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World TB Day | Latest advances in TB research!

Tuberculosis is a serious disease caused by mycobacterium tuberculosis infection, which is mainly transmitted through respiratory tract. According to the 2021 Global Tuberculosis Report released by WHO, tuberculosis still poses a serious threat to global public health. It is estimated that 9.87 million new cases of tuberculosis will be diagnosed globally in 2020, and 1.5 million people will die of tuberculosis. The number of new cases of tuberculosis in China is 842,000, second only to India.

March 24 marks the 27th global TB Day. This year’s theme is “Life first, Action for All, Shared Health to End TB”. In this article, we summarize the latest research progress made by scientists in the field of TUBERCULOSIS research in recent years and share it with you!

[1] Nat Commun: Scientists have identified a potential target that could help develop new treatments for tuberculosis
Doi: 10.1038 / s41467-021-26941-1

The human pathogen Mycobacterium tuberculosis relies on the host body’s fatty acids as a carbon source. However, the β -oxidation of fatty acids is mediated by excess enzymes, which may hinder the development of anti-TB drugs that target this pathway. Recently, Multiple ACyl-coa dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro, published in the international journal Nature Communications In the study, scientists from Weill Cornell Medical College and other institutions found that Mycobacterium tuberculosis (MTB) may have an unexpected weakness that could lead to future drugs that target it.

Here, the researchers investigate the key role of a previously poorly studied m. tuberculosis enzyme that is essential for the bacterium to break down available fatty acids for energy and molecular components for growth and survival. Simply removing the enzyme, called EtfDMtb, may have prevented m. tuberculosis from continuing to infect mice. Professor Sabine Ehrt said the enzyme was an attractive target for TB drugs, and silting it not only starved the bacteria but also had additional toxic effects.

This discovery was made when Dr Tiago Beites observed that while analysing the function of proteins in Mycobacterium tuberculosis, he noticed that the two proteins may be very similar to human metabolic enzymes ETF-α and ETF-β, which are involved in fatty acid metabolism. And its mutation can also cause metabolic diseases. Further investigation led to the discovery of two mycobacterium tuberculosis proteins, named EtfAMtb and EtfBMtb, which act together to form an enzyme that works with another mycobacterium tuberculosis enzyme (EtfDMtb) to perform a similar metabolic function. Specifically, a decomposition-related process called fatty acid beta oxidation.

[2] Cell Rep Med: A novel strategy may help develop an effective tuberculosis vaccine
Doi: 10.1016 / j.x CRM. 2021.100372

One study was published in Cell Reports Medicine, an international journal entitled “A Recombinant bovine adenoviral fish vaccine expressing mycobacterial antigen-85b” In this paper, scientists at Purdue University and other institutions generate robust protection against tuberculosis in mice, and develop a novel strategy that may lead to the development of a novel effective vaccine against tuberculosis.

In this study, we jointly developed a novel TB vaccine formulation that incorporates an autophagy mediated antigen presentation that activates an enhanced T-cell response in the body, suggesting that this novel formulation may improve the body’s TB-specific immune response.

“Our vaccine strategy was equally effective in the absence of the BCG vaccine or in the absence of the BCG vaccine before it was administered,” said Researcher Dr. Mittal. This is important because most people in Mtb endemic countries are already vaccinated against TB with the BCG vaccine.

[3] EMI: Chinese scientists analyzed the THREE-DIMENSIONAL structure of mycobacterium tuberculosis ribosome large subunit binding to antibiotics
Doi: 10.1080/22221751.2021.2022439

Tuberculosis caused by mycobacterium tuberculosis is an important chronic disease in the world. According to the Global TB Report 2019 released by the World Health Organization (WHO), about 1.7 billion people around the world have latent TB infections, accounting for about a quarter of the total population. TB is still one of the top 10 causes of death worldwide. At present, the problem of drug resistance of MYCObacterium tuberculosis is becoming more and more serious. It is of great significance to understand the mechanism of drug resistance of mycobacterium tuberculosis and develop new drugs for the realization of “stop TUBERCULOSIS strategy”.

