cyclic-gmp and Tuberculosis--Pulmonary

Mycobacterium tuberculosis (Mtb) has been a threat to humans since ancient times, and it is the main causative agent of tuberculosis (TB). Until today, the only licensed vaccine against Mtb is the live attenuated M. bovis Bacillus Calmette-Guérin (BCG), which has variable levels of protection against the pulmonary form of infection. The quest for a new vaccine is a priority given the rise of multidrug-resistant Mtb around the world, as well as the tremendous burden imposed by latent TB. The objective of this study was to evaluate the immunogenicity and capacity of protection of a modified BCG strain (BCGΔBCG1419c) lacking the c-di-GMP phosphodiesterase gene BCG1419c, in diverse mice models. In a previous report, we have shown that BCGΔBCG1419c was capable of increasing biofilm production and after intravenous infection of immunocompetent mice; this strain persisted longer in lungs than parental BCG Pasteur. This led us to hypothesize that BCGΔBCG1419c might therefore possess some advantage as vaccine candidate. Our results in this report indicate that compared to conventional BCG, vaccination with BCGΔBCG1419c induced a better activation of specific T-lymphocytes population, was equally effective in preventing weight loss despite being used at lower dose, reduced tissue damage (pneumonic scores), increased local IFNγ(+) T cells, and diminished bacterial burden in lungs of BALB/c mice infected intratracheally with high dose Mtb H37Rv to induce progressive TB. Moreover, vaccination with BCGΔBCG1419c improved resistance to reactivation after immunosuppression induced by corticosterone in a murine model of chronic infection similar to latent TB. Furthermore, despite showing increased persistence in immunocompetent mice, BCGΔBCG1419c was as attenuated as parental BCG in nude mice. To our knowledge, this is the first demonstration that a modified BCG vaccine candidate with increased pellicle/biofilm production has the capacity to protect against Mtb challenge in chronic and reactivation models of infection.

Topics: Animals; Bacterial Load; BCG Vaccine; Cyclic GMP; Female; Latent Tuberculosis; Lung; Mice; Mice, Inbred BALB C; Mice, Nude; Mycobacterium tuberculosis; T-Lymphocytes; Tuberculosis, Pulmonary; Virulence

Dormancy of Mycobacterium tuberculosis is likely to be a major cause of extended chemotherapeutic regimens and wide prevalence of tuberculosis. The molecular mechanisms underlying M. tuberculosis dormancy are not well understood. In this study, single-copy genes responsible for synthesis (dgc) and degradation (pde) of the ubiquitous bacterial second messenger, cyclic di-GMP (c-di-GMP), were deleted in the virulent M. tuberculosis strain H37Rv to generate dgc(mut) and Δpde, respectively. Under aerobic growth conditions, the two mutants and wild-type cells showed similar phenotypes. However, dgc(mut) and Δpde exhibited increased and reduced dormancy, respectively, in both anaerobiosis-triggered and vitamin C-triggered in vitro dormancy models, as determined by survival and growth recovery from dormancy. The transcriptomes of aerobic cultures of dgc(mut) and wild-type H37Rv exhibited no difference, whereas those of anaerobic cultures showed a significant difference with 61 genes that are not a part of the dosR regulon. Furthermore, Δpde but not dgc(mut) showed decreased infectivity with human THP-1 cells. Δpde also showed attenuated pathogenicity in a C57BL/6 mouse infection model. These findings are explained by c-di-GMP-mediated signaling negatively regulating M. tuberculosis dormancy and pathogenicity.

Topics: Anaerobiosis; Animals; Cyclic GMP; Disease Models, Animal; Gene Deletion; Mice; Mice, Inbred C57BL; Microbial Viability; Mycobacterium tuberculosis; Oxidation-Reduction; Oxygen Consumption; Signal Transduction; Stress, Physiological; Tuberculosis, Pulmonary; Virulence

Blood levels of cyclic nucleotides and their actions on central hemodynamics were studied in 129 patients with pulmonary tuberculosis. A direct correlation was established between heart rate, pulmonary artery systolic pressure and concentrations of cyclic adenosine monophosphate. Basing on this finding, the authors propose introduction of beta-adrenoblockers in hyperkinetic circulation tuberculous patients to prevent cor pulmonale. Administration of anapriline in tuberculous patients with compensated cor pulmonale and symptoms of sympathoadrenal hyperfunction improves the patients' condition, promotes a decrease in cardiac output, cardiac index, systolic pressure in the pulmonary artery. No side effects of the drug were reported.

Topics: Adult; Cyclic AMP; Cyclic GMP; Female; Hemodynamics; Humans; Male; Middle Aged; Propranolol; Pulmonary Heart Disease; Tuberculosis, Pulmonary

We previously reported the clinical role of plasma immunoreactive atrial natriuretic polypeptide (ANP) and cyclic GMP in patients with respiratory diseases, bronchial asthma (BA), chronic pulmonary emphysema (CPE) and pulmonary insufficiency induced by pulmonary tuberculosis (TBC). In this study, moreover, we divided patients with respiratory failure induced by tuberculosis sequelae into two groups, patients with oxygen therapy group [O2 (+) group] or ordinary practical treatment group [O2 (-) group], and we evaluated the difference of the roles of ANP in two groups and the correlation of ANP and c-GMP with clinical findings, blood gas analysis, electrocardiogram, chest roentogen photography and spirogram in two groups. In conclusion, the respiratory failure in patients with tuberculosis sequelae is compensated by increased cardiac output, and that causes the rising of right atrial pressure. These results show, addition to the basic effects of ANP, the concentration of plasma ANP is released with relating the degree of respiratory failure.

Topics: Adult; Aged; Atrial Natriuretic Factor; Cyclic GMP; Humans; Middle Aged; Respiratory Insufficiency; Tuberculosis, Pulmonary

The role of cyclic nucleotides and prostaglandins E1 and F2 alpha in pulmonary hypertension formation was elucidated in experimental tuberculosis in dogs and the mechanism of a hypotensive action of sodium oxybutyrate specified with consideration of its influence on the non-gas exchange pulmonary function. The level of the above compounds was studied in the blood taken from the pulmonary artery and aorta in comparison with pulmonary artery pressure prior to and after intravenous injection of sodium oxybutyrate, an antihypoxant. Pulmonary vessel tone was found to depend on the cGMP content and synthesis in the lungs both in health and in tuberculosis and pulmonary hypertension in tuberculosis was associated with a deranged level and correlation of cAMP, cGMP and prostaglandins E1 and F2 alpha in pulmonary circulation. It has been demonstrated that the hypotensive effect of sodium oxybutyrate is associated with its influence on these biochemical parameters in plasma.

Topics: Alprostadil; Animals; Cyclic AMP; Cyclic GMP; Dinoprost; Dogs; Hemodynamics; Hypertension, Pulmonary; Lung; Prostaglandins; Sodium Oxybate; Tuberculosis, Pulmonary

Topics: Adolescent; Adult; Aged; Antitubercular Agents; Cyclic AMP; Cyclic GMP; Humans; Middle Aged; Time Factors; Tuberculosis, Pulmonary

Topics: Adult; Cyclic AMP; Cyclic GMP; Humans; Middle Aged; Tuberculosis, Pulmonary