A study published today in the journal Cell Host & Microbe describes dismaying results on the effects of a toxin unleashed on the immune system by the bacteria Staphylococcus aureus. S. aureus is a highly dangerous bacterium which causes potentially deadly infections in many organs such as the heart and contributes to, for example, biofilm formation in cystic fibrosis patients. While it has been known for many years that S. aureus releases a battery of toxins, the mechanisms of action of these toxins is only beginning to be understood. Meanwhile, S. aureus, like so many other bacterial infections, is developing multi-drug resistance to antibiotics, making it imperative that we develop our understanding of its actions so we can target them with new therapeutic agents.
In the current Cell Host & Microbe study, a research group from NYU Langone Medical Centre looked at an S. aureus toxin called Leukotoxin ED (LukED). The same group had previously shown that LukED could bind to the CCR5 receptor on white blood cells including T cells, the backbone of the acquired immune response, macrophages, which phagocytose microbes, and dendritic cells, which are essential for presenting antigen to T cells. LukED could consequently destroy all these essential immune cells by lysis. However, there was a mystery associated with LukED; it could also kill neutrophils, which do not express CCR5. Neutrophils are granulocytic leukocytes that are the first line of defence against invading pathogens; they kill microbes by phagocytosis and by degranulation to release hydrolytic enzymes. Neutralising them seriously handicaps the rest of the immune response. But how does LukED target neutrophils in the absence of CCR5 expression? The results of the Cell Host & Microbe study show that not only can LukED block CCR5 but it can also block CXCR1 and CXCR2 receptors, which are expressed on neutrophils. These receptors respond to and bind mediators known as CXC- chemokines, which is essential for recruitment of neutrophils to sites of infection. So by blocking CXCR1 and CXCR2, LukED can prevent neutrophils being recruited by chemoattraction to the site of infection.
The multiple chemokine receptor-blocking activity of LukED is bad news as it gives S. aureus a multi-pronged strategy for attacking the immune system at a number of different stages. However, the good news is that the more we understand about how S. aureus targets the immune system, the better equipped we are to begin to develop therapeutic agents to combat it. The strategy must be to try to target the toxin in order to interfere with its chemokine receptor-binding capacity.
Sources
ALONZO, F.,3RD et al., 2012. Staphylococcus aureus leucocidin ED contributes to systemic infection by targeting neutrophils and promoting bacterial growth in vivo. Molecular microbiology, 83(2), pp. 423-435
ALONZO, F.,3RD et al., 2013. CCR5 is a receptor for Staphylococcus aureus leukotoxin ED. Nature, 493(7430), pp. 51-55
Reyes-Robles, T., et al, 2013. Staphylococcus aureus Leukotoxin ED Targets the Chemokine Receptors CXCR1 and CXCR2 to Kill Leukocytes and Promote Infection. Cell Host & Microbe, 14 (4): pp. 453; DOI: 10.1016/j.chom.2013.09.005
NYU Langone Medical Center / New York University School of Medicine. "Study shows how Staph toxin disarms the immune system." ScienceDaily, 16 Oct. 2013. [Accessed 16 Oct. 2013].
In the current Cell Host & Microbe study, a research group from NYU Langone Medical Centre looked at an S. aureus toxin called Leukotoxin ED (LukED). The same group had previously shown that LukED could bind to the CCR5 receptor on white blood cells including T cells, the backbone of the acquired immune response, macrophages, which phagocytose microbes, and dendritic cells, which are essential for presenting antigen to T cells. LukED could consequently destroy all these essential immune cells by lysis. However, there was a mystery associated with LukED; it could also kill neutrophils, which do not express CCR5. Neutrophils are granulocytic leukocytes that are the first line of defence against invading pathogens; they kill microbes by phagocytosis and by degranulation to release hydrolytic enzymes. Neutralising them seriously handicaps the rest of the immune response. But how does LukED target neutrophils in the absence of CCR5 expression? The results of the Cell Host & Microbe study show that not only can LukED block CCR5 but it can also block CXCR1 and CXCR2 receptors, which are expressed on neutrophils. These receptors respond to and bind mediators known as CXC- chemokines, which is essential for recruitment of neutrophils to sites of infection. So by blocking CXCR1 and CXCR2, LukED can prevent neutrophils being recruited by chemoattraction to the site of infection.
The multiple chemokine receptor-blocking activity of LukED is bad news as it gives S. aureus a multi-pronged strategy for attacking the immune system at a number of different stages. However, the good news is that the more we understand about how S. aureus targets the immune system, the better equipped we are to begin to develop therapeutic agents to combat it. The strategy must be to try to target the toxin in order to interfere with its chemokine receptor-binding capacity.
Sources
ALONZO, F.,3RD et al., 2012. Staphylococcus aureus leucocidin ED contributes to systemic infection by targeting neutrophils and promoting bacterial growth in vivo. Molecular microbiology, 83(2), pp. 423-435
ALONZO, F.,3RD et al., 2013. CCR5 is a receptor for Staphylococcus aureus leukotoxin ED. Nature, 493(7430), pp. 51-55
Reyes-Robles, T., et al, 2013. Staphylococcus aureus Leukotoxin ED Targets the Chemokine Receptors CXCR1 and CXCR2 to Kill Leukocytes and Promote Infection. Cell Host & Microbe, 14 (4): pp. 453; DOI: 10.1016/j.chom.2013.09.005
NYU Langone Medical Center / New York University School of Medicine. "Study shows how Staph toxin disarms the immune system." ScienceDaily, 16 Oct. 2013. [Accessed 16 Oct. 2013].
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