PPD-induced monocyte mitochondrial damage is associated with a protective effect to develop tuberculosis in BCG vaccinated individuals: A cohort study.

INTRODUCTION: The mechanisms of mononuclear phagocyte death have been associated with the permissiveness and resistance to mycobacterial replication, but it remains unknown whether or not they help predict the risk of developing TB. OBJECTIVE: To describe the factors associated with the induction of monocyte mitochondrial and membrane damage in response to PPD as well as determine if this type of damage might predict the susceptibility of developing active tuberculosis in a cohort of household contacts (HHCs) from Medellin, Colombia from 2005 to 2008. METHODS: The prospective cohort study contains 2060 HHCs patients with pulmonary tuberculosis who were meticulously followed for two years. A survey of the socio-demographic, clinical, epidemiological factors and blood samples were collected. Mononuclear cell cultures were stimulated with or without PPD and the type of monocyte death was determined by the flow of cytometry, an indicator was also used for its analysis. Logistic regression was adjusted by the Generalized Estimations Equations and the survival was estimated with the Kaplan-Meier and Cox regression. Confidence intervals were used for estimating the association. RESULTS: 1,859 out of 2,060 blood samples of the HHCs patients analyzed showed monocyte death. In response to PPD, 83.4% underwent mitochondrial damage while 50.9% had membrane damage. The membrane damage in response to PPD was higher in children under 4 years (OR: 1.57; (95% CI: 1.1 to 2.4) and the HHCs who slept regularly in the same household has an index case of (OR: 1.54; 95% CI: 1.0 to 2.3). After adjustment by age, comorbidities, nutritional status, proximity to index case and overcrowding, the risk of developing active TB among BCG vaccinated HHCs individuals with induction of mitochondrial damage was HR = 0.19 (95% CI: 0.1 to 0.5). CONCLUSIONS: The induction of monocytes mitochondrial damage by PPD stimulation correlates with protection of TB disease development in BCG-vaccinated HHCs. This represents a potential tool to predict susceptibility of developing active disease in this population.

Fatty acid profile during the differentiation and infection with Mycobacterium tuberculosis of mononuclear phagocytes of patients with TB and healthy individuals.

The blockade of sPLA-2, as well as the removal of calcium during the infection with Mycobacterium tuberculosis, prevents necrosis in mononuclear phagocytes. In addition, previous evidence indicates that the necrosis is modulated by cytokines and may condition the inflammatory environment. The production of cytokines and chemokines in response to infection with M. tuberculosis, fatty acid profile and the lactate dehydrogenase activity in mononuclear phagocytes from tuberculosis patients and healthy controls were interrelated using a principal component analysis in order to establish whether there was an association between the induction and effector stages of necrosis with the production of cytokines and chemokines. Differentiation increased the ratio of saturated/unsaturated fatty acids. The oleate and palmitate correlated with differentiation, laureate, arachidonate and linolenate with infection and necrosis correlates with the production of IL-10. Monocytes from tuberculosis patients seem to be lees differentiated ex vivo.

La necrosis, un mecanismo regulado de muerte celular / Necrosis, a regulated mechanism of cell death

Con base en criterios morfológicos y bioquímicos se han definido tres clases de muerte celular: apoptosis, autofagia y necrosis. La primera es una muerte celular regulada, mediada principalmente por caspasas; en la autofagia ocurre formación de vesículas que se fusionan con vacuolas hidrolíticas para degradar organelas intracelulares alteradas. En cuanto a la necrosis, se la ha definido tradicionalmente por la ruptura de la membrana citoplasmática con salida del material intracelular lo que desencadena una reacción inflamatoria localizada; los mediadores pueden variar dependiendo del tejido: lipasas, proteasas y endonucleasas. Las actividades celulares intrínsecas y los eventos que preceden al colapso celular definen el tipo de daño. Pero el hecho de que los tres tipos de muerte celular puedan coexistir y la ocurrencia de necrosis incluso en presencia de ATP hacen pensar que esta es un evento menos pasivo y que hasta cierto punto se puede regular la inducción del daño. Las alteraciones en la estructura de proteínas y en la actividad de proteasas, lipasas y endonucleasas en presencia de sus cofactores, asociadas con los mecanismos intrínsecos de regulación celular permiten pensar que cada célula puede tener su propio arsenal para producir los eventos designados como necrosis (recientemente denominada parapoptosis). En este artículo se revisan algunas de las evidencias sobre la regulación durante la necrosis en diferentes modelos celulares.

Three types of cellular death have been defined by morphological and biochemical criteria: apoptosis, necrosis and autophagy. Apoptosis is a regulated cell death, mainly mediated by caspases; autophagy induces degradation of intracellular damaged organelles through the formation of vesicles that fuse with hydrolytic vacuoles. Necrosis has been traditionally defined by the rupture the cytoplasmic membrane with subsequent release of intracellular material, triggering localized inflammatory Intrinsic cellular activities and the events preceding cellular collapse are critical to determine the type of tissue damage. The fact that all three types of cellular death can coexist in any organ and tissue with different availabilities of ATP, suggests that necrosis can be conceived as an active event and that to some extent it may be regulated. Alterations in the structure of proteins and in the activity of different proteases, lipases and nucleases, indicate that each cell may have its own arsenal to trigger the events leading to necrosis. In this article we review some of the evidences on cellular regulation during necrosis.