Mycobacterium tuberculosis (Mtb) has the ability to lie dormant in the human body for decades, only progressing to active disease in 5–10% of immunocompetent individuals. The organism is transmitted through aerosols, and enters the pulmonary system through inhalation. Within the lung, the bacillus can take up residence inside an alveolar macrophage triggering the aggregation of immune cells and the formation of a granuloma. During the course of infection, granulomas play a dual role – serving as a niche for the invading bacteria, whilst, protecting the host from active disease. The population of granulomas within the infected host consists of both primary and post-primary lesions. Primary granulomas containing the inhaled founder strain are morphologically different from post-primary granulomas that have developed through disseminated infection. This results in a heterogeneous population of bacilli that are unique to the in vivo experience
Portrait of a Pathogen: The Mycobacterium tuberculosis Proteome In Vivo. (2010) PLoS ONE 5(11): e13938. doi:10.1371/journal.pone.0013938
Background: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a facultative intracellular pathogen that can persist within the host. The bacteria are thought to be in a state of reduced replication and metabolism as part of the chronic lung infection. Many in vitro studies have dissected the hypothesized environment within the infected lung, defining the bacterial response to pH, starvation and hypoxia. While these experiments have afforded great insight, the picture remains incomplete. The only way to study the combined effects of these environmental factors and the mycobacterial response is to study the bacterial response in vivo.
Methodology/Principal Findings: We used the guinea pig model of tuberculosis to examine the bacterial proteome during the early and chronic stages of disease. Lungs were harvested thirty and ninety days after aerosol challenge with Mtb, and analyzed by liquid chromatography-mass spectrometry. To date, in vivo proteomics of the tubercle bacillus has not been described and this work has generated the first large-scale shotgun proteomic data set, comprising over 500 unique protein identifications. Cell wall and cell wall processes, and intermediary metabolism and respiration were the two major functional classes of proteins represented in the infected lung. These classes of proteins displayed the greatest heterogeneity indicating important biological processes for establishment of a productive bacterial infection and its persistence. Proteins necessary for adaptation throughout infection, such as nitrate/nitrite reduction were found at both time points. The PE-PPE protein class, while not well characterized, represented the third most abundant category and showed the most consistent expression during the infection.
Conclusions/Significance: Cumulatively, the results of this work may provide the basis for rational drug design – identifying numerous Mtb proteins, from essential kinases to products involved in metal regulation and cell wall remodeling, all present throughout the course of infection.