Recently, A joint team led by Fudan University and Peking University published a paper entitled “CryO-EM Structure of Mycobacterium tuberculosis 50S Ribosomal in the journal Emerging Microbes & Infections Subunit Bound with Clarithromycin reveals Dynamic and Specific Interactions with Macrolides “, The cryo-electron microscopic structure of Clarithromycin (CTY) bound to the large ribosomal subunit of MYCObacterium tuberculosis was elucidated.

The CTY binding site of the antibiotic is located near adenine A2062 of rRNA in the large subunit of m. tuberculosis ribosomes, which is similar to that of other macrolide antibiotics. Based on the density map obtained by the study, the team concluded that there are two conformations of A2062, a large subunit of M. tuberculosis bound to CTY. It is suggested that the kinetics of A2062 binding to specific macrolides may modulate the development of peptidyl transferase towards translation blockade by comparing with the published structure of ribosome binding to macrolides. The results of this study on the kinetics of the large subunit A2062 of the ribosome and macrolides of M. tuberculosis may contribute to the rational design of the next generation of anti-tuberculosis drugs to combat the growing problem of drug resistance of M. tuberculosis.

[4] Nat Commun: Whole-genome sequencing reveals antibiotic “preresistance” characteristics of Mycobacterium tuberculosis.
Doi: 10.1038 / s41467-021-27616-7

Recent advances in bacterial whole genome sequencing have allowed researchers to successfully map a complete catalog of antibiotic resistance genomic characteristics of M. tuberculosis. In a study titled “Genomic Signatures of Pre-resistance in Mycobacterium Tuberculosis,” published in the international journal Nature Communications, Scientists from imperial College London and others have for the first time identified signs of “pre-resistance” in bacteria, a finding that could help clinicians select the best treatments for bacterial infections in the future.

In this study, researchers sequenced the whole genomes of more than 3,000 TB samples and tracked TB infection in patients for nearly 20 years. Mycobacterium tuberculosis (MTB) is a bacterial infectious disease that affects lung function. In 2020, it caused more deaths from infectious diseases than COVID-19. If use the right antibiotic treatment, TB patients can be cured, but the treatment time is long, and many patients face the risk of not get enough health care, if the patient was unable to complete the whole process of treatment, or no drugs and poor quality, can appear the occurrence of drug-resistant TB.

Multidrug-resistant TB is a huge and unsustainable burden of human disease, and now researchers have identified fully drug-resistant strains in a handful of countries, and global progress in TB treatment has slowed dramatically as health systems struggle to cope with the current COVID-19 pandemic. In order to be able to better understand and eventually developing a new type of therapy, treatment of tuberculosis (TB) in the study, the researchers revealed for the first time how to prevent TB patients before drug resistance mutation of resistance, the researchers call this concept is called its “resistance”, namely when pathogenic microbes such as viruses or bacteria resistant greater inherent risk in the future.

[5] The FASEB J: Scientists discover The innate immune mechanism of tuberculosis resistant people against Mycobacterium tuberculosis infection
Doi: 10.1096 / fj. 202100614 r

The Chinese Academy of Sciences institute of microbiology cui-hua liu Mtb group long-term commitment to research and other important molecular mechanism of interaction between pathogen and host, issued a series of research work in recent years, the mechanism of interaction between pathogen and host has made important achievements, for anti-tuberculosis drugs for treatment, and offers a variety of new ideas and potential new targets.

Previously, it was believed that healthy individuals infected with Mtb would develop into latent infection or active TB patients. Interestingly, in recent years, it has been found that some individuals who have been in close contact with TB patients do not develop active TB patients and show relevant symptoms, nor do they show the immunological diagnostic characteristics of latent infection. Such healthy individuals who have been in close contact with the pathogen for a long time are called TB resistant.

At present, little is known about the anti-infection immune mechanism of such TB resisters, and in-depth understanding of the relevant mechanisms is expected to provide new clues and new strategies for the prevention and treatment of TB. In collaboration with Pang Yu, a professor at Beijing Chest Hospital, Capital Medical University, Liu Cuihua and her team revealed the characteristics of innate immune response in TB resistant populations when dealing with Mtb infection. Compared with the control group, latent infection and active TB patients, peripheral blood mononuclear macrophages of TB resistant patients produced higher levels of cytokines such as TNF-α, IL-1β and IL-6 when infected with Mtb, and their ability to clear intracellular pathogens was stronger.

