The role of protein glycosylation and carbohydrate receptors in macrophage and neutrophil cross-talk during Mycobacterium tuberculosis infection

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Mycobacterium tuberculosis (M.tb) is the pathogen responsible for causing tuberculosis (TB), one of the most prevalent and lethal infectious human diseases worldwide with approximately 2 billion infected individuals and 1.5 million annual deaths. The mycobacterium has adapted alongside humans for tens of thousands of years leaving it with an array of tools to modify the human innate and adaptive immune system in order to gain access and survive within the host. The principal host targets are the air way-patrolling macrophages that normally, together with resident neutrophils, (both white blood cells) quickly eliminate intruders as part of the innate immune system. However, M.tb avoids early recognition and destruction by the innate immune system and is able to reproduce inside the macrophages by compromising their killing mechanisms. Eventually, M.tb causes chronic inflammation that is beneficial for the long-term survival of the pathogen and transmission can happen even after decades of symptom-free (latent) infection of the host.Interestingly, only a subset of M.tb infected individuals develop the active form of TB. There is growing evidence that macrophages and neutrophils are central players in the development of TB. The so-called glycoconjugates, which are molecules containing a carbohydrate portion are known to be intricately involved in TB infection. The modification of proteins (glycoproteins) or lipids (glycolipids) with carbohydrate moieties is common on all cell surfaces. The cells are literally covered in a sugar coating, which serves as an identification tag for other cells. The carbohydrate motifs may also be used for communication purposes as M.tb is known to use these glycoproteins to gain access to the host and the bacterium is able to manipulate the glycosylation of host cells in order to modulate the immune response. The communication between cells of the immune system, which is facilitated through the interaction between the conjugated carbohydrates (glycans) and their specialized receptors on cell surfaces and on large secreted vesicles (microparticles), can also be hijacked by M.tb. However, surprisingly little detailed molecular knowledge has been established regarding the exact role of glycoproteins in the communication between macrophages and neutrophils during M. tb infection.Thus, it is clear that a better understanding of the altered glycobiology of macrophages and neutrophils and how this influences their cross-talk during M.tb infection is essential to allow us to begin to unravel the complex immune processes associated with TB. With this proposal the role of protein glycosylation and their associated carbohydrate receptors in macrophage and neutrophil cross-talk during M.tb infection is meant to be elucidated. System-wide screens (mass spectrometry coupled to liquid chromatography) will be followed up by more targeted studies using molecular biology techniques to determine the function of these molecules.