Interstitial macrophages prevent tuberculosis relapse by restricting Mycobacterium tuberculosis immune evasion 2333276

Abstract

Abstract Introduction Tuberculosis (TB) is the deadliest infectious disease worldwide, causing approximately 1.3 million deaths every year. Infection with Mycobacterium tuberculosis (Mtb), the causative bacteria of this disease, most frequently results in latent tuberculosis infection (LTBI) due to a healthy immune system that can restrict bacterial replication and prevent disease. Macrophages are the predominant host reservoir of Mtb, so elucidating the mechanisms by which they are activated and modulated to impede Mtb growth and survival is vital in understanding the course of TB relapse. Interstitial macrophages (IMs) are recruited to restrict Mtb growth and limit immune evasion after alveolar macrophages, which are the first cells to encounter Mtb, fail to eliminate this pathogen. While IMs have been implicated in the control of acute Mtb infection, their role during LTBI remained unexplored. We hypothesized that IMs contribute to maintaining latency and that their depletion during LTBI would promote Mtb reactivation, leading to TB relapse and disease. Methods To investigate this, we utilized our mouse model of paucibacillary Mtb infection that mimics LTBI in humans by infecting mice with a genetically engineered and inducible Mtb strain that results in apparent sterilization. We used clodronate liposomes administered intravenously to selectively deplete IMs during LTBI. TB relapse was established three months post-depletion. Results IM depletion during latency led to TB relapse in 26% of mice compared to 2% in control mice. This transitory depletion of IMs led to a two-fold increase in the recruitment of neutrophils to the lung. Additionally, mice that relapsed exhibited an increased frequency of pro-inflammatory IMs and a reprogramming of the pulmonary cytokine milieu, with elevated concentrations of G-CSF, GM-CSF, IL-3, IL-12, IL-13, IL-17A and KC compared to control mice. Conclusion These findings indicate that interstitial macrophages play a critical role in controlling latent Mtb and preventing TB relapse. Funding Source Potts Memorial Foundation Fellowship, American Association of University Women International Fellowship Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)