About this Research Topic
Tuberculosis (TB) is the leading cause of death by a single infectious agent worldwide, responsible for over 1.5 million deaths annually. Several barriers preclude successful control of TB, including an incomplete understanding of the immune mechanisms required for protection. Recent work has highlighted that the binary classification of TB as either latent infection or active disease is an oversimplification. Instead, TB should be considered as a spectrum disease to capture the biological heterogeneity and overlap between infection states. Upon initial exposure, the majority of individuals will contain Mycobacterium tuberculosis (Mtb) (latent infection), but about 5-15% will progress to active TB during their lifetime (progressors). A few individuals may be able to eliminate the pathogen upon primary exposure (reverters or resisters).
The high variability observed in susceptibility to Mtb infection and clinical outcomes in humans is the result of host and environmental factors. Host genetics, co-morbid illnesses, prior exposure to mycobacteria through vaccination or exposure to non-tuberculous mycobacteria all play a role in shaping Mtb infection outcomes, and likely many additional factors do contribute but have not been characterized yet. One major challenge in studying Mtb susceptibility to infection is the limited and univariate clinical definition of latent TB. For instance, it is not possible yet to predict which individuals will be susceptible vs. resistant to infection, which would be of high interest for improving TB control and vaccine development. Another challenge is that the immune cell subsets, phenotype and functions that contribute to the immune variability to Mtb infection are not fully characterized.
This research topic will welcome publications aiming at better defining clinical outcomes after exposure to Mtb, such as ‘resistance’, and understanding the molecular mechanisms driving intra-individual variability in Mtb infection. In particular, this collection will aim to identify key molecular components that constitute a desirable immune response in “resister” populations, and which extrinsic (e.g. environmental), intrinsic (e.g. genetics) and immune factors drive progression to active disease in “susceptible” populations or lead to more severe outcomes or treatment failure in active disease populations. In order to achieve a high level of molecular granularity, we encourage submission of systems-level immune profiling studies such as genome-wide (epigenome, transcriptome, TCR repertoire), proteomic and metabolomic studies. Comparison of blood versus tissues such as lymph nodes or lung biopsies will also be of high interest. While our primary focus is on humans, we will also consider animal studies that can allow for a deeper mechanistic understanding of the immune variability to Mtb infection outcomes and the development of Mtb-specific immunity. We will consider the submission of most article types of the journal, including Original Research, Clinical Trial, Case Report, Methods, Review, Mini Review, Systematic Review, Classification, Perspective, Hypothesis and Theory and Opinion articles, focused on the following topics, but not limited to:
1. Identification of novel clinical, environmental, or genetic factors driving immune susceptibility to Mtb infection in humans.
2. Mechanistic studies of known and novel factors driving immune susceptibility to Mtb infection: which pathways or immune cell subsets are dysregulated?
3. Comparative immune profiling in blood and/or tissues of progressors vs. resistors using high-dimensional molecular profiling techniques: innate immunity, T cells, B cells/antibodies.
4. Frequency, phenotype, and function of Mtb-specific T cells in progressors vs. resistors. Conventional CD4 and CD8 T cells, but also non-conventional T cells such as donor-unrestricted T cells (DURT), including MAIT and gamma-delta T cells.
5. The impact of non-tuberculous environmental bacteria and BCG vaccination in driving susceptibility or protection to Mtb infection.
Keywords: Tuberculosis, Immunological Memory
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