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1.
Int J Mol Sci ; 23(15)2022 Aug 01.
Article in English | MEDLINE | ID: covidwho-1994084

ABSTRACT

Tuberculosis remains a major threat to global public health, with more than 1.5 million deaths recorded in 2020. Improved interventions against tuberculosis are urgently needed, but there are still gaps in our knowledge of the host-pathogen interaction that need to be filled, especially at the site of infection. With a long history of infection in humans, Mycobacterium tuberculosis (Mtb) has evolved to be able to exploit the microenvironment of the infection site to survive and grow. The immune cells are not only reliant on immune signalling to mount an effective response to Mtb invasion but can also be orchestrated by their metabolic state. Cellular metabolism was often overlooked in the past but growing evidence of its importance in the functions of immune cells suggests that it can no longer be ignored. This review aims to gain a better understanding of mucosal immunometabolism of resident effector cells, such as alveolar macrophages and mucosal-associated invariant T cells (MAIT cells), in response to Mtb infection and how Mtb manipulates them for its survival and growth, which could address our knowledge gaps while opening up new questions, and potentially be applied for future vaccination and therapeutic strategies.


Subject(s)
Mucosal-Associated Invariant T Cells , Mycobacterium tuberculosis , Tuberculosis , Host-Pathogen Interactions , Humans , Immunity, Innate , Tuberculosis/microbiology
2.
Front Immunol ; 13: 870768, 2022.
Article in English | MEDLINE | ID: covidwho-1957155

ABSTRACT

Tuberculosis (TB), considered an ancient disease, is still killing one person every 21 seconds. Diagnosis of Mycobacterium tuberculosis (M.tb) still has many challenges, especially in low and middle-income countries with high burden disease rates. Over the last two decades, the amount of drug-resistant (DR)-TB cases has been increasing, from mono-resistant (mainly for isoniazid or rifampicin resistance) to extremely drug resistant TB. DR-TB is problematic to diagnose and treat, and thus, needs more resources to manage it. Together with+ TB clinical symptoms, phenotypic and genotypic diagnosis of TB includes a series of tests that can be used on different specimens to determine if a person has TB, as well as if the M.tb strain+ causing the disease is drug susceptible or resistant. Here, we review and discuss advantages and disadvantages of phenotypic vs. genotypic drug susceptibility testing for DR-TB, advances in TB immunodiagnostics, and propose a call to improve deployable and low-cost TB diagnostic tests to control the DR-TB burden, especially in light of the increase of the global burden of bacterial antimicrobial resistance, and the potentially long term impact of the coronavirus disease 2019 (COVID-19) disruption on TB programs.


Subject(s)
COVID-19 , Mycobacterium tuberculosis , Tuberculosis, Multidrug-Resistant , Tuberculosis , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , COVID-19/diagnosis , Humans , Microbial Sensitivity Tests , Mycobacterium tuberculosis/genetics , Tuberculosis/diagnosis , Tuberculosis/drug therapy , Tuberculosis/microbiology , Tuberculosis, Multidrug-Resistant/diagnosis , Tuberculosis, Multidrug-Resistant/drug therapy , Tuberculosis, Multidrug-Resistant/microbiology
3.
Int J Mol Sci ; 23(13)2022 Jun 29.
Article in English | MEDLINE | ID: covidwho-1911406

ABSTRACT

Tuberculosis (TB), caused by the bacillus Mycobacterium tuberculosis (Mtb), remains a leading cause of death by infectious disease, overshadowed only recently by the COVID-19 pandemic [...].


