The Tim3-galectin 9 pathway induces antibacterial activity in human macrophages infected with Mycobacterium tuberculosis.

T cell Ig and mucin domain 3 (Tim3) is an inhibitory molecule involved in immune tolerance, autoimmune responses, and antiviral immune evasion. However, we recently demonstrated that Tim3 and Galectin-9 (Gal9) interaction induces a program of macrophage activation that results in killing of Mycobacterium tuberculosis in the mouse model of infection. In this study, we sought to determine whether the Tim3-Gal9 pathway plays a similar role in human pulmonary TB. We identified that pulmonary TB patients have reduced expression of Tim3 on CD14(+) monocytes in vivo. By blocking Tim3 and Gal9 interaction in vitro, we show that these molecules contribute to the control of intracellular bacterial replication in human macrophages. The antimicrobial effect was partially dependent on the production of IL-1ß. Our results establish that Tim3-Gal9 interaction activates human M. tuberculosis -infected macrophages and leads to the control of bacterial growth through the production of the proinflammatory cytokine IL-1ß. Data presented in this study suggest that one of the potential pathways activated by Tim3/Gal9 is the secretion of IL-1ß, which plays a crucial role in antimicrobial immunity by modulating innate inflammatory networks.

Prevalence of latent and active tuberculosis among dairy farm workers exposed to cattle infected by Mycobacterium bovis.

BACKGROUND: Human tuberculosis caused by M. bovis is a zoonosis presently considered sporadic in developed countries, but remains a poorly studied problem in low and middle resource countries. The disease in humans is mainly attributed to unpasteurized dairy products consumption. However, transmission due to exposure of humans to infected animals has been also recognized. The prevalence of tuberculosis infection and associated risk factors have been insufficiently characterized among dairy farm workers (DFW) exposed in settings with poor control of bovine tuberculosis. METHODOLOGY/PRINCIPAL FINDINGS: Tuberculin skin test (TST) and Interferon-gamma release assay (IGRA) were administered to 311 dairy farm and abattoir workers and their household contacts linked to a dairy production and livestock facility in Mexico. Sputa of individuals with respiratory symptoms and samples from routine cattle necropsies were cultured for M. bovis and resulting spoligotypes were compared. The overall prevalence of latent tuberculosis infection (LTBI) was 76.2% (95% CI, 71.4-80.9%) by TST and 58.5% (95% CI, 53.0-64.0%) by IGRA. Occupational exposure was associated to TST (OR 2.72; 95% CI, 1.31-5.64) and IGRA (OR 2.38; 95% CI, 1.31-4.30) adjusting for relevant variables. Two subjects were diagnosed with pulmonary tuberculosis, both caused by M. bovis. In one case, the spoligotype was identical to a strain isolated from bovines. CONCLUSIONS: We documented a high prevalence of latent and pulmonary TB among workers exposed to cattle infected with M. bovis, and increased risk among those occupationally exposed in non-ventilated spaces. Interspecies transmission is frequent and represents an occupational hazard in this setting.

Bacille Calmette-Guérin infection and disease with fatal outcome associated with a point mutation in the interleukin-12/interleukin-23 receptor beta-1 chain in two Mexican families.

Patients with Mendelian susceptibility to mycobacterial diseases (MSMD) mainly suffer from Mycobacterium and Salmonella infections, which are due to mutations in genes controlling the interleukin (IL)-12/IL-23-dependent IFN-γ production. We performed a molecular diagnosis in two Mexican patients with persistent mycobacterial infections. Patients 1 (P1) and 2 (P2) from two unrelated, non-consanguineous families from two villages near Mexico City developed bacille Calmette-Guérin (BCG) disease secondary to vaccination; patients and their families were studied at the immunological level for production and response to IFN-γ. The ß1 subunit of the IL-12 receptor (encoded by the IL12RB1 gene) was not expressed in cells from P1 or P2, or in two siblings of P1. Sequencing of the IL12RB1 gene showed the same point mutation 1791+2 T>G, homozygous in patients and heterozygous in parents. P1 and P2 died at the ages of 4 and 16 years, respectively, with disseminated and uncontrolled BCG disease and with Candida albicans infections in spite of multiple anti-mycobacterial drug treatments. One of P2's siblings also died following disseminated mycobacterial infection secondary to BCG vaccination. These are the first cases in Mexico of patients with BCG disease traced to a mutation in the IL12RB1 gene, with a fatal outcome. Doctors must be alert to the adverse reactions to BCG vaccination and to persistent Mycobacterium infections, and in such cases should investigate possible mutations in the genes of the IL-12/IL-23-IFN-γ axis.

Papel de las células epiteliales en la respuesta inmune del pulmón / Immunological role of epithelial cells of the lung

El sistema respiratorio se encuentra en contacto con agentes patógenos; sin embargo, gracias a la respuesta inmune innata de éste, sólo en raras ocasiones se produce la enfermedad. Las células epiteliales del tracto respiratorio desempeñan un papel importante para evitar la colonización del pulmón por agentes infecciosos, identificando a los microorganismos a través de receptores especializados como los toll-like. Asimismo, son capaces de secretar citocinas, péptidos antimicrobianos y otras moléculas proinflamatorias, las cuales evitan el establecimiento de patógenos.

