Zhidong Hu
Theolis Barbosa
Xiao-Yong Fan- 1Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
- 2Instituto Goncalo Moniz, Fundacao Oswaldo Cruz, Salvador, Bahia, Brazil
Editorial on the Research Topic
Immunology of tuberculosis
The causing agent of tuberculosis (TB), Mycobacterium tuberculosis (Mtb), is a respiratory pathogen that is estimated to infect one-quarter of the population globally, Mtb has killed more people than any other microorganisms during the history of human beings. With the improvement of people’s living standards and the regulated use of anti-TB chemotherapy, the number of TB-related death kept declining during the past decades. However, this trend was reversed in the last three years, especially as a result of resource limitation due to the COVID-19 pandemic. As a result, an estimated 10.6 million people fell ill and 1.6 million was dead with TB in 2021 (1). Till now, TB is still the leading cause of death from a single infectious agent besides COVID-19.
Bacille Calmette-Gueérin (BCG) vaccine and anti-TB chemotherapy were regarded as two of the most powerful weapons combating TB. However, BCG is only effective in offering protection against aggressive childhood forms of the disease: meningeal and miliary TB. Its protection against pulmonary TB prevention ranges from 0% to 80% in different populations (2). In addition, human immunodeficiency virus coinfection and the emergency and dissemination of multidrug- and extensively drug-resistant TB pose challenges to TB control due to insufficient treatment success rates (3). Knowledge gaps still exist for the successful development of novel therapies, vaccines, and diagnostics for this old pathogen (4, 5). In this Research Topic, we summarize a number of studies addressing TB diagnosis, treatment, and pathogenic mechanisms.
One of the fundamental pillars to reduce the spread of TB disease is rapid and accurate diagnostics. The current TB diagnosis methods include culture, smear, real-time polymerase chain reaction-based (GeneXpert MTB/RIF, Xpert), interferon-γ release assays (IGRAs), imaging examination, etc. However, no diagnostic method fits the bill perfectly (6–8): 1) The traditional bacterial culture method is time-consuming. 2) The stained smear method is low in sensitivity. 3) Although Xpert assay is rapid, sensitive, and has high accuracy, it is expensive and impractical for widespread clinical use in developing countries. 4) IGRA is a T-cell-based assay that is used to measure Mtb-specific IFN-γ immune response to determine whether the individuals are infected or historically infected with Mtb, it cannot distinguish between latent TB infection and active TB diseases. 5) The imaging examination could be only used as an auxiliary diagnosis in TB due to its low specificity. Thus, the diagnosis of TB remains a huge challenge.
The loop-mediated isothermal amplification (LAMP) for TB, which is much cheaper than Xpert (50–70% less cost in China), is a nucleic acid amplification assay approved by WHO for TB diagnosis. Lin et al. conducted a multi-center study with a relatively large sample size to determine the performance of LAMP in diagnosing pulmonary TB in China. It was found that the sensitivity of LAMP was slightly lower than Xpert (209/304 vs 250/304), however, its specificity was slightly higher (439/495 vs 426/495). Thus, the authors concluded that the LAMP assay performed as well as Xpert assay. Considering that the LAMP assay requires less infrastructure, has a shorter turnover time, and is cheaper than Xpert, it could facilitate the early diagnosis of TB in resource-limiting countries. Yao et al. retrospectively analyzed the diagnostic performance of CapitalBio Mycobacterium real-time polymerase chain reaction assay (CapitalBio test) by using samples from suspected spinal TB. Their data showed that the sensitivity and specificity of the CapitalBio test were 75.2% and 98.0%, respectively, compared with composite reference standard. The combination of histopathology and CapitalBio test showed an enhanced sensitivity (81.0%) without reducing specificity (98.0%). These two studies provide us new information on TB diagnosis.
As the most fatal type of TB, central nervous system TB (CNSTB) includes TB meningitis, tuberculoma without meningitis, and spinal TB (9). Although early treatment with glucocorticoids could improve the prognosis of CNSTB patients and reduce mortality (10), a few CNSTB patients do not respond well to glucocorticoids and anti-TB chemotherapy. It was shown that an immunomodulatory drug, thalidomide, could be used in CNSTB patients if glucocorticoids are ineffective (11). Liu et al. retrospectively reviewed the clinical efficacy and safety of thalidomide in treating four complicated CNSTB patients in a case reports article, supporting that thalidomide is an effective and well-tolerated drug for the treatment of CNSTB.
Besides chemotherapy, therapy targeting the host factors is an alternative approach to developing new treatment strategies against TB (12). As an intracellular pathogen, Mtb colonized into the cell, thus, the host cellular immune and inflammatory responses as well as basic cellular physiologic mechanisms play critical roles in TB disease establishment and progression (13). Host-directed therapies (HDTs) usually aim at optimizing the host immune responses by interfering with host cellular processes required for Mtb survival/replication, or improving the microbicidal activity of macrophages and other infected cells, or by alleviating exacerbated inflammation that may cause damage to host tissues (14, 15). In a perspective article, Baindara et al. focused on the Notch signaling pathway, which is one of the highly conserved pathways that transmit signals through direct contact with adjacent cells in a very short range of cellular communications. The authors summarized studies illustrating the role of the Notch signaling pathway during Mtb infection, which suggested that the Notch signaling might be a potential host factor target for the development of clinical therapeutics against TB.
