Glucose metabolism and its role in the maturation and migration of human CD1c+ dendritic cells following exposure to BCG.

Introduction: Tuberculosis (TB) still kills over 1 million people annually. The only approved vaccine, BCG, prevents disseminated disease in children but shows low efficacy at preventing pulmonary TB. Myeloid dendritic cells (mDCs) are promising targets for vaccines and immunotherapies to combat infectious diseases due to their essential role in linking innate and adaptive immune responses. DCs undergo metabolic reprogramming following exposure to TLR agonists, which is thought to be a prerequisite for a successful host response to infection. We hypothesized that metabolic rewiring also plays a vital role in the maturation and migration of DCs stimulated with BCG. Consequently, we investigated the role of glycolysis in the activation of primary human myeloid CD1c+ DCs in response to BCG. Methods/results: We show that CD1c+ mDC mature and acquire a more energetic phenotype upon challenge with BCG. Pharmacological inhibition of glycolysis with 2-deoxy-D-glucose (2-DG) decreased cytokine secretion and altered cell surface expression of both CD40 and CCR7 on BCG-challenged, compared to untreated, mDCs. Furthermore, inhibition of glycolysis had differential effects on infected and uninfected bystander mDCs in BCG-challenged cultures. For example, CCR7 expression was increased by 2-DG treatment following challenge with BCG and this increase in expression was seen only in BCG-infected mDCs. Moreover, although 2-DG treatment inhibited CCR7-mediated migration of bystander CD1C+ DCs in a transwell assay, migration of BCG-infected cells proceeded independently of glycolysis. Discussion: Our results provide the first evidence that glycolysis plays divergent roles in the maturation and migration of human CD1c+ mDC exposed to BCG, segregating with infection status. Further investigation of cellular metabolism in DC subsets will be required to determine whether glycolysis can be targeted to elicit better protective immunity against Mtb.

Tuberculosis vaccine BCG: the magical effect of the old vaccine in the fight against the COVID-19 pandemic.

Bacillus Calmette-Guérin (BCG) is a live attenuated M. bovis vaccine that was developed about 100 years ago by Albert Calmette and Camille Guérin. Many countries have been using the vaccine for decades against tuberculosis (TB). The World Health Organization (WHO) recommends a single dose of BCG for infants in TB endemic as well as leprosy high risk countries, and globally almost 130 million infants are vaccinated yearly. The role of BCG is well known in reducing neonatal and childhood death rates. Epidemiological and retrospective cross-sectional studies demonstrated that the BCG vaccination protects the children against respiratory tract infections and lowers the risk of malaria in children. In addition, BCG enhances IFN-γ and IL-10 levels, thus providing immunity against respiratory tract infection even in elderly people. The BCG is also known to provide nonspecific innate immunity against viruses and parasites, through an innate immune mechanism termed 'trained immunity' and is defined as the immunological recall of the innate immune system by epigenetic reprogramming. Based on these studies it is suggested that the BCG has the potential to act as a protective agent against COVID-19. Further proven safety records of BCG in humans, its adjuvant activity and low-cost manufacturing make it an attractive option to stop the pandemic and reduce the COVID-19 related mortality. In this review we discuss the heterologous effects of BCG, induction of trained immunity and its implication in development of a potential vaccine against COVID-19 pandemic.

Relación entre la enfermedad tuberculosa y la vacuna del bacilo de Calmette-Guérin (BCG) en niños

La tuberculosis (TB) es una enfermedad infecciosa, reemergente, ligada a condiciones de pobreza, curable, de presentación clínica variable y con formas graves de enfermedad prevenibles con la vacuna del BCG. Objetivo: Determinar las características de la enfermedad tuberculosa y su asociación con la presencia de la cicatriz de la vacuna (BCG) en los niños que asistieron a la unidad de Tisiología del Ambulatorio docente del HUC. Métodos: Se realizó un estudio de tipo descriptivo, observacional, de corte transversal mediante revisión de las históricas clínicas de todos los niños con el diagnóstico de enfermedad tuberculosa en cualquiera de sus formas clínicas que acudieron al Ambulatorio Docente del HUC durante los años 2014 al 2018, verificando la presencia de la cicatriz de la BCG y su correlación con las formas de la enfermedad. Resultados: Se incluyeron 68 pacientes que cumplieron con los criterios de inclusión y exclusión. El 57 % fue del sexo femenino, el grupo preescolar fue el más frecuente (41 %). La forma clínica predominante fue la pulmonar (63 %), seguida por ganglionar (10 %), meníngea y pleural (5,8 %), la TB miliar (2,9 %). 52 pacientes (76 %) presentaron cicatriz de BCG, siendo en este grupo la forma de presentación clínica más frecuente TB pulmonar (69 %). De los pacientes con ausencia de la cicatriz, el 43,6 % presentó formas graves y extrapulmonares. Conclusiones: La ausencia de cicatriz de BCG, se relacionó con mayoría de formas graves de TB, destacándose la importancia de realizar la vacunación con BCG para la prevención de la enfermedad o de sus formas graves.

