Mycobacterium tuberculosis Cell-Surface GAPDH Functions as a Transferrin Receptor
VishantM. Boradia1,2, Manoj Raje3, and Chaaya Iyengar Raje1
1 Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER),
SAS Nagar, Punjab, India
- 2 Present address: Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- 3 Council of Scientific and Industrial Research (CSIR), Institute of Microbial Technology (CSIR-IMTECH), Chandigarh, India
Tuberculosis (TB) is one of the leading causes of death worldwide due to infectious diseases. It is estimated that in the year 2013 alone, 9 million individuals were infected with TB and 1.5 million persons succumbed to the disease (WHO 2014). Mycobacterium tuberculosis (M. tb) is the causative agent of the disease where infection is usually initiated by inhalation of aerosols carrying the bacilli. Although primary infection occurs in the lungs, extrapulmonary TB can affect almost any other organ of the body including the brain, digestive system, spine, and urinogenital system. Infection is initiated when alveolar macrophages engulf the bacilli which can then replicate and survive for long periods within a specialized intracellular compartment known as the phagosome.
Iron is a necessity for the survival of both prokaryotes and eukaryotes, due to its importance as a cofactor in several enzymes. However, since excess iron can be toxic due to the synthesis of free radicals by the Fenton reaction, most organisms have evolved intricate mechanisms to acquire and store iron. Several studies have documented the close correlation between iron availability and pathogenesis. During an infection, pathogens utilize multiple mechanisms to obtain iron from host resources such as macromolecules involved in iron storage and transport. At the same time the host attempts to withhold available iron in order to limit infection, a process known as nutritional immunity. The availability and successful acquisition of surplus iron can enhance virulence and in fact skew the physiological outcome in favor of the pathogen (Andrews et al. 2003; Skaar 2010). This tug- of-war for iron between invading pathogen and mammalian host is similar to the circumstances in which an invading army attempts to seize the strategic resources
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of a territory under their occupation, for their own growth and sustenance, while the invaded nation attempts to deny the availability of the same to the aggressor.
As with other pathogens, iron is critical for the survival of M. tb; the bacilli are known to acquire iron from heme, which is readily available in the macrophage due to its role in the breakdown of effete RBCs (red blood cells) for recycling of heme iron (Tullius etal. 2011). They also synthesize small iron-chelating molecules (siderophores) that withdraw iron from host sources such as transferrin, ferritin, and lactoferrin (Ratledge 2004). Very recently a novel mechanism for iron uptake has been identified in M. tb wherein iron-replete transferrin binds on the cell surface to specific receptors, followed by internalization of the receptor-ligand complex into the bacterial cell effecting iron delivery into the microorganism (Boradia et al. 2014). The glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a well-known pleiotropic molecule, was identified as one of the receptors involved in this process. It is pertinent that, in macrophages, the host GAPDH also functions as a receptor for transferrin and is involved in the influx as well as the efflux of transferrin iron (Raje et al. 2007; Sheokand et al. 2014).
The other M. tb transferrin receptors to have been identified are: iron-regulated elongation factor tu (Rv0685); L-Lactate dehydrogenase (Rv1872c); Acyl-carrier protein desaturase (Rv0824c); and the 50S ribosomal proteins L1 (Rv0641) and L2 (Rv0704) (Boradia et al. 2014). Interestingly, homologs of some of these conserved proteins are known to possess alternate functions in other organisms (Wool 1996; Piatigorsky 2009; Fu et al. 2012).