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- Title
Contained Mycobacterium tuberculosis infection induces concomitant and heterologous protection.
- Authors
Nemeth, Johannes; Olson, Gregory S.; Rothchild, Alissa C.; Jahn, Ana N.; Mai, Dat; Duffy, Fergal J.; Delahaye, Jared L.; Srivatsan, Sanjay; Plumlee, Courtney R.; Urdahl, Kevin B.; Gold, Elizabeth S.; Aderem, Alan; Diercks, Alan H.
- Abstract
Progress in tuberculosis vaccine development is hampered by an incomplete understanding of the immune mechanisms that protect against infection with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. Although the M72/ASOE1 trial yielded encouraging results (54% efficacy in subjects with prior exposure to Mtb), a highly effective vaccine against adult tuberculosis remains elusive. We show that in a mouse model, establishment of a contained and persistent yet non-pathogenic infection with Mtb ("contained Mtb infection", CMTB) rapidly and durably reduces tuberculosis disease burden after re-exposure through aerosol challenge. Protection is associated with elevated activation of alveolar macrophages, the first cells that respond to inhaled Mtb, and accelerated recruitment of Mtb-specific T cells to the lung parenchyma. Systems approaches, as well as ex vivo functional assays and in vivo infection experiments, demonstrate that CMTB reconfigures tissue resident alveolar macrophages via low grade interferon-γ exposure. These studies demonstrate that under certain circumstances, the continuous interaction of the immune system with Mtb is beneficial to the host by maintaining elevated innate immune responses. Author summary: Paradoxically, although tuberculosis (TB) ranks as the deadliest infectious disease world-wide, the immune mechanisms that protect against the disease are quite effective: Despite a high prevalence of infection with Mycobacterium tuberculosis (Mtb), the vast majority of individuals with an intact immune system contain the infection indefinitely with no clinical symptoms. Historical cohort studies and contemporary epidemiological studies indicate that prior infection with Mtb is actually protective against the development of active TB after re-exposure. Understanding the mechanisms underlying this natural protection would inform vaccine design efforts, however progress has been hampered by the lack of a small animal model of the protective effects of contained Mtb infection (CMTB). Previously, the protective effects have been attributed to adaptive immune responses. This study shows that CMTB also affects the innate immune response and is associated with low-level interferon-γ cytokinemia. While experiments in mice have elucidated many of the fundamental mechanisms underlying the immune response to Mtb, a small-animal model for the protective effect of CMTB, a critical feature of the human disease, has been elusive. Here, we demonstrate a mouse model that can enable mechanistic studies of the well-established but poorly understood role of CMTB in protection against re-infection.
- Subjects
MYCOBACTERIAL diseases; MYCOBACTERIUM tuberculosis; ALVEOLAR macrophages; VACCINE development; COMMUNICABLE diseases; TUBERCULOSIS
- Publication
PLoS Pathogens, 2020, Vol 16, Issue 7, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1008655