Tuberculosis (TB) is an infectious disease, reemerging, linked to conditions of poverty, curable, with variable clinical presentation and with serious forms of disease, preventable through the BCG vaccine. Objective: To determine the characteristics of tuberculosis disease and its association with the presence of the BCG scar in children who attended the consultation of the Tisiology unit of the Teaching Outpatient HUC, in the period January 2014 to December 2018. Methods: A descriptive, observational, cross-sectional study was carried out by reviewing the clinical histories of all children with a diagnosis of tuberculosis disease in any of its clinical forms who attended the HUC Teaching Outpatient Clinic during the period of study, verifying the presence of the BCG scar and its correlation with the different forms of the disease. Results: 68 patients who met the inclusion and exclusion criteria were included. 57 % were female, the most frequent age group was preschool (41 %). The predominant clinical form was pulmonary (63 %), followed by lymph node (10 %), meningeal and pleural (5.8 %), miliary TB (2.9 %). 52 patients (76 %) presented BCG scar, being the most frequent clinical presentation of pulmonary TB (69 %) in this group. Of the patients with absence of the scar, 43.6 % presented severe and extrapulmonary forms. Conclusions: The absence of BCG scar was related to the majority of severe forms of TB, highlighting the importance of BCG vaccination for the prevention of the disease or its serious forms.

Estratégia de vacinação da BCG: unidade de saúde versus maternidade / BCG vaccination strategy: health unit versus maternity

Objetivo: comparar a estratégia atual de vacinação BCG em Unidade de Saúde com a alternativa de aplicação em maternidades/hospitais no município de Porto Alegre - Rio Grande do Sul. Metodologia: trata-se de um estudo de abordagem quantitativa, com base em dados de espelhos dos registros físicos das carteiras de vacinação e dados secundários de sistemas de informação de saúde, relativos ao período 2010 a 2014. Resultados: apenas 3,7% dos nascidos vivos foram vacinados nas primeiras 12 horas de vida, enquanto 50,1% o foram na primeira semana e 22,9% após os 15 dias de vida, aumentando o risco de exposição à tuberculose. Somente 22% das doses distribuídas às unidades de saúde foram aplicadas indicando elevado desperdício de doses e recursos financeiros. Conclusão: a estratégia de aplicação da BCG em Unidade de Saúde não corresponde à melhor alternativa de vacinação para o município sugerindo-se, portanto, a aplicação ainda na maternidade/hospital de nascimento.

Objective: To compare the current BCG vaccination strategy in Health Units with the alternative of application in maternity/hospitals in the city of Porto Alegre - Rio Grande do Sul. Methodology: This is a quantitative study based on mirror data from physical records of vaccination cards and secondary data from health information systems from 2010 to 2014. Results: Only 3.7% of live births were vaccinated in the first 12 hours of life, while 50.1% were in the first week, and 22.9% after 15 days of life, increasing the risk of exposure to tuberculosis. Only 22% of the doses distributed to the health units were applied, indicating high waste of doses and financial resources. Conclusion: The strategy of BCG application in Health Units does not correspond to the best vaccination alternative for the city, suggesting, therefore, the application still in the maternity/hospital of birth.

Is the tuberculosis vaccine BCG an alternative weapon for developing countries to defeat COVID-19?

BACKGROUD: Coronavirus disease (COVID-19) is a new respiratory infectious disease, and there is no vaccine currently. Previous studies have found that BCG vaccination can provide extensive protection against respiratory infectious diseases. METHODS: Herein, we obtained the latest data from the World Health Organization (WHO) as of August 12, 2020, and determined the relationship between three parameters (including the BCG vaccination coverage, human development index (HDI), and transmission classifications) and the incidence rate and mortality of COVID-19. RESULTS: The results showed that the morbidity and mortality of COVID-19 in countries with BCG vaccination recommendation were significantly lower than these in countries without BCG vaccination recommendation, and countries with lower HDI have lower morbidity and mortality. In addition, we also found that the mode of virus transmission is also related to the morbidity and mortality of COVID-19. CONCLUSIONS: Although our data supports the hypothesis that BCG vaccination is beneficial in reducing the morbidity and mortality of COVID-19, the data supporting this result may be inaccurate due to many confounders such as PCR testing rate, population characteristics, and protection strategies, the reliability of this result still needs to be verified by clinical trials.

