Pair of NIAID-Funded Studies Reveals Mechanisms of Nerve Damage and Immune Evasion
Leprosy-causing bacteria alter the behavior of the body’s macrophages, leading these normally protective immune cells to initiate nerve damage during early infection, a new NIAID-supported study in a zebrafish model shows. An international team of scientists found that a molecule on the bacteria’s surface, called phenolic glycolipid (PGL), is responsible for reprogramming the macrophages.
PGL is present on the surfaces of many pathogenic mycobacteria, including those that cause leprosy (Mycobacterium leprae) and tuberculosis (Mycobacterium tuberculosis). In a related NIAID-funded study using a zebrafish model of tuberculosis, the researchers found that mycobacterial PGL also helps the bacteria establish infection by escaping macrophage defenses. A small difference in the chemical structure of M. leprae PGL confers upon it the additional ability to contribute to nerve damage.
Findings from this pair of studies shed light on how nerve damage is initiated in leprosy and suggest PGL as a potential target for the development of strategies to prevent tuberculosis and other mycobacterial diseases. The studies appeared Aug. 24 in Cell and Immunity.
Leprosy and tuberculosis are chronic infectious diseases that include the formation of granulomas, or aggregates of immune cells. M. leprae primarily infects the skin and peripheral nerves, while M. tuberculosis targets the lungs, as well as other internal organs and tissues. Both diseases are of significant global concern. Tuberculosis ranks as the world’s leading cause of death from an infectious disease. While the global prevalence of leprosy has decreased dramatically over the past few decades, the disease remains a public health problem in endemic countries, including India and Brazil.
Leprosy is the only mycobacterial infection that causes widespread damage to the peripheral nerves. This nerve damage eventually results in debilitating symptoms such as blindness and loss of fingers and toes. Understanding the mechanisms underlying leprosy-induced nerve damage has been challenging, in part because of the inability to grow M. leprae in the lab and the lack of useful animal models. In the current study published in Cell, researchers took advantage of the transparency of zebrafish larvae to visualize the earliest events of M. leprae-induced nerve damage.
Normally, macrophages patrol nerve fibers, repairing damage as they go. The researchers found that M. leprae-infected macrophages can settle on the fibers and injure the nerve cells and their protective coatings, called myelin sheaths. PGL triggers this destructive response in infected macrophages by causing the cells to overproduce nitric oxide. Nitric oxide enters the nerve, where it damages mitochondria—the intracellular powerhouses that provide energy to cells—and destroys myelin sheaths. This mechanism is similar to the nerve damage that occurs in inflammatory nerve diseases like multiple sclerosis, the researchers note.
In the complementary study appearing in Immunity, the researchers describe the main function of mycobacterial PGL using a zebrafish model of tuberculosis. Typically, macrophages engulf and then kill bacterial invaders. The researchers found that PGL-bearing mycobacteria circumvent this immune defense by escaping from macrophages before they are killed. Within the macrophage, PGL activates a signaling pathway that leads the macrophage to produce a signaling molecule called CCL2. CCL2 attracts monocytes, a type of immune cell that can develop into macrophages, from the bloodstream. These monocytes fuse with the macrophages, allowing the mycobacteria to transfer into the monocytes, in which they can survive and grow. Inside monocytes, the bacteria can travel through the body and establish infection.
While M. leprae PGL retains this ancestral macrophage-escape function, a small difference in its chemical structure gives it the unique ability to reprogram macrophages to cause nerve damage. These studies set the stage for more detailed investigations into whether and how these insights can be harnessed to prevent mycobacterial infections and to develop ways to prevent or treat nerve damage in leprosy.
CA Madigan et al. A macrophage response to Mycobacterium leprae phenolic glycolipid initiates nerve damage in leprosy. Cell DOI: 10.1016/j.cell.2017.07.030 (2017)
CJ Cambier et al. Phenolic glycolipid facilitates mycobacterial escape from microbicidal tissue-resident macrophages. Immunity DOI: 10.1016/j.immuni.2017.08.003 (2017)