Virulence Factors of Mycobacterium tuberculosis as Modulators of Cell Death Mechanisms.

Mycobacterium tuberculosis (Mtb) modulates diverse cell death pathways to escape the host immune responses and favor its dissemination, a complex process of interest in pathogenesis-related studies. The main virulence factors of Mtb that alter cell death pathways are classified according to their origin as either non-protein (for instance, lipomannan) or protein (such as the PE family and ESX secretion system). The 38 kDa lipoprotein, ESAT-6 (early antigen-secreted protein 6 kDa), and another secreted protein, tuberculosis necrotizing toxin (TNT), induces necroptosis, thereby allowing mycobacteria to survive inside the cell. The inhibition of pyroptosis by blocking inflammasome activation by Zmp1 and PknF is another pathway that aids the intracellular replication of Mtb. Autophagy inhibition is another mechanism that allows Mtb to escape the immune response. The enhanced intracellular survival (Eis) protein, other proteins, such as ESX-1, SecA2, SapM, PE6, and certain microRNAs, also facilitate Mtb host immune escape process. In summary, Mtb affects the microenvironment of cell death to avoid an effective immune response and facilitate its spread. A thorough study of these pathways would help identify therapeutic targets to prevent the survival of mycobacteria in the host.

Arterial Blood Gases in Normal Subjects at 2240 Meters Above Sea Level: Impact of Age, Gender, and Body Mass Index

ABSTRACT Background The values of arterial blood gases (ABG) change with altitude above sea level; empirical verification is essential because ventilatory acclimatization varies with ethnicity and a population's adaptation. Objective The aim of the study was to describe ABG in a healthy population residing at 2,240 meters above sea level, to identify the mean level of alveolar ventilation (PaCO2), and to know whether a progressive increase in PaCO2 occurs with age and the impact of increasing body mass index (BMI). Methods We conducted a cross-sectional study in a referral center for respiratory diseases in Mexico City. Associations among variables with correlation coefficient and regression models of PaO2, SaO2, and P(A-a)O2 as dependent variables as a function of age, BMI, minute ventilation, or breathing frequency were explored. Results Two hundred and seventeen healthy subjects were evaluated with a mean age of 40 ± 15 years, mean of the PaO2 was 71 ± 6 mmHg, SaO2 94% ± 1.6%, PaCO2 30.2 ± 3.4 mmHg, HCO3 20 ± 2 mmol/L, BE-2.9 ± 1.9 mmol/L, and the value of pH was 7.43 ± 0.02. In a linear regression, the main results were PaO2 = 77.5-0.16*age (p < 0.0001) and with aging P(A-a)O2 tended to increase 0.12 mmHg/year. PaCO2 in women increased with age by 0.075 mmHg/year (p = 0.0012, PaCO2 =26.3 + 0.075*age). SaO2 and PaO2 decreased significantly in women with higher BMI 0.14% and 0.52 mmHg per kg/m2, (p = 0.004 and 0.002 respectively). Conclusion Mean PaCO2 was 30.7 mmHg, implying a mean alveolar ventilation of around 30% above that at sea level.

Anti-tuberculosis chemotherapy alters TNFR2 expression on CD4+ lymphocytes in both drug-sensitive and -resistant tuberculosis: however, only drug-resistant tuberculosis maintains a pro-inflammatory profile after a long time.

BACKGROUND: Tuberculosis (TB) is an infectious disease. During TB, regulatory T cells (Treg) are related to poor prognosis. However, information about conventional and unconventional Treg (cTreg and uTreg, respectively) is limited. The tumour necrosis factor (TNF) and its receptors (TNFR1 and TNFR2) are necessary for mycobacterial infection, and TNFR2 signalling is required to maintain Treg. METHODS: A blood sample of drug-susceptible (DS-TB) and drug-resistant tuberculosis (DR-TB) patients was obtained before (basal) and after 2 and 6 months of anti-TB therapy. Expression of TNF, TNFR1, and TNFR2 (transmembrane form, tm) on cTreg, uTreg, activated CD4+ (actCD4+), and CD4+ CD25- (CD4+) T cell subpopulations were evaluated. The main objective was to identify immunological changes associated with sensitive/resistant Mtb strains and with the use of anti-TB therapy. RESULTS: We found that after 6 months of anti-TB therapy, both DS- and DR-TB patients have decreased the frequency of cTreg tmTNF+, CD4+ tmTNFR1+ and CD4+ tmTNFR2+. Nevertheless, after 6 months of therapy, only DR-TB patients decreased the frequency of actCD4+ tmTNF+ and actCD4+ tmTNFR2+, exhibited a systemic inflammatory status (high levels of TNF, IFN-γ and IL-12), and their purified CD4+ T cells showed that TNF and TNFR2 are up-regulated at the transcriptional level. Moreover, DS- and DR-TB down-regulated TNFR1 and other proteins associated with Treg (FOXP3 and TGFß1) in response to the anti-TB therapy. CONCLUSION: These results partially explain the differences in the immune response of DS-TB vs DR-TB. The frequency of actCD4+ tmTNFR2+ cells and inflammatory status should be considered in the follow-up of therapy in DR-TB patients.