A series of subsequent screening and functional validation experiments showed that histone deacetylase 6 (HDAC6) only maintained a stable expression level and enzyme activity in macrophages from TB resistant individuals during Mtb infection, while significantly decreased in other experimental groups. Furthermore, further inhibition or silencing of HDAC6 could inhibit the secretion of cytokines and the acidification ability of Mtb containing vesicles in tB-resistant macrophages. These results suggest that the ability of TB resistor-derived macrophages to efficiently clear Mtb infection depends on HDAC6, which may be a key host factor that promotes cytokine production and autophagy flow to accelerate Mtb clearance. In conclusion, this study reveals a new innate immune mechanism of TB resistant population that relies on HDAC6 to clear Mtb infection, provides an important new marker for the prediction of TB infection and incidence risk in close contacts of TB patients, and provides a new idea for host-targeted TB treatment.

[6] PLoS Pathog: Identifying a novel pathway of Mycobacterium tuberculosis to inhibit host immunity
Doi: 10.1371 / journal. Ppat. 1009712

When mycobacterium tuberculosis (Mtb) infects a person, the body’s immune response is crucial to the progression of the disease, either helping the body fight it off or accelerating the infection. The paper, published in the international journal PLoS Pathogens, is entitled “Mycobacterium tuberculosis inhibits THE NLRP3 inflammasome activation via its phosphokinase. PknF “research report, from the university of Maryland institutions such as scientists have discovered a mycobacterium tuberculosis causes the body’s immune cells reduce a new way of the defense force, in particular, the researchers identified in the mycobacterium tuberculosis is a kind of special genes, its or inhibit the infected human cells in the immune defense force, so as to accelerate the process of infection.

This study may provide an effective target for the development of gene-based therapies or preventive therapies for the treatment of conjugate disease. According to the World Health Organization, approximately 10 million people worldwide fall ill with TB each year, and 1 to 2 million patients die from the disease. Current treatments are only 85 percent effective, and MDR-TB poses a major public health threat in many parts of the world.

In order to develop novel therapeutic targets, it is important to understand the mechanisms by which bacterial proteins interact with human cells, said Professor Volker Briken. To our excitement, we found a novel form of interaction between M. tuberculosis and the signaling system in human cells, which is crucial for cellular defense against pathogens, and which has not been observed before.

In this study, the researchers infected white blood cells called macrophages with either Mycobacterium tuberculosis or a non-virulent bacterium. They found that protein complexes called inflammasomes were significantly restricted in cells infected with mycobacterium tuberculosis, but not in cells infected with non-virulent bacteria. This inflammatory microbe “surveys” the cell for pathogens and sends signals to the cell to initiate an immune response.

[7] Cell: New study reveals vulnerability and non-vulnerability genes in Mycobacterium tuberculosis
doi:10.1016/j.cell.2021.06.033

Developing drugs to combat tuberculosis can be a frustrating affair. Once a gene critical to the life cycle of a bacterium is identified, scientists rush to develop drugs that inhibit that target, followed by disappointment. A series of compounds targeting the essential gene target has little effect on the growth of Mycobacterium tuberculosis. The bacterium continued to survive. Scientists were back to square one.

Now, a new study helps explain why target-based antibiotics have had so much trouble getting off the ground. One answer is that essential genetic targets differ in their vulnerability to antibiotics. Researchers from The Rockefeller University and Weill Cornell Medical College found that the ideal target is so vulnerable that when it is slightly inhibited, the cell cannot survive. On the other hand, the invulnerable gene can withstand almost complete suppression and can barely maintain enough target activity to keep cells alive when attacked by antibiotics. In addition, these authors quantified the vulnerability of the pathogen for the first time, generating an index to rank nearly every essential gene in M. tuberculosis according to the amount of inhibition required to disable the gene and paralyze the cell.

The findings were published online July 22, 2021, in the journal Cell, under the title “Genome-wide gene expression tuning reveals diverse vulnerabilities of M. tuberculosis “.

