bacterial dissemination in fish infected with WT M. marinum strains than in fish infected with the PPE38 mutant strain, which may correlates with higher levels of TNF and IL-6 production induced by the former in macrophages.…”

Section: Discussionmentioning

confidence: 99%

PPE38 Modulates the Innate Immune Response and Is Required for Mycobacterium marinum Virulence

Dong

Wang

et al. 2012

Infect Immun

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The proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) family proteins are prevalent in pathogenic mycobacteria and play a diverse role in mycobacterial pathogenesis. While some members have been studied, the function of most PE/PPE proteins remains unknown. In this study, we isolated a transposon-inactivated PPE38 mutant of Mycobacterium marinum and characterized its phenotype. We found that the PPE38 protein is associated with the cell wall and exposed on the cell surface. The inactivation of PPE38 altered the bacterial cell surface properties and led to deficiencies in cord formation, sliding motility, and biofilm formation. The PPE38 mutant was defective in phagocytosis by macrophages and exhibited reduced virulence in adult zebrafish. We also found that PPE38 is involved in the induction of proinflammatory cytokines in infected macrophages. Together, our results indicate that PPE38, a previously uncharacterized protein, plays a role in mycobacterial virulence, presumably by modulating the host innate immune response. Mycobacterium tuberculosis is a highly successful human pathogen that latently infects one-third of the world's population, causing 10 million new infections and 2 million deaths annually. One reason for the success of M. tuberculosis lies in its ability to evade host immune defense mechanisms and to create a niche within host cells, enabling the bacterium to persist for long periods. M. tuberculosis infects and survives within macrophages by evading macrophage killing mechanisms through a variety of strategies (reviewed in references 51 and 56). During persistent infection, M. tuberculosis is thought to reside within a granuloma, a cellular accumulation around the bacilli that is comprised mainly of macrophages, dendritic cells, T cells, B cells, and fibroblasts (reviewed in reference 31). Granulomas are generally thought to contain the infection by limiting bacterial growth and spread (21, 61). However, recent studies by Ramakrishnan and coworkers using zebrafish embryos demonstrated that the granuloma is a dynamic structure and that Mycobacterium marinum, an aquatic mycobacterium closely related to M. tuberculosis, uses the granuloma as a niche to recruit uninfected macrophages, raising the possibility that granulomas are exploited by the pathogen for expansion and dissemination in early infection (23,25,26).PE and PPE family proteins, named for the conserved N-terminal-domain-containing proline-glutamic acid (PE) motif or proline-proline-glutamine (PPE) motif, are unique to mycobacteria and particularly prevalent in pathogenic mycobacteria (35). They account for a significant fraction (ϳ10%) of the coding capacity of pathogenic mycobacteria. There are 168 PE/PPE proteins in M. tuberculosis (22) and 281 in M. marinum (64). The relatively conserved N termini are approximately 110 and 180 amino acids in the PE and PPE families, respectively. The C-terminal domains of both the PE and PPE protein families are highly variable in both size and sequence and often contain repetitive ...

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A Clinical Correlate of the Dysregulated Immunoendocrine Response in Human Tuberculosis

Cited by 13 publications

References 22 publications

A Multifaceted Analysis of Immune-Endocrine-Metabolic Alterations in Patients with Pulmonary Tuberculosis

A Multifaceted Analysis of Immune-Endocrine-Metabolic Alterations in Patients with Pulmonary Tuberculosis

Mycobacterium TuberculosisPPE Family Protein Rv1808 Manipulates Cytokines Profile via Co-Activation of MAPK and NF-κB Signaling Pathways

PPE38 Modulates the Innate Immune Response and Is Required for Mycobacterium marinum Virulence

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