Malnutrition and tuberculosis: the gap between basic research and clinical trials.

Mycobacterium tuberculosis (M.tb) is the causative agent of tuberculosis (TB), an infectious disease that leads to numerous deaths worldwide. Malnutrition, smoking, alcohol abuse, Human Immunodeficiency Virus infection, and diabetes are some of the most important risk factors associated with TB development. At present, it is necessary to conduct studies on risk factors to establish new effective strategies and combat this disease. Malnutrition has been established as a risk factor since several years ago; although there is in vitro experimental evidence that reveals the importance of micronutrients in activating the immune response against M.tb, evidence from clinical trials is controversial. Currently, nutritional assessment is recommended in all TB patients upon diagnosis. However, there is insufficient evidence to indicate micronutrient supplementation as adjuvant therapy or prophylactic to prevent micronutrient depletion. Strengthening the interaction between basic and clinical research is necessary to carry out studies that will help establish adjuvant therapies to improve outcomes in TB patients. In this review, we discuss the experimental evidence, provided by basic research, regarding micronutrients in the TB field. However, when these studies are applied to clinical trials, the data are inconsistent, indicating that still missing mechanisms are necessary to propose alternatives to the treatment of TB patients.

Mycobacterium tuberculosis H37Rv Strain Increases the Frequency of CD3+TCR+ Macrophages and Affects Their Phenotype, but Not Their Migration Ability.

In mycobacterial infections, the number of cells from two newly discovered subpopulations of CD3+ myeloid cells are increased at the infection site; one type expresses the T cell receptor (CD3+TCRαß+) and the other does not (CD3+TCRαß-). The role of Mycobacterium tuberculosis (Mtb) virulence in generating these subpopulations and the ability of these cells to migrate remains unclear. In this study, monocyte-derived macrophages (MDMs) infected in vitro with either a virulent (H37Rv) or an avirulent (H37Ra) Mtb strain were phenotypically characterized based on three MDM phenotypes (CD3-, CD3+TCRαß+, and CD3+TCRαß-); then, their migration ability upon Mtb infection was evaluated. We found no differences in the frequency of CD3+ MDMs at 24 h of infection with either Mtb strain. However, H37Rv infection increased the frequency of CD3+TCRαß+ MDMs at a multiplicity of infection of 1 and altered the expression of CD1b, CD1c, and TNF on the surface of cells from both the CD3+ MDM subpopulations; it also modified the expression of CCR2, CXCR1, and CCR7, thus affecting CCL2 and IL-8 levels. Moreover, H37Rv infection decreased the migration ability of the CD3- MDMs, but not CD3+ MDMs. These results confirm that the CD3+ macrophage subpopulations express chemokine receptors that respond to chemoattractants, facilitating cell migration. Together, these data suggest that CD3+ MDMs are a functional subpopulation involved in the immune response against Mtb.

Chronic obstructive pulmonary disease: perspectives for primary health care

Abstract Background Chronic obstructive pulmonary disease (COPD) has become a major health challenge worldwide due to its increasing incidence and mortality, which have serious repercussions for health-care systems. Methods We conducted a review of international efforts to control COPD in primary care. Results The WHO created the Alma-Ata declaration which established for the first time, access to health care as a human right. This precept led to the implementation of numerous programs including practical approach to Lung Health and variants in several countries; schemes designed to centralize medical care; and resources to improve attention of respiratory diseases by adapting approaches to the health-care needs of local populations. Primary respiratory health care should include actions for timely detection, health education, and targeted treatment, but the challenge for all health systems is to ensure that their programs function adequately, for they still show shortcomings in terms of their application. Conclusions We conclude that offering primary health care based on models that combine opportune diagnoses with suitable treatment can positively influence the course of COPD by treating early stages, thus slowing its progression. However, more extensive education and broader dissemination of information are necessary to achieve this goal.