Role of immunotherapy in Bacillus Calmette-Guérin unresponsive: non-muscle invasive bladder cancer.

Bacillus Calmette-Guérin (BCG) is recommended as the first-line treatment option for intermediate to high risk non-muscle invasive bladder cancer (NMIBC) by current clinical guidelines. However, despite the intravesical instillation of BCG, a significant proportion of patients with intermediate to high risk NMIBC develop intravesical recurrence. Moreover, the treatment of BCG-unresponsive NMIBC is currently challenging. There are no reliable treatment options for these patients with BCG-unresponsive NMIBC except radical cystectomy, which reported to show acceptable oncological outcomes. In this regards, reliable and safe non-invasive or less-invasive treatment options with acceptable oncological outcomes are awaited for the treatment of BCG-unresponsive NMIBC. The treatment of advanced or metastatic urothelial carcinoma has greatly advanced following the recent introduction of immunotherapeutic agents. These advancements have triggered an increasing interest in the use of immunotherapeutic agents for NMIBC, and especially for BCG-unresponsive NMIBC. The current review article aims to introduce and discuss the cutting-edge knowledge on the role of immunotherapy in BCG-unresponsive NMIBC and the currently available therapeutic strategies for its treatment. In addition, this article also summarizes the ongoing studies in this field.

Enhancement of antimycobacterial Th1-cell responses by a Mycobacterium bovis BCG prime-protein boost vaccination strategy.

Tuberculosis is a major global health problem, and the only available vaccine Bacille Calmette-Guérin (BCG) is not sufficiently effective against the disease. It is extremely urgent to develop novel vaccine approaches. Previous research demonstrated that there were several Regions of Difference (RD1-16) between the substrains of BCG and Mycobacterium tuberculosis or Mycobacterium bovis. The ORFs Rv1769 and Rv1772 are located in the RD14 deletions and have not been major targets of study. However, some studies have demonstrated that the two genes (Rv1769 and Rv1772) are excellent T cell antigens, which might induce an immune response. What kind of role these ORFs might play in anti-mycobacterial immunity, however, is still unknown. In our research we used the BCG prime-protein boost strategy to immunize BALB/c mice and evaluated its immunogenicity. Our data suggest that our novel BCG-P+PRO69 vaccine could elicit the most long-lasting and strongest Th1 type cellular immune responses. This response is characterized by a strong antibody response, the proliferation rate of splenocytes, a high percentage of CD4+ and CD8+ T cells and high levels of IFN-γ in antigen-stimulated splenocyte cultures. These results indicate that prime-boost is a potent strategy and the protein of gene Rv1769 is a potential antigen or subunit vaccine to TB for further study.

DNA Prime-BCG Boost Vaccination Strategy Improved The Protective Efficacy Against M. tuberculosis H37Rv in Mice / 生物化学与生物物理进展

The immunogenicity and protective efficacy of combined DNA priming, Bacillus Calmeette Guerin(BCG) boosting vaccination in mice were examined. Following intravenous challenge with virulent M. tuberculosis H37Rv, the BCG boost approach resulted in significant protection in both lungs (1.3, P

Effect of mitomycin C instilled immediately after TUR added with low dose BCG maintenance therapy to prevent recurrence of superficial bladder cancer / 中国康复理论与实践

@#Objective To observe therapeutic effects of intravesical instillation of mitomycin C (MMC) immediately after TUR added with low dose BCG maintenance therapy to prevent recurrence of superficial bladder cancer. Methods 83 patients with superficial bladder cancer were randomly divided into two groups, 50 cases were managed with intravesical instillation of mitomycin C immediately after TUR added with low dose BCG maintenance therapy (group A), 33 cases were treated with traditional method of MMC therapy (group B) to prevent recurrence of superficial bladder cancer. Results After 12-66 months (mean 32 months) following up, 3 patients had tumor recurrence in the group A and 7 patients in the group B, the rate of tumor recurrence of the group A was 6.0% (3/50) and that of the group B was 21.2%(7/33), and there was a significantly difference between two groups (P<0.05). Side effects of the group B were obviously more than that of the group A. Conclusion Intravesical instillation of MMC immediately after TUR added with low dose BCG maintenance therapy is effective to prevent patients with superficial bladder cancer from recurrence.