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.
Highlights
Tuberculosis (TB) ranks as the deadliest infectious disease world-wide with an estimated 10.4 million cases of active disease and 1.8 million deaths annually [1]
Tuberculosis (TB) ranks as the deadliest infectious disease worldwide, 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
To establish a system in which to examine the protective effect of contained Mtb infection (CMTB), we adopted a model that was originally developed to study mechanisms of Mtb containment [21]
Summary
Tuberculosis (TB) ranks as the deadliest infectious disease world-wide with an estimated 10.4 million cases of active disease and 1.8 million deaths annually [1]. The immune mechanisms that protect against TB are quite powerful: despite an extraordinarily high prevalence of Mycobacterium tuberculosis (Mtb) (some estimates suggest that at least 25% of the world’s population has been exposed [10]), the vast majority (~90%) of individuals with an intact immune system are able to contain and control the infection for their lifetimes with no clinical symptoms [10,11,12]. Both historical cohort studies and contemporary epidemiological studies demonstrate that prior infection is protective against re-infection [13,14]. Despite the strong evidence that prior infection with Mtb confers protection against reinfection, the underlying mechanisms have not been defined, in part due to the lack of a suitable small animal model
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