Tumor necrosis factor is a determinant of pathogenesis and disease progression in mycobacterial infection in the central nervous system (original) (raw)
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Proceedings of the National Academy of Sciences, 1999
The pathogenesis of tuberculous meningitis, a devastating complication of tuberculosis in man, is poorly understood. We previously reported that rabbits with experimental tuberculous meningitis were protected from death by a combination of antibiotics and thalidomide therapy. Survival was associated with inhibition of tumor necrosis factor α (TNF-α) production by thalidomide. To test whether cerebrospinal fluid (CSF) levels of TNF-α correlated with pathogenesis, the response of rabbits infected in the central nervous system (CNS) with various mycobacterial strains was studied. CNS infection with Mycobacterium bovis Ravenel, M. bovis bacillus Calmette–Guérin (BCG) Pasteur, and M. bovis BCG Montreal were compared. M. bovis Ravenel induced the highest levels of TNF-α in the CSF in association with high leukocytosis, protein accumulation, and severe meningeal inflammation. BCG Pasteur had intermediate effects, and BCG Montreal was the least virulent. In addition, M. bovis Ravenel number...
Cerebrospinal Fluid Cytokines in Patients with Tuberculous Meningitis
Clinical Immunology and Immunopathology, 1997
The levels of tumor necrosis factor (TNF)-a, soluble tion in patients with a more severe form of tuberculosis, TNF receptors p75 (sTNFR-75) and sTNFR-55, intersuch as tuberculous meningitis (TBM). To gain insight feron (IFN)-g, and interleukin (IL)-10 and IL-12 were into the role that cytokines play in the tuberculous measured in 59 cerebrospinal fluid (CSF) samples from infection of the central nervous system (CNS), we eval-15 patients with tuberculous meningitis (TBM). TBM uated cerebrospinal fluid (CSF) concentrations of tuwas associated with elevated concentrations of TNFmor necrosis factor (TNF)-a, soluble TNF receptors p75 a, sTNFR-75, sTNFR-55, IFN-g, and IL-10, while CSF IL-(sTNFR-75) and sTNFR-55, IFN-g, and interleukin 12 was undetectable in all TBM patients. A significant (IL)-10 and IL-12 in patients with TBM. The kinetics correlation between cytokines and CSF adenosine deof these cytokines during the course of the disease was aminase activity was also found. The levels of TNF-a also investigated in most patients. did not decrease over time, being still detectable in the CSF 16 months after starting antibiotic therapy, MATERIALS AND METHODS whereas IFN-g along with anti-inflammatory mediators sTNFR-75, sTNFR-55, and IL-10 remained elevated Subjects in the CSF for 4-8 months. The chronic release of cytokines in the CSF compartment was related neither to The patient population consisted of 15 patients with the TBM stage nor to the clinical outcome of the dis-TBM, admitted to the Department of Infectious and ease, thus suggesting the presence of a continuous ac-Tropical Diseases of La Sapienza University of Rome, tivity of the inflammatory process at the site of infec-Italy. All patients had a history and clinical findings tion. ᭧ 1997 Academic Press compatible with the diagnosis of TBM. For six cases, the diagnosis was confirmed by isolation of M. tuberculosis from CSF. In the remaining 9 patients, diagnosis
Journal of Tuberculosis Research, 2017
Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis. Mycobacterium tuberculosis will form the primary focus or Ghon focus in the lungs of infected people. The primary focus can break and get into the bloodstream and/or lymph to the entire body, including the central nervous system, especially the brain. Tuberculosis infection in the brain can cause microglia secrete inflammatory factors such as TNF-α and IL-1β is emerging as the body's immune response. The factors that can trigger microglia to secrete iNOS (Inducible Nitric Oxide Synthase) in order to protect the brain from attacking bacteria. iNOS is shown to have an important role in tuberculosis infection in the brain. TNF-α is a pro-inflammatory cytokine which is mostly produced by macrophages/microglia through several mechanisms. Therefore, to investigate how the expression of TNF-α and iNOS in the brain tissue of the mice is not infected with tuberculosis, tuberculosis infection with an incubation period of 8 weeks and 16 weeks. This study is a semiquantitative study by comparing the amount of expression of TNF-α and iNOS and all three groups of samples with treatment as has been mentioned. The expressions observation of TNF-α and iNOS in brain cell tissue of mice was conducted using immunohistochemical staining, and was seen in a microscope with a magnification of ×100. Brain cells that express TNF-α and iNOS are brown core, cytoplasm and cell walls. The results were obtained by the longer exposure to infection of the higher expression of TNF-α (r > 0688) and the expression of iNOS decreased (−0.993