The respiratory tract is one of the main systems which is in perennial contact with a wide variety of pathogenic microorganisms; however, infection is seldom produced due to its innate immune response. Respiratory tract epithelial cells play a very important role to avoid colonization of the lung by infectious agents, because they recognize microbial molecules through very specialized receptors, such as toll-like receptors; moreover, these cells posses a broad variety of molecules which are related to local immunity. Respiratory tract epithelial cells produce chemokines, antimicrobial peptides and other proinflammatory molecules that prevent the establishment of pathogenic microorganisms.

Mecanismos moleculares de la respuesta inmune en la tuberculosis pulmonar humana / Molecular mechanisms of the immune response in human pulmonary tuberculosis

La tuberculosis pulmonar humana es una enfermedad infecciosa causada por M. tuberculosis; el control de la infección requiere el desarrollo de una respuesta inmune protectora. Este tipo de respuesta inmunológica incluye la participación de los macró-fagos alveolares, linfocitos T (CD4+,CD8+, NK y yδ) y la producción de citocinas como: 1L-2, IFN-γ, IL-12, IL-18 y TNF-α. Asimismo, de quimiocinas como: RANTES, MCP-1, MlP-lα e 11-8 que tienen un papel muy importante en la migración de las diferentes subpoblaciones celulares al sitio de infección para la formación del granuloma. El objetivo de este trabajo es ofrecer un panorama de los mecanismos inmunológicos involucrados en la respuesta inmune celular en la tuberculosis pulmonar humana.

Human pulmonary tuberculosis is an infectious disease caused by M. tuberculosis; the protective immune response plays a central role in the control and progression of this disease. The immune response includes the participation of alveolar macrophages, lymphocytes (subsets CD4+, CD8+, NK and yδ) and cytokine production such as IL-2, IFN-γ, IL-12, IL-18 and TNF-α. Moreover, chemokines like RANTES, MCP-1, MIP-lα and IL-8 play an important role in the chemotaxis of different cell populations at the infection site for the formation of granulomas. This paper provides an overview of the immune mechanisms involved in the cellular immune response in human pulmonary tuberculosis.

Valoración del uso de inmunoensayos para el diagnóstico rápido de tuberculosis en población abierta / Evaluation of immunoassays use for the fast diagnosis of tuberculosis in open population

Se valoró la utilización de técnicas inmunológicas como métodos alternativos en el diagnóstico de tuberculosis pulmonar(TBP), realizando la búsqueda de antígenos de M. tuberculosis y anticuerpos dirigidos contra la misma bacteria en suero de pacientes con sospecha clínica de tuberculosis. El antígeno -lipoarabinomanana- (LAM) de M. tuberculosis, se detectó por coaglutinación e inmunoensayo en papel (DOT) utilizando suero hiperinmune de conejo y un anticuerpo monoclonal. Para la detección de anticuerpos se usaron dos sistemas de ELISA utilizando en ellos, como antígenos, un extracto soluble de M. tuberculosis y lipoarabinomanana purificada. Los resultados demostraron que la detección del antígeno en estos sistemas fue poco eficiente, para coaglutinación la sensibilidad fue 32 por ciento y la especificidad 81 por ciento, mientras que para DOT fueron 38 por ciento y 84 por ciento respectivamente. La detección por ELISA de anticuerpos utilizando extracto de M tuberculosis mostró una sensibilidad del 80 por ciento con especificidad del 60 por ciento. Con LAM la sensibilidad fue 50 por ciento con especificidad de 90 por ciento. Los resultados anteriores sugieren que el uso de inmunoensayos utilizando sueros de pacientes para la búsqueda de LAM y, para la detección de anticuerpos en contra de estos antígenos, no tiene suficiente especificidad y sensibilidad para ser de utilidad en el diagnóstico rutinario de tuberculosis en población abierta. Es necesario desarrollar métodos rápidos para el diagnóstico de TBP, especialmente en países en desarrollo en los que la prevalencia de TBP es mayor

Inmunogenética en tuberculosis pulmonar / Immunogenetics in pulmonar tuberculosis

La predisposición genética a la tuberculosis y enfermeades infecciosas crónicas similares, ha sido tema de numerosos estudios y controversias, debido a la diversidad de resultados obtenidos. En un estudio previo realizado en una población abierta de enfermos, determinando los antígenos de histocompatibilidad se describió una disminución importante en expresión de estos marcadores. También se describió un incremento en la beta 2 microglobulina, péptido asociado estructuralmente a estos antígenos. En este trabajo, se estudiaron 19 familias de tuberculosos (23 enfermos y 58 sanos) los antígenos HLA (incluyendo el locus DQ) y la beta 2 microglobulina, así como, las subpoblaciones de linfocitos T. Encontrando que la coincidencia en enfermos del alelo DQ1 e incremento de la beta 2 microglobulina sérica es altamente significativa (p<0.00001). Estos datos apoyan la existencia de una predisposición genética en la mayoría de los enfermos con tuberculosis.