Cationic Amino Acid Transporters and Salmonella Typhimurium ArgT Collectively Regulate Arginine Availability towards Intracellular Salmonella Growth

Cationic amino acid transporters (mCAT1 and mCAT2B) regulate the arginine availability in macrophages. How in the infected cell a pathogen can alter the arginine metabolism of the host remains to be understood. We reveal here a novel mechanism by which Salmonella exploit mCAT1 and mCAT2B to acquire host arginine towards its own intracellular growth within antigen presenting cells. We demonstrate that Salmonella infected bone marrow derived macrophages and dendritic cells show enhanced arginine uptake and increased expression of mCAT1 and mCAT2B. We show that the mCAT1 transporter is in close proximity to Salmonella containing vacuole (SCV) specifically by live intracellular Salmonella in order to access the macrophage cytosolic arginine pool. Further, Lysosome associated membrane protein 1, a marker of SCV, also was found to colocalize with mCAT1 in the Salmonella infected cell. The intra vacuolar Salmonella then acquire the host arginine via its own arginine transporter, ArgT for growth. The argT knockout strain was unable to acquire host arginine and was attenuated in growth in both macrophages and in mice model of infection. Together, these data reveal survival strategies by which virulent Salmonella adapt to the harsh conditions prevailing in the infected host cells

Platinum drugs in the treatment of non-small-cell lung cancer

The use of chemotherapy is considered standard therapy in patients with locally advanced non-small-cell lung cancer that cannot be treated with radiotherapy and in those with metastatic non-small-cell lung cancer and good performance status. This approach is also accepted in patients with earlier stage disease, when combined with radiotherapy in those with non-resectable locally advanced disease, or in the preoperative setting. Randomised clinical studies and meta-analyses of the literature have confirmed the beneficial survival effect of platinum-based chemotherapy. Cisplatin and carboplatin have been successfully used with other drugs in a wide variety of well-established two-drug combinations while three-drug combinations are still under investigation. Cisplatin and carboplatin use is limited by toxicity and inherent resistance. These considerations have prompted research into new platinum agents, such as the trinuclear platinum agent BBR3464, the platinum complex ZD0473 and oxaliplatin. These compounds could be developed in combination with agents such as paclitaxel, gemcitabine or vinorelbine in patients with advanced and/or refractory solid tumours

Macrophage-microbe interaction: lessons learned from the pathogen Mycobacterium tuberculosis

Macrophages, being the cornerstone of the immune system, have adapted the ancient nutrient acquisition mechanism of phagocytosis to engulf various infectious organisms thereby helping to orchestrate an appropriate host response. Phagocytosis refers to the process of internalization and degradation of particulate material, damaged and senescent cells and microorganisms by specialized cells, after which the vesicle containing the ingested particle, the phagosome, matures into acidic phagolysosomes upon fusion with hydrolytic enzyme-containing lysosomes. The destructive power of the macrophage is further exacerbated through the induction of macrophage activation upon a variety of inflammatory stimuli. Despite being the end-point for many phagocytosed microbes, the macrophage can also serve as an intracellular survival niche for a number of intracellular microorganisms. One microbe that is particularly successful at surviving within macrophages is the pathogen Mycobacterium tuberculosis, which can efficiently manipulate the macrophage at several levels, including modulation of the phagocytic pathway as well as interfering with a number of immune activation pathways that normally would lead to eradication of the internalized bacilli. M. tuberculosis excels at circumventing destruction within macrophages, thus establishing itself successfully for prolonged times within the macrophage. In this contribution, we describe a number of general features of macrophages in the context of their function to clear an infection, and highlight the strategies employed by M. tuberculosis to counter macrophage attack. Interestingly, research on the evasion tactics employed by M. tuberculosis within macrophages not only helps to design strategies to curb tuberculosis, but also allows a better understanding of host cell biology