MMPs and NETs are detrimental in human CNS-tuberculosis and MMP inhibition in a mouse model improves survival (original) (raw)
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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.
Pathogenesis and immune response in tuberculous meningitis
The Malaysian journal of medical sciences : MJMS, 2014
Cerebral tuberculosis is the most severe type of extrapulmonary disease that is in developing countries highly predominant in children. Meningeal tuberculosis is the most common form and usually begins with respiratory infection followed by early haematogenous dissemination to extrapulmonary sites involving the brain. In comparison with the lung, Mycobacterium tuberculosis induces a very different immune response when infect the central nervous system. Herein, we review several aspects of the pathogenesis and immune response in pulmonary and cerebral tuberculosis in humans and experimental models and discuss the implications of this response in the cerebral infection outcome.
International Journal of Healthcare and Medical Sciences, 2019
Background: Tuberculous meningitis is defined as an inflammatory response to mycobacterial bacterial infection of the pia, arachnoid and CSF of the subarachnoid space. It is a dangerous form of extrapulmonary tuberculosis because it can cause permanent neurological disabilities and even death. Stroke is a devastating complication which further increase the morbidity and mortality in the disease. Matrix metalloproteinases are endopeptidases which degrade all the components of the extracellular matrix and thus have potential to disrupt blood brain barrier and cause CNS damage. Matrix metalloproteinases have been associated with pathophysiology of ischemic stroke. MMP levels in serum and CSF have also been seen to rise with advancing stage of TBM. So it is postulated that MMP may have role in the pathophysiology of stroke in TBM and may serve as a biomarker to predict stroke in TBM. Aims: To compare Serum Matrix metalloproteinase-9 in patients with Tuberculous Meningitis with and witho...
The Journal of infectious diseases, 2018
Mycobacterium tuberculosis (Mtb) bacillary load in the brain of those with tuberculous meningitis (TBM) may reflect the host ability to control the pathogen and determine disease severity and treatment outcomes. We measured pre-treatment cerebrospinal fluid (CSF) Mtb bacterial load by GeneXpert in 692 adults with TBM. We sought to understand the relationship between CSF bacterial load and inflammation, and their respective impact on disease severity and treatment outcomes. Ten-fold higher Mtb load was associated with increased disease severity (Odds Ratio=1.59, p=0.001 for grade 1 versus grade 3), and increased CSF neutrophils (r=0.364, p<0.0001) and cytokine concentrations (r=0.438, p<0.0001). High Mtb load predicted new neurological events after starting treatment (Multinomial logistic regression, p=0.005), but not death. Death was previously associated with attenuated inflammatory response at the start of treatment, with reduced cytokine concentrations compared to survivors...
Journal of Neuroinflammation, 2015
Background: Tuberculosis (TB) affects one third of the global population, and TB of the central nervous system (CNS-TB) is the most severe form of tuberculosis which often associates with high mortality. The pro-inflammatory cytokine tumour necrosis factor (TNF) plays a critical role in the initial and long-term host immune protection against Mycobacterium tuberculosis (M. tuberculosis) which involves the activation of innate immune cells and structure maintenance of granulomas. However, the contribution of TNF, in particular neuron-derived TNF, in the control of cerebral M. tuberculosis infection and its protective immune responses in the CNS were not clear. Methods: We generated neuron-specific TNF-deficient (NsTNF −/− ) mice and compared outcomes of disease against TNF f/f control and global TNF −/− mice. Mycobacterial burden in brains, lungs and spleens were compared, and cerebral pathology and cellular contributions analysed by microscopy and flow cytometry after M. tuberculosis infection. Activation of innate immune cells was measured by flow cytometry and cell function assessed by cytokine and chemokine quantification using enzyme-linked immunosorbent assay (ELISA). Results: Intracerebral M. tuberculosis infection of TNF −/− mice rendered animals highly susceptible, accompanied by uncontrolled bacilli replication and eventual mortality. In contrast, NsTNF −/− mice were resistant to infection and presented with a phenotype similar to that in TNF f/f control mice. Impaired immunity in TNF −/− mice was associated with altered cytokine and chemokine synthesis in the brain and characterised by a reduced number of activated innate immune cells. Brain pathology reflected enhanced inflammation dominated by neutrophil influx.
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
PLoS ONE, 2009
Background: Adjunctive dexamethasone reduces mortality from tuberculous meningitis, but how it produces this effect is not known. Matrix metalloproteinases (MMPs) are important in the immunopathology of many inflammatory CNS diseases thus we hypothesized that that their secretion is important in TBM and might be influenced by dexamethasone. Methodology/Principal Findings: The kinetics of cerebrospinal fluid (CSF) MMP and tissue inhibitors of MMPs (TIMPs) concentrations were studied in a subset of HIV uninfected adults (n = 37) with TBM recruited to a randomized, placebocontrolled trial of adjuvant dexamethasone. Analysis followed a pre-defined plan. Dexamethasone significantly reduced CSF MMP-9 concentrations in early follow up samples (median 5 days (range 3-8) of treatment), but had no significant influence on other MMPs/TIMPs. Additionally CSF MMP-9 concentration was strongly correlated to concomitant CSF neutrophil count. Conclusions/Significance: Dexamethasone decreased CSF MMP-9 concentrations early in treatment and this may represent one mechanism by which corticosteroids improve outcome in TBM. The strong correlation between CSF MMP-9 and neutrophil count suggests that polymorphonuclear leukocytes may play a central role in the early pathogenesis of TBM.
Host immune response to tuberculous meningitis
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2015
Tuberculous meningitis (TBM) is a severe complication of tuberculosis predominantly affecting young children. Early treatment is vital to prevent morbidity and mortality, emphasizing the importance of early diagnosis. The lack of sensitive methods for early diagnosis is the most common cause of delay. Attempts have been made to develop simplified tests for tuberculosis, but their diagnostic power remains poor. The clinical picture of TBM is mainly driven by the host's immune response to Mycobacterium tuberculosis; therefore, identification of disease-specific biomarkers may have diagnostic and therapeutic value and improve our understanding of its pathogenesis. We investigated disease-specific biomarkers of childhood TBM in a cohort of children aged 3 months-13 years with symptoms and signs suggestive of meningitis. Cerebrospinal fluid (CSF) and serum from 56 patients with and 55 patients without TBM were assessed for 28 soluble mediators. Unsupervised hierarchical clustering an...