A novel mouse model of the protective effects of contained tuberculous infection could lead to the development of a more effective vaccine, according to a study published July 16 in the open-access journal PLOS Pathogens by Alan Diercks of Seattle Children's Research Institute, and colleagues.
Tuberculosis, which is caused by the bacterium Mycobacterium tuberculosis (Mtb), is the deadliest infectious disease worldwide. But the vast majority of individuals with an intact immune system contain the infection indefinitely with no clinical symptoms. Prior infection with Mtb protects against the development of active tuberculous after re-exposure. Understanding the elusive mechanisms underlying this natural protection would inform vaccine design efforts - an important goal, given the lack of a highly effective vaccine against adult tuberculosis. Unfortunately, progress toward this goal has been hampered by the lack of a small animal model of the protective effects of contained Mtb infection -- a critical feature of the human disease.
Using a mouse model, Diercks and colleagues showed that contained and persistent yet non-pathogenic infection with Mtb rapidly and durably reduces tuberculosis disease burden after re-exposure. Previous studies attributed the protective effects of contained Mtb infection to adaptive immune responses, which unfold over a longer timescale, but target pathogens more accurately. By contrast, the new study reveals an important role for innate immune responses - nonspecific defense mechanisms that are quickly activated. Specifically, the researchers found that the protective effects of contained Mtb infection is associated with amplified innate immune activation, which is dependent on low blood levels of a signaling molecule called interferon-?. The findings suggest that the continuous interaction of the immune system with Mtb benefits the host by maintaining elevated innate immune responses. According to the authors, a deeper understanding of the protective mechanisms generated by contained Mtb infection could substantially inform clinical practice.
The authors conclude, "This study highlights the continued and evolving role of the mouse model in TB vaccine development."
Funding: Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (Grant numbers U19AI135976, U19AI100627, and R01AI032972, to AA, http://www.nih.gov). JN was supported by Swiss National Science Foundation (SNSF, http://www.snf.ch/en/Pages/default.aspx) grant #P300PB_164742. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Citation: Nemeth J, Olson GS, Rothchild AC, Jahn AN, Mai D, Duffy FJ, et al. (2020) Contained Mycobacterium tuberculosis infection induces concomitant and heterologous protection. PLoS Pathog 16(7): e1008655. https://doi.org/10.1371/journal.ppat.1008655
Seattle Children's Research Institute, Seattle, Washington, United States of America
Medical Scientist Training Program, University of Washington School of Medicine, Seattle, Washington, United States of America
Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
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