Tuberculous Meningitis Genetic predisposition: Understanding cellular interactions, molecular mechanisms and genetic dimensions.

Tuberculous meningitis, a severe form of tuberculosis caused by Mycobacterium tuberculosis (BK), remains a major public health challenge worldwide. In addition to the complex mechanisms of the innate and adaptive immune response against Mycobacterium tuberculosis, there is a crucial genetic dimension to consider. Individuals with specific genetic variations may have altered immune responses that make them more susceptible to this form of tuberculosis. Genetic mutations in genes encoding surface receptors, adaptor proteins, kinases, transcription factors, nucleic receptors and other molecules involved in cellular interactions and molecular mechanisms have been associated with susceptibility to TB. Understanding the molecular mechanisms of immune interactions in host response to Mycobacterium tuberculosis is crucial to understanding the genetic dimension in susceptibility to tuberculosis, particularly its dreaded form of tuberculous meningitis. The aim of this update is to explore in details the key interactions between the main players in innate and adaptive immunity during infection with Mycobacterium tuberculosis, with particular emphasis on the genetic factors associated with susceptibility to tuberculosis, especially its dreaded form of tuberculous meningitis.

Single-cell transcriptome reveals highly complement activated microglia cells in association with pediatric tuberculous meningitis.

Background: Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB) causing high mortality and disability. TBM arises due to immune dysregulation, but the underlying immune mechanisms are unclear. Methods: We performed single-cell RNA sequencing on peripheral blood mononuclear cells (PBMCs) and cerebrospinal fluid (CSF) cells isolated from children (n=6) with TBM using 10 xGenomics platform. We used unsupervised clustering of cells and cluster visualization based on the gene expression profiles, and validated the protein and cytokines by ELISA analysis. Results: We revealed for the first time 33 monocyte populations across the CSF cells and PBMCs of children with TBM. Within these populations, we saw that CD4_C04 cells with Th17 and Th1 phenotypes and Macro_C01 cells with a microglia phenotype, were enriched in the CSF. Lineage tracking analysis of monocyte populations revealed myeloid cell populations, as well as subsets of CD4 and CD8 T-cell populations with distinct effector functions. Importantly, we discovered that complement-activated microglial Macro_C01 cells are associated with a neuroinflammatory response that leads to persistent meningitis. Consistently, we saw an increase in complement protein (C1Q), inflammatory markers (CRP) and inflammatory factor (TNF-α and IL-6) in CSF cells but not blood. Finally, we inferred that Macro_C01 cells recruit CD4_C04 cells through CXCL16/CXCR6. Discussion: We proposed that the microglial Macro_C01 subset activates complement and interacts with the CD4_C04 cell subset to amplify inflammatory signals, which could potentially contribute to augment inflammatory signals, resulting in hyperinflammation and an immune response elicited by Mtb-infected tissues.

Tratamiento de meningitis tuberculosa en paciente HIV negativo, posible reacción paradojal / Possible paradoxical reaction to treatment of tubercular meningitis in an HIV negative patient

La respuesta paradojal al tratamiento tuberculoso es la aparición de manifestaciones clínico-radiológicas nuevas, o el empeoramiento de las previas, luego de una mejoría inicial con el tratamiento específico. Se puede observar en 6-30% de los casos de tuberculosis meníngea. Es una reacción inmunológica exagerada y debe tenerse presente ya que su tratamiento se basa en el uso de inmunomoduladores y no en el cambio de las drogas antituberculosas. Presentamos el caso de una paciente adulta HIV negativa con meningitis tuberculosa que, luego de una adecuada respuesta inicial al tratamiento, intercurre a las 10 semanas con una reacción paradojal tratada satisfactoriamente con corticoides.

The paradoxical response to tuberculosis treatment consists in the appearance of new clinical or radiologic manifestations or worsening of previous injuries after an initial improvement with anti-tuberculosis therapy. It can be observed in 6 to 30 percent of the cases of tubercular meningitis. It is the consequence of an exaggerated immune reaction that should be considered since the treatment is based on the use of immunomodulators and not in the change of anti-tuberculous drugs. We present the case of an HIV negative adult with tuberculous meningitis with a good initial response to specific therapy who showed, 10 weeks later, a paradoxical reaction to treatment that responded successfully to corticosteroids.