Failure of target-based drug discovery is often attributed to problems with the compound, such as its inability to cross the bacterial envelope, the researchers said. That’s the other side of the coin. If you choose a highly vulnerable genetic target, you’re not setting yourself up for success.” New antibacterial drugs often come from extensive screening trials. Scientists dump a library of compounds on bacteria cultured in the lab to see which ones stop the bacteria from growing further. It’s a fast and very effective method – every drug approved for treating tuberculosis has been discovered this way.

[8] Cell Chem Bio: New antibiotic treats drug-resistant Mycobacterium tuberculosis infection
doi:10.1016/j.chembiol.2021.03.008

Drug-resistant mutations in Mycobacterium tuberculosis can have an impact on the development of effective therapies. In a recent study published in Cell Chemical Biology, Robert Schnell’s team from the Karolinska Institutet in Sweden evaluated the bactericidal efficacy of monocyclic β-lactam compounds targeting cell wall remodeling in Mycobacterium tuberculosis.

By designing against L.D-transpeptidase-2 (LdtMt2, a potent target for Mycobacterium tuberculosis), the authors synthesized and characterized a series of novel N-thio-β-lactams. Biochemical analyses evaluated these drug candidates and identified five compounds from them that had the same or higher target-specific kinetic constants as meropenem. Mass spectra combined with crystallographic structures collectively suggest that the above five N-thio-β-lactams act in an unconventional manner by transferring sulfur residues from the lactam ring to the active site cysteine of LdtMt2, which in turn leads to long-term inactivation of the target protein. Finally, the aforementioned drug candidates were evaluated in in vitro drug susceptibility and multi-drug resistant clinical isolates against Mycobacterium tuberculosis, thus confirming the mycobacterial killing effect of these novel compounds.

[9] AJHG: Using ancient DNA may reveal the molecular mechanism by which tuberculosis shapes the function of the human organism’s immune system
doi:10.1016/j.ajhg.2021.02.009

COVID-19 is a new infectious disease that has had a huge impact on human life. Recently, scientists from the Institut de Recherche de la Paix in France and other institutions have used ancient human DNA to reveal how tuberculosis has affected the health of European populations over the past 2,000 years, especially the impact of the disease on the human genome. The study, published in the American Journal of Human Genetics, will not only help study the evolutionary genetics of humans, but also reveal how genetic factors affect the function of the body’s immune system.

Today’s humans are the descendants of those who survived many events such as environmental changes and major pandemics, including the Black Death, Spanish flu and tuberculosis, said researcher Lluis Quintana-Murci. In the article, the researchers use the genetic characteristics of the population to analyze how natural selection affects our organism’s genome; they focus on a mutant of the gene TYK2, called P1104A, which they previously found to be associated with an increased risk of disease in the population when infected with Mycobacterium tuberculosis when the P1104A mutant is pure. TYK2 is involved in the immune function of the body through its effect on the interferon signaling pathway.

[10] Cell Host & Microbe: Scientists identify potential targets that may help treat and control tuberculosis infection
doi:10.1016/j.chom.2020.11.013

In a recent study published in the international journal Cell Host & Microbe, scientists from the Texas Biomedical Research Institute and other institutions have identified a novel pathway to treat and control tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), using single-cell RNA sequencing technology (scRNAseq). Scientists were then able to gain insight into the molecular mechanisms that induce TB infection and latency.

In this study, researchers have used scRNAseq for the first time to study TB in macaques in depth, explains researcher Kaushal. scRNAseq is a new technology developed over the past 3-4 years that allows us to look at the body’s immune response in greater detail and with higher resolution. Today we can look at the body’s immune response to Mtb infection, and in some cases the infection progresses to disease, while in others it is effectively controlled.

Today, the number of TB-related deaths has decreased by 30% globally, yet according to WHO data, 1.4 million people will die from TB in 2019 alone, and the disease remains one of the major infectious diseases afflicting populations in low-income countries; it is also one of several diseases negatively impacted by COVID-19 due to the impact of the new coronavirus on global health systems. Tuberculosis is transmitted primarily through the coughing or sneezing of an infected person; however, latent TB is not infectious, and TB can be prevented and treated, but latent TB can become active if interfered with by another invasive infection, such as HIV infection, and drug resistance remains a major obstacle to clinical treatment today.

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