Subject(s)
COVID-19 , Mycobacterium tuberculosis , Tuberculosis , Humans , Pandemics , Tuberculosis/microbiology
4.
PLoS Pathog ; 18(5): e1010490, 2022 05.
Article in English | MEDLINE | ID: covidwho-1902645

ABSTRACT

Tuberculosis (TB), one of the deadliest threats to human health, is mainly caused by 2 highly related and human-adapted bacteria broadly known as Mycobacterium tuberculosis and Mycobacterium africanum. Whereas M. tuberculosis is widely spread, M. africanum is restricted to West Africa, where it remains a significant cause of tuberculosis. Although several differences have been identified between these 2 pathogens, M. africanum remains a lot less studied than M. tuberculosis. Here, we discuss the genetic, phenotypic, and clinical similarities and differences between strains of M. tuberculosis and M. africanum. We also discuss our current knowledge on the immune response to M. africanum and how it possibly articulates with distinct disease progression and with the geographical restriction attributed to this pathogen. Understanding the functional impact of the diversity existing in TB-causing bacteria, as well as incorporating this diversity in TB research, will contribute to the development of better, more specific approaches to tackle TB.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Africa, Western , Geography , Humans , Mycobacterium tuberculosis/genetics , Tuberculosis/microbiology
5.
Int J Mol Sci ; 23(11)2022 May 27.
Article in English | MEDLINE | ID: covidwho-1892895

ABSTRACT

Identification of alternative attenuation targets of Mycobacterium tuberculosis (Mtb) is pivotal for designing new candidates for live attenuated anti-tuberculosis (TB) vaccines. In this context, the CtpF P-type ATPase of Mtb is an interesting target; specifically, this plasma membrane enzyme is involved in calcium transporting and response to oxidative stress. We found that a mutant of MtbH37Rv lacking ctpF expression (MtbΔctpF) displayed impaired proliferation in mouse alveolar macrophages (MH-S) during in vitro infection. Further, the levels of tumor necrosis factor and interferon-gamma in MH-S cells infected with MtbΔctpF were similar to those of cells infected with the parental strain, suggesting preservation of the immunogenic capacity. In addition, BALB/c mice infected with Mtb∆ctpF showed median survival times of 84 days, while mice infected with MtbH37Rv survived 59 days, suggesting reduced virulence of the mutant strain. Interestingly, the expression levels of ctpF in a mouse model of latent TB were significantly higher than in a mouse model of progressive TB, indicating that ctpF is involved in Mtb persistence in the dormancy state. Finally, the possibility of complementary mechanisms that counteract deficiencies in Ca2+ transport mediated by P-type ATPases is suggested. Altogether, our results demonstrate that CtpF could be a potential target for Mtb attenuation.


Subject(s)
Mycobacterium tuberculosis , Tuberculosis , Animals , Calcium , Calcium-Transporting ATPases , Cell Membrane/pathology , Mice , Tuberculosis/microbiology , Virulence/genetics
6.
Braz J Microbiol ; 53(2): 633-639, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1872828

ABSTRACT

Tuberculosis (TB) and COVID-19 affect the lungs and are transmitted mainly by aerosols or particles of saliva from infected persons. Clinical similarities between diseases can affect correct diagnosis. Individuals belonging to the population deprived of liberty (PDL) are at increased risk of contagion due to precarious sanitary conditions and overcrowded environments. A variety of specimens may be suitable for the diagnosis of COVID-19, using molecular diagnostic techniques; however, there is little data on the analysis of sputum samples with the Xpert Xpress SARS-CoV-2® for the diagnosis of COVID-19, especially in this population group. The present study reports a case of TB and COVID-19 co-infection detected in sputum from an individual belonging to the PDL. For the detection, it used the GeneXpert platform (Cepheid, USA). Mycobacterium tuberculosis complex (MTC) was detected using the Xpert MTB/RIF Ultra® cartridge and SARS-CoV-2 was detected using the Xpert Xpress SARS-CoV-2® cartridge. The genes IS6110 and IS1081 were detected within 80 min indicating the presence of MTC, with no mutations related to resistance to rifampicin. The SARS-CoV-2 E and N2 genes were detected within 45 min. The result was confirmed by RT-qPCR with detection of E, N, and RdRP/S genes in the sputum and nasopharyngeal (NP) specimens. Rapid diagnoses that allow the identification and differentiation of such diseases are important for adequate epidemiological surveillance, isolation of infected individuals, and interruption of the transmission chain. Using the GeneXpert platform, specimens can be tested as soon as they are received, without the need for prior preparation. The US Food and Drug Administration has issued emergency authorization for the use of the Cepheid Xpert Xpress SARS-CoV-2 for the rapid detection of SARS-CoV-2 using specimens from a NP or nasal wash/aspirate. The case presented here gains an innovation with the use of the sputum to COVID-19 diagnosis.


