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Recent progress in mycobacteriology

by Masaji Okada, Kazuo Kobayashi
Kekkaku : [Tuberculosis] ()

Abstract

Mycobacterium tuberculosis is one of the most successful bacterial parasites of humans, infecting over one-third of the population of the world as latent infection without clinical manifestations. Over 8.8 million new cases and nearly 2 million deaths by tuberculosis (TB) occur annually. TB poses a significant health threat to the world population. The goal of this symposium is to open new avenues for combating tuberculosis. The speakers have presented their data and provided control strategies against tuberculosis and pulmonary disease due to M. avium complex (MAC) from aspects of molecular epidemiology, pathogenesis, serodiagnosis, new anti-TB drugs, and vaccine development. Drs. Maeda and Murase have reported that the 12-locus VNTR analysis is very useful for molecular epidemiology of M. tuberculosis strains isolated in Japan better than IS6110-RFLP and suggested that the analysis is powerful tool for the molecular epidemiology. Drs. Matsumoto and Kobayashi have discovered a protein, mycobacterial DNA-binding protein 1 (MDPl), overproduced in dormant M. tuberculosis that plays key roles in latent/ persistent infection, disease progression, and host protection. They have concluded that MDP1 may be a possible target for anti-tuberculosis drugs and vaccines. Drs. Kitada and Maekura have developed serodiagnosis of MAC disease based on enzyme immunoassay (EIA) by detecting anti-glycopeptidolipid (GPL) antibody in sera of human patients. GPL is specific for MAC. The EIA is a simple, rapid and accurate measure with high sensitivity and specificity. The levels of antibody also reflect disease activity. A large-scale clinical multicenter study is currently in progress. Dr. Makoto Matsumoto has discovered an innovative new anti-TB drug, OPC-67683 that is a derivative of nitroimidazole compounds. OPC-67683 inhibited mycolic acid synthesis and exerted potent antimycobacterial activity, including multidrug-resistant M. tuberculosis. Multidrug therapy using OPC-67683 could also shorten the course of chemotherapy. The drug is clearly the most promising new anti-TB agent that has been identified in many years. Dr. Okada has presented the vaccine candidates for TB, such as HVJ-liposome/HSP65 DNA+IL-12 DNA and HVJ-envelope/HSP65 DNA+IL-12 DNA. The candidates exhibited an excellent protective efficacy in mice compared to current BCG vaccine, and improved histopathologic lesions induced by M. tuberculosis infection. The candidates also exerted the therapeutic effect in mice against both drugsusceptible TB and extensively drug-resistant TB. Using the cynomolgus monkey model (similar to human TB), HVJ-liposome/ HSP65 DNA+IL-12 DNA provided higher protective efficacy than BCG assessed by mortality. The combination of BCG and HVJ-liposome/HSP65 DNA+IL-12 DNA by the prime-booster procedure could lead to a synergistic effect of 100% survival in infected monkeys. These data suggest that the novel DNA vaccine is a possible candidate for human clinical trials. This symposium has highlighted new advances in our understanding of molecular epidemiology and pathogenesis of "Mycobacteriology" and development of new serodiagnostics, anti-TB drugs, and vaccines. 1. The establishment of the quick genotyping method for TB in Japan using the variable numbers of tandem repeats (VNTR): Shinji MAEDA, Yoshiro MURASE (Research Institute of Tuberculosis, Japan Anti-Tuberculosis Association) The 12-locus VNTR analysis that we have established optimally for Mycobacteriun tuberculosis in Japan was superior to the proposed 15-locus VNTR method in European countries. The discriminatory power of our system was also higher than that of IS6110-based restriction fragment length polymorphism analysis. In future, we will investigate the stability of copy number in each locus by using the strains that suspected epidemiological links in contact investigations. 2. A virulence factor of Mycobacterium tuberculosis, which contributes to persistent infection, reactivation, and host protection: Sohkichi MATSUMOTO (Department of Host Defense, Osaka City University Graduate School of Medicine), Kazuo KOBAYASHI (Department of Immunology, National Institute of Infectious Diseases) Majority of adult tuberculosis is caused by reactivation of previously implanted Mycobacterium tuberculosis. During latent infection, some bacilli are in dormant state, which confers some survival advantage to not only bacteria but also the host. We presented that a protein overproduced in dormant M. tuberculosis plays key roles in persistent infection, disease progression, and host protection. We also presented utility of this protein, such as development of anti-tuberculosis drug and vaccine. 3. Serodiagnosis of Mycobacterium avium complex pulmonary disease by enzyme immunoassay using glycopeptidolipid antigen: Seigo KITADA, Ryoji MAEKURA (Department of Internal Medicine, National Hospital Organization National Toneyama Hospital) The diagnosis of Mycobacterium avium complex pulmonary disease (MAC-PD) and/or its discrimination from pulmonary tuberculosis is sometimes complicated and time consuming. We have developed serological test by enzyme immunoassay that detect serum antibody to glycopeptidolipid antigen. The serodiagnosis is useful for the rapid diagnosis of MAC-PD and differential diagnosis from pulmonary TB. The antibody levels reflected the disease activity including radiographic severity. 4. A novel antituberculous agent, OPC-67683: Research and development: Makoto MATSUMOTO (Microbiological Research Institute, Otsuka Pharmaceutical Co., Ltd.) We initiated a program to screen new antituberculous agents that have potential to shorten the total duration of treatment, provide improved efficacy against MDR-TB, be useful in treating HIV co-infected patients, and target latent TB infections. Our efforts led to the discovery of OPC-67683, a novel oxazo-imidazole derivative with a distinctive characteristic as a subclass mycolic acid inhibitor. Our evaluation studies confirmed OPC-67683 to possess potent in vitro and in vivo antituberculous activity, suggesting potential usefulness in alleviating the current TB problems. 5. The development of novel vaccines against M. tuberculosis: Masaji OKADA (Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center) We have developed a novel tuberculosis (TB) vaccine (HVJ-liposome/ or HVJ-envelope/HSP65 DNA+ IL-12 DNA). The vaccine provided remarkable protective efficacy in mouse compared to BCG vaccine, and improved the histopathological tuberculosis lesions. This vaccine also exerted therapeutic effect in vivo against XDR-TB as well as drug-sensitive TB in mice. Furthermore, by using the cynomolgus monkey (similar to human tuberculosis), this novel vaccine provided higher protective efficacy (mortality) than BCG mortality. Furthermore, the combination of HSP65+IL-12/HVJ and BCG by the priming-booster method showed a synergistic effect in the TB-infected cynomolgus monkey (100% survival). These data indicate that our novel DNA vaccine might be useful against TB for human clinical trials.

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