Lena Nguyen, Class of 2021
Tuberculosis (TB), despite having been studied for centuries, continues to be a major epidemic worldwide, with an estimated 1 in 4 people in the world infected with latent TB (Houben et al. 2016). Thankfully, a latent TB isn’t life-threatening or contagious until it becomes active, which does not occur in roughly 90% of latent TB infections (Sable et al. 2020). The causative agent of TB is the bacteria Mycobacterium tuberculosis, and in the latent form, the bacteria is not actively multiplying or damaging tissue. How exactly the bacteria switches to its active infection state is still an ongoing subject of research. Even though most latent infections do not progress to an active state, TB is so prevalent that according to a 2020 report by the World Health Organization (WHO), it remains the leading cause of death by a single infectious agent (WHO 2020).
Current efforts to prevent TB infections focus on developing a vaccine. Bacille Calmette-Guérin (BCG), a live vaccine made from a relative of M. tuberculosis, has been in use since 1921 (Sable et al. 2020). However, as the current state of the TB epidemic suggests, there are limitations to the effectiveness of the BCG vaccine. Some of its limitations are its inability to effectively treat pulmonary TB and its reduced efficacy in areas where TB has infected a higher proportion of the population, making it difficult to reduce TB infection rates where it is most essential (Sable et al. 2020). Therefore, much of the current research focuses on a new, more efficient vaccine to prevent infections. The WHO notes that as of August 2020, there are 14 potential vaccine candidates in clinical trials (WHO 2020). The M72/AS01E vaccine is a promising candidate, and is composed of the M72 antigen, a fusion protein made from protein identifiers on the surface of M. tuberculosis, and an adjuvant system to boost the immune response of the vaccine (Montoya et al. 2013). The M72/AS01E vaccine recently showed positive results in Phase II trials with a 54% vaccine efficacy reported and is planned for further trials (Sable et. al 2020).
In addition to preventing infections, researchers are looking to find ways to better treat TB infections. Common treatments involve rifampicin or isoniazid, or a combination of both. However, drug-resistant strains of M. tuberculosis have increased over time. In 2019, there were about 500,000 cases of drug-resistant TB, 78% of which were multidrug-resistant (MDR-TB) cases (WHO 2020). Drug resistance generally starts from mutations in the DNA, which can then be shared to other bacteria. Surprisingly, M. tuberculosis has a naturally low mutation rate, yet the bacteria adapts quickly to drug treatments (Cohen et al. 2015). Along with the genome, a recent study also looked into the epigenome of M. tuberculosis (Modlin et. al 2020). The epigenome are the modifications on the DNA that leave its sequence unchanged, and can be additions or removals of chemical groups, such as methyl groups, on the DNA. The results of the study showed a link between certain genes and an increased diversity of epigenetic modifications, which is associated with drug-resistance (Modlin et al. 2020). The genes encoded methyltransferases, which are enzymes that add methyl groups, and these methyltransferases appeared to add methyl groups at random sites. Their indiscriminate nature allows for individual bacteria within a population to all contain unique epigenomes, termed “intercellular mosaic methylation,” and increases the potential for drug resistance (Modlin et al. 2020). These genes are now potential targets for treatment and prevention of MDR-TB.
As of 2020, The WHO notes that drug-resistant TB has a global treatment success rate of 57% (WHO 2020) compared to the 85% overall success rate of TB, a statistic from 2018. Drug resistance is a threat in most diseases that require a drug regimen treatment, and constantly requires the search for new drugs to outpace the development of drug resistance. Research has shown vaccine development and combating drug resistance by epigenetics are two novel and promising areas for curbing the tuberculosis epidemic. The WHO aims for an 80% reduction in the TB incidence rate by 2030 (WHO 2020), and such advancements in research could very well lead to reaching that goal.
References:
Cohen K.A., Abeel T., McGuire A.M., Desjardins C.A., Munsamy V., Shea T.P., Walker B.J., Bantubani N., Almeida D.V., Alvarado L., et al. Evolution of Extensively Drug-Resistant Tuberculosis over Four Decades: Whole Genome Sequencing and Dating Analysis of Mycobacterium tuberculosis Isolates from KwaZulu-Natal. PLoS Medicine. 2015; 12(9): e1001880
Houben R.M.G.J., Dodd P.J. The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling. PLoS Medicine. 2016; 13(10): e1002152
Modlin S.J., Conkle-Gutierrez D., Kim C., Mitchell S.N., Morrissey C., Weinrick B.C., Jacobs W.R., Ramirez-Busby S.M.,
Hoffner S.E., Valafar F. Drivers and sites of diversity in the DNA adenine methylomes of 93 Mycobacterium tuberculosis complex clinical isolates. eLife. 2020; 9:e58542
Montoya J., Solon J.A., Cunanan S.R.C., Acosta L., Bollaerts A., Moris P., Janssens M., Jongert E., Demoitié M., Mettens P., et al. A Randomized, Controlled Dose-Finding Phase II Study of the M72/AS01 Candidate Tuberculosis Vaccine in Healthy PPD-Positive Adults. Journal of Clinical Immunology. 2013; 33(8):1360-1375
Sable S.B., Posey J.E., Scriba T.J. Tuberculosis Vaccine Development: Progress in Clinical Evaluation. Clinical Microbiology Reviews. 2020; 33(1):e00100-19
World Health Organization. Global Tuberculosis Report. 2020 Retrieved from: https://www.who.int/docs/default-source/documents/tuberculosis/execsumm-11nov2020.pdf?sfv rsn=e1d925f_4
Image from:
https://elifesciences.org/digests/41129/tuberculosis-bacteria-thrive-on-a-nitrogen-source-buffet
Current efforts to prevent TB infections focus on developing a vaccine. Bacille Calmette-Guérin (BCG), a live vaccine made from a relative of M. tuberculosis, has been in use since 1921 (Sable et al. 2020). However, as the current state of the TB epidemic suggests, there are limitations to the effectiveness of the BCG vaccine. Some of its limitations are its inability to effectively treat pulmonary TB and its reduced efficacy in areas where TB has infected a higher proportion of the population, making it difficult to reduce TB infection rates where it is most essential (Sable et al. 2020). Therefore, much of the current research focuses on a new, more efficient vaccine to prevent infections. The WHO notes that as of August 2020, there are 14 potential vaccine candidates in clinical trials (WHO 2020). The M72/AS01E vaccine is a promising candidate, and is composed of the M72 antigen, a fusion protein made from protein identifiers on the surface of M. tuberculosis, and an adjuvant system to boost the immune response of the vaccine (Montoya et al. 2013). The M72/AS01E vaccine recently showed positive results in Phase II trials with a 54% vaccine efficacy reported and is planned for further trials (Sable et. al 2020).