Subject(s)
COVID-19 , Coinfection , Mycobacterium tuberculosis , Tuberculosis , COVID-19/diagnosis , COVID-19 Testing , Coinfection/diagnosis , Humans , Molecular Diagnostic Techniques/methods , Mycobacterium tuberculosis/genetics , Rifampin , SARS-CoV-2/genetics , Sensitivity and Specificity , Sputum/microbiology , Tuberculosis/diagnosis , Tuberculosis/microbiology
7.
Int J Mol Sci ; 23(7)2022 Mar 23.
Article in English | MEDLINE | ID: covidwho-1785727

ABSTRACT

The field of immunometabolism seeks to decipher the complex interplay between the immune system and the associated metabolic pathways. The role of small molecules that can target specific metabolic pathways and subsequently alter the immune landscape provides a desirable platform for new therapeutic interventions. Immunotherapeutic targeting of suppressive cell populations, such as myeloid-derived suppressor cells (MDSC), by small molecules has shown promise in pathologies such as cancer and support testing of similar host-directed therapeutic approaches in MDSC-inducing conditions such as tuberculosis (TB). MDSC exhibit a remarkable ability to suppress T-cell responses in those with TB disease. In tumors, MDSC exhibit considerable plasticity and can undergo metabolic reprogramming from glycolysis to fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) to facilitate their immunosuppressive functions. In this review we look at the role of MDSC during M. tb infection and how their metabolic reprogramming aids in the exacerbation of active disease and highlight the possible MDSC-targeted metabolic pathways utilized during M. tb infection, suggesting ways to manipulate these cells in search of novel insights for anti-TB therapies.


Subject(s)
Mycobacterium tuberculosis , Myeloid-Derived Suppressor Cells , Neoplasms , Tuberculosis , Biology , Humans , Neoplasms/metabolism , Tuberculosis/microbiology
8.
PLoS One ; 17(2): e0262734, 2022.
Article in English | MEDLINE | ID: covidwho-1699186

ABSTRACT

BACKGROUND AND OBJECTIVE: Tuberculosis (Tuberculosis, TB) is a public health problem in China, which not only endangers the population's health but also affects economic and social development. It requires an accurate prediction analysis to help to make policymakers with early warning and provide effective precautionary measures. In this study, ARIMA, GM(1,1), and LSTM models were constructed and compared, respectively. The results showed that the LSTM was the optimal model, which can be achieved satisfactory performance for TB cases predictions in mainland China. METHODS: The data of tuberculosis cases in mainland China were extracted from the National Health Commission of the People's Republic of China website. According to the TB data characteristics and the sample requirements, we created the ARIMA, GM(1,1), and LSTM models, which can make predictions for the prevalence trend of TB. The mean absolute error (MAE), root mean square error (RMSE), and mean absolute percentage error (MAPE) were applied to evaluate the effects of model fitting predicting accuracy. RESULTS: There were 3,021,995 tuberculosis cases in mainland China from January 2018 to December 2020. And the overall TB cases in mainland China take on a downtrend trend. We established ARIMA, GM(1,1), and LSTM models, respectively. The optimal ARIMA model is the ARIMA (0,1,0) × (0,1,0)12. The equation for GM(1,1) model was X(k+1) = -10057053.55e(-0.01k) + 10153178.55 the Mean square deviation ratio C value was 0.49, and the Small probability of error P was 0.94. LSTM model consists of an input layer, a hidden layer and an output layer, the parameters of epochs, learning rating are 60, 0.01, respectively. The MAE, RMSE, and MAPE values of LSTM model were smaller than that of GM(1,1) and ARIMA models. CONCLUSIONS: Our findings showed that the LSTM model was the optimal model, which has a higher accuracy performance than that of ARIMA and GM (1,1) models. Its prediction results can act as a predictive tool for TB prevention measures in mainland China.