Laboratory Investigation, 2000
Tumour necrosis factor-␣ (TNF) plays a central role in the recruitment and activation of mononuclear cells in mycobacterial infection. In the absence of type 1 TNF receptor, Mycobacterium bovis Bacillus Calmette-Gué rin (BCG) infection of mice is not contained, leading to fatal disease. Because type 1 TNF receptor binds both TNF and lymphotoxin-␣, we used TNF-deficient mice to determine the specific role of TNF in the host resistance to BCG infection. The bacterial burden of the lungs of TNF-deficient mice was substantially increased and the mice succumbed to pneumonia between 8 and 12 weeks with a defective granuloma response. Atypical granulomas developed by 4 weeks expressing low levels of MHC class II, intracellular adhesion molecule (ICAM-1), CD11b and CD11c. Macrophages showed little signs of activation and had low levels of acid phosphatase activity and inducible nitric oxide synthase (INOS) expression. Despite the defective cellular recruitment, the chemokines, monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1␣), were increased in broncho-alveolar lavage fluid of TNF-deficient mice. The defective host response was corrected by the transplantation of normal bone marrow cells into irradiated TNF-deficient mice. These results demonstrate that TNF derived from hemopoietic cells rather than from mesenchymal origin are essential for a normal host response to BCG infection. Furthermore, TNF dependent expression of adhesion molecules may be essential for the recruitment of mononuclear cells for the formation of bactericidal BCG granulomas. (Lab Invest 2000, 80:901-914).
Infection and Immunity, 2005
The effects of total and partial inhibition of tumor necrosis factor (TNF) on sensitivity to Mycobacterium bovis BCG infection were investigated by using transgenic mice in which hepatocytes produced different amounts of human soluble TNF receptor 1 (sTNFR1) fused to the Fc fragment of human immunoglobulin G3 that could be detected in the serum. Transgenic mice expressing high serum levels of sTNFR1, neutralizing all circulating TNF, failed to develop differentiated granulomas and bactericidal mechanisms, and they succumbed to BCG infection. sTNFR1 transgenic mice did not activate BCG-induced Th1-type cytokines early in infection, but uncontrolled cytokine release was found late in infection. In this work we also evaluated the effect of partial inhibition of TNF on resistance to BCG infection. Transgenic mice expressing low levels of sTNFR1 were protected against BCG infection, and they developed increased bactericidal mechanisms, such as enhanced inducible nitric oxide synthase activity, increased macrophage activation, and showed higher numbers of liver granulomas early in infection compared to their negative littermates. Our data suggest that while total inhibition of TNF prevented BCG-induced cell-mediated immune responses, partial inhibition of TNF could contribute to macrophage activation, induction of bactericidal mechanisms, and granuloma formation in the early phase of BCG infection.
Infection and Immunity, 2015
Tumor necrosis factor (TNF) is an important cytokine for host defense against pathogens but is also associated with the development of human immunopathologies. TNF blockade effectively ameliorates many chronic inflammatory conditions but compromises host immunity to tuberculosis. The search for novel, more specific human TNF blockers requires the development of a reliable animal model. We used a novel mouse model with complete replacement of the mouse TNF gene by its human ortholog (human TNF [huTNF] knock-in [KI] mice) to determine resistance to Mycobacterium bovis BCG and M. tuberculosis infections and to investigate whether TNF inhibitors in clinical use reduce host immunity. Our results show that macrophages from huTNF KI mice responded to BCG and lipopolysaccharide similarly to wild-type macrophages by NF-κB activation and cytokine production. While TNF-deficient mice rapidly succumbed to mycobacterial infection, huTNF KI mice survived, controlling the bacterial burden and acti...