Epidemiological studies showed that type 2 diabetes mellitus (T2DM) increased the risk of latent TB infection and active TB diseases, and worsened the TB treatment outcomes (16, 17). However, the mechanisms underlying this observation are not well elucidated. Ssekamatte et al. reviewed studies that focused on the effect of T2DM on the innate/adaptive immune responses against TB infection, and on the immunometabolic, gene-transcriptional mechanisms of TB susceptibility. The authors summarized the current challenges and future perspectives that might facilitate novel modulators to lessen the combined burden of the diseases.
Overall, the manuscripts published within this Research Topic provided new information on TB research. With more advanced knowledge, we are hopeful that more effective therapies, vaccines, and diagnostics will be achieved in the near future.
Author contributions
ZH, TB and X-YF conceived, designed, and wrote the manuscript. All the authors contributed to the article and approved the submitted version.
Acknowledgments
We are thankful to the authors who submitted their articles to support this Research Topic, and to the grants from the National Natural and Science Foundation of China (82171739, and 82171815).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Authors ZH, TB and X-YF declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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References
1. World Health Organization. WHO Global TB Report. (2021). Available at: https://www.who.int/teams/global-tuberculosisprogramme/TB-reports/global-tuberculosis-report-2022.
2. Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet (2006) 367(9517):1173–80. doi: 10.1016/S0140-6736(06)68507-3
3. Mangtani P, Abubakar I, Ariti C, Beynon R, Pimpin L, Fine PEM, et al. Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials. Clin Infect Dis (2014) 58(4):470–80. doi: 10.1093/cid/cit790
4. Hu Z, Lu SH, Lowrie DB, Fan XY. Research advances for virus-vectored tuberculosis vaccines and latest findings on tuberculosis vaccine development. Front Immunol (2022) 13:895020. doi: 10.3389/fimmu.2022.895020
5. Graciaa DS, Schechter MC, Fetalvero KB, Cranmer LM, Kempker RR, Castro KG, et al. Updated considerations in the diagnosis and management of tuberculosis infection and disease: integrating the latest evidence-based strategies. Expert Rev Anti Infect Ther (2023) 21(6):595–616. doi: 10.1080/14787210.2023.2207820
6. Dong B, He Z, Li Y, Xu X, Wang C, Zeng J, et al. Improved conventional and new approaches in the diagnosis of tuberculosis. Front Microbiol (2022) 13:924410. doi: 10.3389/fmicb.2022.924410
7. Gong W, Wu X. Differential diagnosis of latent tuberculosis infection and active tuberculosis: A key to a successful tuberculosis control strategy. Front Microbiol (2021) 12:745592. doi: 10.3389/fmicb.2021.745592
8. Hu Z, Fan XY. Editorial: Novel approaches to rapid diagnosis and treatment monitoring of active tuberculosis, vol II. Front Microbiol (2022) 13:1044314. doi: 10.3389/fmicb.2022.1044314
9. Navarro-Flores A, Fernandez-Chinguel JE, Pacheco-Barrios N, Soriano-Moreno DR, Pacheco-Barrios K. Global morbidity and mortality of central nervous system tuberculosis: a systematic review and meta-analysis. J Neurol (2022) 269(7):3482–94. doi: 10.1007/s00415-022-11052-8
10. Critchley JA, Young F, Orton L, Garner P. Corticosteroids for prevention of mortality in people with tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis (2013) 13(3):223–37. doi: 10.1016/S1473-3099(12)70321-3
11. Liu P, Pei N, Liu X, Huang W, Lu S. Thalidomide in the treatment of human immunodeficiency virus-negative tuberculous meningitis: A case report. Med (Baltimore) (2020) 99(40):e22639. doi: 10.1097/MD.0000000000022639
12. Wallis RS, O’Garra A, Sher A, Wack A. Host-directed immunotherapy of viral and bacterial infections: past, present and future. Nat Rev Immunol (2023) 23(2):121–33. doi: 10.1038/s41577-022-00734-z
13. Chandra P, Grigsby SJ, Philips JA. Immune evasion and provocation by Mycobacterium tuberculosis. Nat Rev Microbiol (2022) 20(12):750–66. doi: 10.1038/s41579-022-00763-4
14. Matteucci KC, Correa AAS, Costa DL. Recent advances in host-directed therapies for tuberculosis and malaria. Front Cell Infect Microbiol (2022) 12:905278. doi: 10.3389/fcimb.2022.905278
15. Cubillos-Angulo JM, Nogueira BMF, Arriaga MB, Barreto-Duarte B, Araújo-Pereira M, Fernandes CD, et al. Host-directed therapies in pulmonary tuberculosis: Updates on anti-inflammatory drugs. Front Med (Lausanne) (2022) 9:970408. doi: 10.3389/fmed.2022.970408
16. Dooley KE, Chaisson RE. Tuberculosis and diabetes mellitus: convergence of two epidemics. Lancet Infect Dis (2009) 9(12):737–46. doi: 10.1016/S1473-3099(09)70282-8
Keywords: tuberculosis, immunology & infectious diseases, mycobacteria, diagnosis, mechanism
Citation: Hu Z, Barbosa T and Fan X-Y (2023) Editorial: Immunology of tuberculosis. Front. Trop. Dis 4:1252114. doi: 10.3389/fitd.2023.1252114
Received: 03 July 2023; Accepted: 07 July 2023;
Published: 20 July 2023.
Edited and Reviewed by:
Emanuele Nicastri, National Institute for Infectious Diseases Lazzaro Spallanzani (IRCCS), ItalyCopyright © 2023 Hu, Barbosa and Fan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zhidong Hu, huzhidong@fudan.edu.cn; Theolis Barbosa, theolis@gmail.com; Xiao-Yong Fan, xyfan008@fudan.edu.cn