Subject(s)
Deep Learning , Models, Statistical , Mycobacterium tuberculosis , Seasons , Tuberculosis/epidemiology , China/epidemiology , Forecasting/methods , Humans , Incidence , Prevalence , Probability , Prognosis , Public Health , Tuberculosis/microbiology
9.
Int J Mol Sci ; 22(22)2021 Nov 21.
Article in English | MEDLINE | ID: covidwho-1534090

ABSTRACT

Twenty lupane type A-ring azepano-triterpenoids were synthesized from betulin and its related derivatives and their antitubercular activity against Mycobacterium tuberculosis, mono-resistant MTB strains, and nontuberculous strains Mycobacterium abscessus and Mycobacterium avium were investigated in the framework of AToMIc (Anti-mycobacterial Target or Mechanism Identification Contract) realized by the Division of Microbiology and Infectious Diseases, NIAID, National Institute of Health. Of all the tested triterpenoids, 17 compounds showed antitubercular activity and 6 compounds were highly active on the H37Rv wild strain (with MIC 0.5 µM for compound 7), out of which 4 derivatives also emerged as highly active compounds on the three mono-resistant MTB strains. Molecular docking corroborated with a machine learning drug-drug similarity algorithm revealed that azepano-triterpenoids have a rifampicin-like antitubercular activity, with compound 7 scoring the highest as a potential M. tuberculosis RNAP potential inhibitor. FIC testing demonstrated an additive effect of compound 7 when combined with rifampin, isoniazid and ethambutol. Most compounds were highly active against M. avium with compound 14 recording the same MIC value as the control rifampicin (0.0625 µM). The antitubercular ex vivo effectiveness of the tested compounds on THP-1 infected macrophages is correlated with their increased cell permeability. The tested triterpenoids also exhibit low cytotoxicity and do not induce antibacterial resistance in MTB strains.


Subject(s)
Antitubercular Agents/chemistry , Mycobacterium tuberculosis/drug effects , Triterpenes/chemistry , Tuberculosis/drug therapy , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antitubercular Agents/pharmacology , DNA-Directed RNA Polymerases/antagonists & inhibitors , DNA-Directed RNA Polymerases/genetics , Drug Design , Drug Resistance, Bacterial/genetics , Humans , Molecular Docking Simulation , Molecular Structure , Mycobacterium tuberculosis/pathogenicity , Rifampin/pharmacology , Triterpenes/pharmacology , Tuberculosis/genetics , Tuberculosis/microbiology
11.
Microbiologyopen ; 10(3): e1211, 2021 06.
Article in English | MEDLINE | ID: covidwho-1281235

ABSTRACT

Tuberculosis (TB) is the leading cause of death in humans by a single infectious agent worldwide with approximately two billion humans latently infected with the bacterium Mycobacterium tuberculosis. Currently, the accepted method for controlling the disease is Tuberculosis Directly Observed Treatment Shortcourse (TB-DOTS). This program is not preventative and individuals may transmit disease before diagnosis, thus better understanding of disease transmission is essential. Using whole-genome sequencing and single nucleotide polymorphism analysis, we analyzed genomes of 145 M. tuberculosis clinical isolates from active TB cases from the Rubaga Division of Kampala, Uganda. We established that these isolates grouped into M. tuberculosis complex (MTBC) lineages 1, 2, 3, and 4, with the most isolates grouping into lineage 4. Possible transmission pairs containing ≤12 SNPs were identified in lineages 1, 3, and 4 with the prevailing transmission in lineages 3 and 4. Furthermore, investigating DNA codon changes as a result of specific SNPs in prominent virulence genes including plcA and plcB could indicate potentially important modifications in protein function. Incorporating this analysis with corresponding epidemiological data may provide a blueprint for the integration of public health interventions to decrease TB transmission in a region.