Background. The immunopathogenesis of tuberculosis-associated immune reconstitution inflammatory syn- drome (IRIS) remains incompletely understood, and we know of only 1 disease site-specific study of the underlying immunology; we recently showed that Mycobacterium tuberculosis culture positivity and increased neutrophils in the cerebrospinal fluid (CSF) of patients with tuberculous meningitis (TBM) are associated with TBM-IRIS. In this study we investigated inflammatory mediators at the disease site in patients with TBM-IRIS. Methods. We performed lumbar puncture at 3–5 time points in human immunodeficiency virus (HIV)–infected patients with TBM (n = 34), including at TBM diagnosis, at initiation of antiretroviral therapy (ART) (day 14), 14 days after ART initiation, at presentation of TBM-IRIS, and 14 days thereafter. We determined the concentrations of 40 mediators in CSF (33 paired with blood) with Luminex or enzyme-linked immunosorbent assays. Findings were compared between patients who developed TBM-IRIS (n = 16) and those who did not (TBM-non-IRIS; n = 18). Results. At TBM diagnosis and 2 weeks after ART initiation, TBM-IRIS was associated with severe, compartmental- ized inflammation in the CSF, with elevated concentrations of cytokines, chemokines, neutrophil-associated mediators, and matrix metalloproteinases, compared with TBM-non-IRIS. Patients with TBM-non-IRIS whose CSF cultures were positive for M. tuberculosis at TBM diagnosis (n = 6) showed inflammatory responses similar to those seen in patients with TBM-IRIS at both time points. However, at 2 weeks after ART initiation, S100A8/A9 was significantly increased in patients with TBM-IRIS, compared with patients with TBM-non-IRIS whose cultures were positive at baseline. Conclusions. A high baseline M. tuberculosis antigen load drives an inflammatory response that manifests clinically as TBM-IRIS in most, but not all, patients with TBM. Neutrophils and their mediators, especially S100A8/A9, are closely associated with the central nervous system inflammation that characterizes TBM-IRIS.
The Journal of Immunology, 2002
The contribution of a transmembrane (Tm) form of TNF to protective immunity against Mycobacterium bovis bacillus Calmette-Guérin (BCG) was studied in transgenic (tg) mice expressing a noncleavable Tm TNF but lacking the TNF/lymphotoxin-␣ (LT-␣) locus (Tm TNF tg mice). These mice were as resistant to BCG infection as wild-type mice, whereas TNF/LT-␣ ؊/؊ , TNF ؊/؊ , and LT-␣ ؊/؊ mice succumbed. Tm TNF tg mice developed granulomas of smaller size but at 2-to 4-fold increased frequencies compared with wild-type mice. Granulomas were mainly formed by monocytes and activated macrophages expressing Tm TNF mRNA and accumulating acid phosphatase. NO synthase 2 activation as a key macrophage bactericidal mechanism was low during the acute phase of infection in Tm TNF tg mice but was still sufficient to limit bacterial growth and increased in late infection. While infection with virulent Mycobacterium tuberculosis resulted in very rapid death of TNF/LT-␣ ؊/؊ mice, it also resulted in survival of Tm TNF tg mice which presented an increase in the number of CFU in spleen (5-fold) and lungs (10-fold) as compared with bacterial load of wild-type mice. In conclusion, the Tm form of TNF induces an efficient cell-mediated immunity and total resistance against BCG even in the absence of LT-␣ and secreted TNF. However, Tm TNF-mediated protection against virulent M. tuberculosis infection can also be efficient but not as strong as in BCG infection, in which cognate cellular interactions may play a more predominant role in providing long-term surveillance and containment of BCG-infected macrophages.