Evaluation of Lionex TB kits and mycobacterial antigens for IgG and IgA detection in cerebrospinal fluid from tuberculosis meningitis patients

To evaluate commercial Lionex TB together with four antigens of Mycobacterium tuberculosis (MPT-64, MT10.3, 16 kDa and 38 kDa) for IgG and IgA cerebrospinal fluid (CSF) detection in the diagnosis of tuberculosis meningitis (TBM) with CSF negative acid-fast bacilli staining, 19 cases of TBM, 64 cases of other infectious meningoencephalitis and 73 cases of other neurological disorders were tested by enzyme linked immunosorbent assay. IgA-MPT-64 and IgG Lionex showed the highest sensitivities, specificities, positive predictive value and negative predictive value (63.2 percent, 47.4 percent; 95 percent, 93.7 percent; 40 percent, 98 percent and 28.4 percent, 97.1 percent, respectively). However, while grey zone was 12.7 percent and 6 percent, respectively, lowering sensitivity but maintains high specificity (> 95 percent). High protein concentration in CSF was associated with antibody positivity CSF/HIV+ which did not influence the sensitivity of both tests. To our knowledge, this is the first description of IgA-MPT-64 and IgG Lionex antibodies in CSF-TBM and, although there is good specificity, adjustments are needed based on antigen composition to enhance sensitivity.

CD4+ cell counts in patients with different clinical manifestations of tuberculosis

Tuberculosis is the prototype of infections that require a cellular immune response for their control. It has been shown that CD4+ T-lymphocytes are most important in the protective response against Mycobacterium tuberculosis. CD8+ T-lymphocytes are also important for effective T-cell immune response. This study compares CD4+ and CD8+ baseline values in patients with different manifestations of tuberculosis. CD4+ and CD8+ in three groups of patients with tuberculosis (pulmonary, lymphadenitis, meningitis/milliary involvement) and a group of healthy volunteers were enumerated using flowcytometry. Twenty-six patients with pulmonary tuberculosis, 10 with adenitis, 16 with meningitis or milliary tuberculosis and 16 healthy volunteers entered the study. Mean CD4 in meningitis/milliary group was significantly lower than all other groups (p<0.05). Mean CD4 counts of patients with pulmonary tuberculosis was also significantly lower than control group (p=0.01). Mean CD8 in meningitis/milliary group was significantly lower than control group (p=0.02). No relation was found between results of TSTs and CD4 values in three groups. CD4 depletion is an expectable phenomenon in patients with tuberculosis. This study shows that patients with more severe form of disease had the lowest number of both CD4 and CD8 cells which can be a sign of suppressed cellular immunity in these patients.

Inmunoglobulinas en líquidos cefalorraquídeo y suero de pacientes con meningitis tuberculosa / Inmunoglobulins in cerebrospinal fluid and serum of patients with tuberculous meningitis

Se realizaron determinaciones de las concentraciones séricas y en líquido cefalorraquídeo de IgG, IgA, e IgM por medio de nefelometría y se calcularon los valores absolutos y normalizados con base en los valores esperados en población normal, así como con el índice LCR/suero en: a) veinte pacientes con meningitis tuberculosa (M-TBC) comprobados por hallazgos bacteriológicos y/o autopsia; b) ocho pacientes con cuadro clínico de meningitis tuberculosa, en los cuales no se encontró el microorganismo; c) catorce pacientes cuyas evolución clínica se asemejó a la meningitis tuberosa pero luego se esclareció otra patologia y d) como controles 16 sujetos sin sintomatología ni signología meníngea y con citoquímico normal del LCR. Teniendo como base los valores establecidos en el grupo control, se apreció un gran aumento de las tres proteínas estudiadas en LCR en sus índices respectivos en los grupos de M-TBC. En el gupo con otros diagnósticos la IgA presentó valores muy elevados en LCR, mientras que para la IgG y la IgM los aumentos fueron moderados. Las concentraciones séricas de IgG e IgA fueron normales en todos los grupos de pacientes y la de IgM presentó un ligero aumento en M-TBC y en otras patologías. La edad en los controles correlacionó con los valores de IgG en el LCR y en menor grado con los de IgA e IgM. Igualmente los índices de IgG e IgM correlacionaroan con los de IgA en los pacientes con M-TBC y otros diagnósticos. La elevación de las Igs en LCR no parece ser de ayuda en el diagnóstico diferencial de la M-TBC, pero sí explica parcialmente la inmunopatolgénesis de la reación inflamatoria a nivel de SNC