Subject(s)
Mycobacterium tuberculosis/genetics , Mycobacterium tuberculosis/isolation & purification , Polymorphism, Single Nucleotide , Tuberculosis/microbiology , Bacterial Proteins/genetics , Cities/statistics & numerical data , Cross-Sectional Studies , Genome, Bacterial , Genotype , Humans , Mycobacterium tuberculosis/classification , Mycobacterium tuberculosis/physiology , Phylogeny , Tuberculosis/epidemiology , Tuberculosis/transmission , Uganda/epidemiology , Virulence Factors/genetics , Whole Genome Sequencing
12.
PLoS One ; 16(6): e0253169, 2021.
Article in English | MEDLINE | ID: covidwho-1278188

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has created a remarkable and varying impact in every country, inciting calls for broad attention. Recently, the Bacillus Calmette-Guérin (BCG) vaccination has been regarded as a potential candidate to explain this difference. Herein, we hypothesised that the past epidemic of Mycobacterium tuberculosis (M. tuberculosis) may act as a latent explanatory factor for the worldwide differences seen in COVID-19 impact on mortality and incidence. We compared two indicators of past epidemic of M. tuberculosis, specifically, incidence (90 countries in 1990) and mortality (28 countries in 1950), with the mortality and incidence of COVID-19. We determined that an inverse relationship existed between the past epidemic indicators of M. tuberculosis and current COVID-19 impact. The rate ratio of the cumulative COVID-19 mortality per 1 million was 2.70 (95% confidence interval [CI]: 1.09-6.68) per 1 unit decrease in the incidence rate of tuberculosis (per 100,000 people). The rate ratio of the cumulative COVID-19 incidence per 1 million was 2.07 (95% CI: 1.30-3.30). This association existed even after adjusting for potential confounders (rate of people aged 65 over, diabetes prevalence, the mortality rate from cardiovascular disease, and gross domestic product per capita), leading to an adjusted rate ratio of COVID-19 mortality of 2.44, (95% CI: 1.32-4.52) and a COVID-19 incidence of 1.31 (95% CI: 0.97-1.78). After latent infection, Mycobacterium survives in the human body and may continue to stimulate trained immunity. This study suggests a possible mechanism underlying the region-based variation in the COVID-19 impact.


Subject(s)
BCG Vaccine/immunology , COVID-19/prevention & control , Mycobacterium tuberculosis/immunology , SARS-CoV-2/isolation & purification , Tuberculosis/immunology , COVID-19/epidemiology , COVID-19/virology , Epidemics , Humans , Incidence , Models, Theoretical , Mycobacterium tuberculosis/physiology , Prevalence , SARS-CoV-2/physiology , Survival Rate , Tuberculosis/epidemiology , Tuberculosis/microbiology , Vaccination
13.
Emerg Microbes Infect ; 10(1): 1217-1218, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1276098

ABSTRACT

A simple mRNA vaccine was shown to protect mice against tuberculosis more than 15 years ago. Like COVID-19, tuberculosis is a respiratory infection killing over a million people per year. It too presents a global emergency. Can the stunning success of RNA vaccination against COVID-19 be replicated for TB?


Subject(s)
Tuberculosis Vaccines/immunology , Tuberculosis/prevention & control , Vaccines, Synthetic/immunology , Humans , Tuberculosis/immunology , Tuberculosis/microbiology
14.
J Med Virol ; 93(4): 2385-2395, 2021 04.
Article in English | MEDLINE | ID: covidwho-1217388

