Tuberculosis (TB) is one of the most devastating infectious diseases causing 1.5-2.0 million deaths per year. Upon infection by the causative agent, Mycobacterium tuberculosis (Mtb), most people do not develop an overt disease, but latent infections (LTBI), with Mtb becoming dormant. LTBI can reactivate at any time, resulting in disease and transmission to others. The evolution strategy of mycobacterial parasitism, presumably, combines slowly developing an infection (ensuring long survival of a given bacterial population) with the guaranteed reactivation in a proportion of individuals with LTBI (ensuring horizontal transmission). At the present level of biomedical knowledge, this combination looks unbeatable, since too little is known about the mechanisms of protective immunity to and pathogenesis of TB in general and LTBI in particular.
Currently, there is no reliable method to detect dormant bacilli, which is a crucial barrier for effective prophylaxis, the first major gap in TB prevention and control. Additionally, the only currently available anti-TB vaccine, BCG, often fails to protect against pulmonary diseases in adults, which accounts for 95% of TB cases. Finally, the emergence of MDR (multidrug resistant) and XDR (extremely drug resistant) Mtb strains seriously interferes with the treatment of active TB. Furthermore, the effect of existing anti-TB drugs on dormant bacteria remains inconclusive. The lack of reliable diagnostics and effective drugs/vaccines, despite a huge research effort in the past half-century, emphasizes the requirements of new approaches and technologies that can evolve the field. Even less is known about the biology of non-tuberculous mycobacteria (NTM), some of which are important human pathogens resistant to most anti-TB drugs.
The three major topics outlined in the title of this project form the nucleus of current TB research and are closely interrelated. Genetic investigations of TB susceptibility to and severity of Mtb-triggered disease have been ongoing for decades both in experimental and clinical settings but gained a lot recently from functional studies, including microRNAs, transcriptomics, and epigenetics of the host and parasite. Effective adaptive immune responses, including the key activity of mycobacteria-specific and bystander CD4+ effector and regulatory T cell populations, limit disease throughout the body, but can also promote the development of progressively destructive lesions in the lung. Recent work on so-called “trained immunity” has revealed unexpected roles for innate host resistance mechanisms in TB. The role of B cells and humoral immunity, long overlooked by TB researchers, has received renewed interest. Host genomics are most powerful when focusing on carefully selected immune/pathology phenotypes and specific host-pathogen combinations. Genetic manipulation of Mtb and the rational selection of genetically defined hosts in experimental settings provide useful information about how mycobacteria manipulate innate and acquired immune responses of the host, and what features of lung pathology underlie protective vs. pathogenic inflammatory responses. We believe that a series of articles within the framework of the proposed Research Topic would make a valuable contribution to a better understanding of these very important, rapidly developing and still highly controversial aspects of TB research.
Tuberculosis (TB) is one of the most devastating infectious diseases causing 1.5-2.0 million deaths per year. Upon infection by the causative agent, Mycobacterium tuberculosis (Mtb), most people do not develop an overt disease, but latent infections (LTBI), with Mtb becoming dormant. LTBI can reactivate at any time, resulting in disease and transmission to others. The evolution strategy of mycobacterial parasitism, presumably, combines slowly developing an infection (ensuring long survival of a given bacterial population) with the guaranteed reactivation in a proportion of individuals with LTBI (ensuring horizontal transmission). At the present level of biomedical knowledge, this combination looks unbeatable, since too little is known about the mechanisms of protective immunity to and pathogenesis of TB in general and LTBI in particular.
Currently, there is no reliable method to detect dormant bacilli, which is a crucial barrier for effective prophylaxis, the first major gap in TB prevention and control. Additionally, the only currently available anti-TB vaccine, BCG, often fails to protect against pulmonary diseases in adults, which accounts for 95% of TB cases. Finally, the emergence of MDR (multidrug resistant) and XDR (extremely drug resistant) Mtb strains seriously interferes with the treatment of active TB. Furthermore, the effect of existing anti-TB drugs on dormant bacteria remains inconclusive. The lack of reliable diagnostics and effective drugs/vaccines, despite a huge research effort in the past half-century, emphasizes the requirements of new approaches and technologies that can evolve the field. Even less is known about the biology of non-tuberculous mycobacteria (NTM), some of which are important human pathogens resistant to most anti-TB drugs.
The three major topics outlined in the title of this project form the nucleus of current TB research and are closely interrelated. Genetic investigations of TB susceptibility to and severity of Mtb-triggered disease have been ongoing for decades both in experimental and clinical settings but gained a lot recently from functional studies, including microRNAs, transcriptomics, and epigenetics of the host and parasite. Effective adaptive immune responses, including the key activity of mycobacteria-specific and bystander CD4+ effector and regulatory T cell populations, limit disease throughout the body, but can also promote the development of progressively destructive lesions in the lung. Recent work on so-called “trained immunity” has revealed unexpected roles for innate host resistance mechanisms in TB. The role of B cells and humoral immunity, long overlooked by TB researchers, has received renewed interest. Host genomics are most powerful when focusing on carefully selected immune/pathology phenotypes and specific host-pathogen combinations. Genetic manipulation of Mtb and the rational selection of genetically defined hosts in experimental settings provide useful information about how mycobacteria manipulate innate and acquired immune responses of the host, and what features of lung pathology underlie protective vs. pathogenic inflammatory responses. We believe that a series of articles within the framework of the proposed Research Topic would make a valuable contribution to a better understanding of these very important, rapidly developing and still highly controversial aspects of TB research.