In addition to preventing infections, researchers are looking to find ways to better treat TB infections. Common treatments involve rifampicin or isoniazid, or a combination of both. However, drug-resistant strains of M. tuberculosis have increased over time. In 2019, there were about 500,000 cases of drug-resistant TB, 78% of which were multidrug-resistant (MDR-TB) cases (WHO 2020). Drug resistance generally starts from mutations in the DNA, which can then be shared to other bacteria. Surprisingly, M. tuberculosis has a naturally low mutation rate, yet the bacteria adapts quickly to drug treatments (Cohen et al. 2015). Along with the genome, a recent study also looked into the epigenome of M. tuberculosis (Modlin et. al 2020). The epigenome are the modifications on the DNA that leave its sequence unchanged, and can be additions or removals of chemical groups, such as methyl groups, on the DNA. The results of the study showed a link between certain genes and an increased diversity of epigenetic modifications, which is associated with drug-resistance (Modlin et al. 2020). The genes encoded methyltransferases, which are enzymes that add methyl groups, and these methyltransferases appeared to add methyl groups at random sites. Their indiscriminate nature allows for individual bacteria within a population to all contain unique epigenomes, termed “intercellular mosaic methylation,” and increases the potential for drug resistance (Modlin et al. 2020). These genes are now potential targets for treatment and prevention of MDR-TB.
As of 2020, The WHO notes that drug-resistant TB has a global treatment success rate of 57% (WHO 2020) compared to the 85% overall success rate of TB, a statistic from 2018. Drug resistance is a threat in most diseases that require a drug regimen treatment, and constantly requires the search for new drugs to outpace the development of drug resistance. Research has shown vaccine development and combating drug resistance by epigenetics are two novel and promising areas for curbing the tuberculosis epidemic. The WHO aims for an 80% reduction in the TB incidence rate by 2030 (WHO 2020), and such advancements in research could very well lead to reaching that goal.
References:
Cohen K.A., Abeel T., McGuire A.M., Desjardins C.A., Munsamy V., Shea T.P., Walker B.J., Bantubani N., Almeida D.V., Alvarado L., et al. Evolution of Extensively Drug-Resistant Tuberculosis over Four Decades: Whole Genome Sequencing and Dating Analysis of Mycobacterium tuberculosis Isolates from KwaZulu-Natal. PLoS Medicine. 2015; 12(9): e1001880
Houben R.M.G.J., Dodd P.J. The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling. PLoS Medicine. 2016; 13(10): e1002152
Modlin S.J., Conkle-Gutierrez D., Kim C., Mitchell S.N., Morrissey C., Weinrick B.C., Jacobs W.R., Ramirez-Busby S.M.,
Hoffner S.E., Valafar F. Drivers and sites of diversity in the DNA adenine methylomes of 93 Mycobacterium tuberculosis complex clinical isolates. eLife. 2020; 9:e58542
Montoya J., Solon J.A., Cunanan S.R.C., Acosta L., Bollaerts A., Moris P., Janssens M., Jongert E., Demoitié M., Mettens P., et al. A Randomized, Controlled Dose-Finding Phase II Study of the M72/AS01 Candidate Tuberculosis Vaccine in Healthy PPD-Positive Adults. Journal of Clinical Immunology. 2013; 33(8):1360-1375
Sable S.B., Posey J.E., Scriba T.J. Tuberculosis Vaccine Development: Progress in Clinical Evaluation. Clinical Microbiology Reviews. 2020; 33(1):e00100-19
World Health Organization. Global Tuberculosis Report. 2020 Retrieved from: https://www.who.int/docs/default-source/documents/tuberculosis/execsumm-11nov2020.pdf?sfv rsn=e1d925f_4
Image from:
https://elifesciences.org/digests/41129/tuberculosis-bacteria-thrive-on-a-nitrogen-source-buffet
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