ABSTRACT

The burden and impact of secondary superadded infections in critically ill coronavirus disease 2019 (COVID-19) patients is widely acknowledged. However, there is a dearth of information regarding the impact of COVID-19 in patients with tuberculosis, HIV, chronic hepatitis, and other concurrent infections. This review was conducted to evaluate the consequence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in patients with concurrent co-infections based on the publications reported to date. An extensive comprehensive screening was conducted using electronic databases up to 3rd September 2020 after obtaining registration with PROSPERO (CRD420202064800). The observational studies or interventional studies in English, evaluating the impact of SARS-CoV-2 in patients with concurrent infections are included for the meta-analyses. Our search retrieved 20 studies, with a total of 205,702 patients. Patients with tuberculosis (RR = 2.10; 95% CI, 1.75-2.51; I2 = 0%), influenza (RR = 2.04; 95% CI, 0.15-28.25, I2 = 99%) have an increased risk of mortality during a co-infection with SARS-CoV-2. No significant impact is found in people living with HIV (RR = 0.99; 95% CI, 0.82-1.19; I2 = 30%), Chronic hepatitis (RR = 1.15; 95% CI, 0.73-1.81; I2 = 10%). Several countries (Brazil, Paraguay, Argentina, Peru, Colombia, and Singapore) are on the verge of a dengue co epidemic (cumulative 878,496 and 5,028,380 cases of dengue and COVID-19 respectively). The impact of COVID-19 in patients of concurrent infections with either tuberculosis or influenza is detrimental. The clinical outcomes of COVID-19 in HIV or chronic hepatitis patients are comparable to COVID-19 patients without these concurrent infections.


Subject(s)
COVID-19/epidemiology , COVID-19/microbiology , Coinfection/epidemiology , Coinfection/microbiology , Coinfection/virology , Databases, Factual , Dengue/epidemiology , Dengue/microbiology , HIV Infections/epidemiology , HIV Infections/microbiology , Hepatitis, Chronic/epidemiology , Hepatitis, Chronic/microbiology , Humans , Influenza, Human/epidemiology , Influenza, Human/microbiology , SARS-CoV-2/isolation & purification , Tuberculosis/epidemiology , Tuberculosis/microbiology
19.
PLoS One ; 15(10): e0240203, 2020.
Article in English | MEDLINE | ID: covidwho-835961

ABSTRACT

The COVID-19 pandemic, caused by type 2 Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), puts all of us to the test. Epidemiologic observations could critically aid the development of protective measures to combat this devastating viral outbreak. Recent observations, linked nation based universal Bacillus Calmette-Guerin (BCG) vaccination to potential protection against morbidity and mortality from SARS-CoV-2, and received much attention in public media. We wished to validate the findings by examining the country based association between COVID-19 mortality per million population, or daily rates of COVID-19 case fatality (i.e. Death Per Case/Days of the endemic [dpc/d]) and the presence of universal BCG vaccination before 1980, or the year of the establishment of universal BCG vaccination. These associations were examined in multiple regression modeling based on publicly available databases on both April 3rd and May 15th of 2020. COVID-19 deaths per million negatively associated with universal BCG vaccination in a country before 1980 based on May 15th data, but this was not true for COVID-19 dpc/d on either of days of inquiry. We also demonstrate possible arbitrary selection bias in such analyses. Consequently, caution should be exercised amidst the publication surge on COVID-19, due to political/economical-, arbitrary selection-, and fear/anxiety related biases, which may obscure scientific rigor. We argue that global COVID-19 epidemiologic data is unreliable and therefore should be critically scrutinized before using it as a nidus for subsequent hypothesis driven scientific discovery.


Subject(s)
BCG Vaccine , Betacoronavirus , Coronavirus Infections/epidemiology , Coronavirus Infections/mortality , Pneumonia, Viral/epidemiology , Pneumonia, Viral/mortality , Vaccination , Adult , Aged , Animals , COVID-19 , Child , Child, Preschool , Coronavirus Infections/prevention & control , Coronavirus Infections/virology , Humans , Infant , Infant, Newborn , Mycobacterium tuberculosis/immunology , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Pneumonia, Viral/virology , Population Health , SARS-CoV-2 , Tuberculosis/microbiology , Tuberculosis/prevention & control , Young Adult
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