Morphoproteomics Identifies the Foamy Alveolar Macrophage as an M2 Phenotype with PD-L1 Expression in the Early Lesion of Post-Primary Tuberculosis: Implications for Host Immune Surveillance and Therapy.

Abstract

Post-primary tuberculosis (TB) disease is characterized by paucibacillary necrosis of the early lesion, tuberculous pneumonia, in the adult human lung. The mechanism is speculated to be a strong localized delayed type hypersensitive response (DTH). However, up to this date, no one has been able to identify the source of the large accumulation of MTB antigens required for the DTH response. Although it is known and accepted that the pathogen, Mycobacterium tuberculosis (MTB), significantly affects macrophage function and activity, few studies have focused on macrophages at the site of the early lesion of developing post-primary MTB in human lungs. In vitro studies have examined the effect of MTB on skewing the macrophage phenotype, specifically the dynamic of the M1 and M2 differentiation. Additionally, it is also well documented that MTB infection induces macrophages to become foamy, accumulating host, and potentially MTB, lipids in the cytoplasm. The foamy macrophage is necessary for prolonging MTB survival in the infected lung. Using autopsy derived lung samples from untreated TB diseased individuals, this report, by applying morphoproteomics, demonstrates that the alveolar macrophages present in the early lesion of TB are primarily of the M2 phenotype. The M2 foamy alveolar macrophages (FAM) are also loaded with MTB antigens by immunohistochemistry and are paucibacillary. Moreover, the M2 alveolar macrophages predominately express PD-L1, leading to suppression of PD-1+ lymphocytes and host immunosurveillance. These morphoproteomic analyses indicate that early lesion of MTB in the adult human lung leads to a skewed M2 foamy alveolar macrophage phenotype that creates a protective microenvironment that accumulates high concentrations of MTB antigens, which when released can lead to necrosis and eventual cavitation.