Collaboration between the National University of Singapore (NUS) and The Hebrew University of Jerusalem (HUJ) on inflammation research may lead to a potential treatment for deadly bacterial infections
Scientists from the NUS-HUJ-CREATE Inflammation Research Programme based in Singapore have found that asparaginase (ASNASE) – the enzyme that degrades the amino acid asparagine and serves as a common chemotherapeutic agent – arrests Group A Streptococcus (GAS) growth in human blood and blocks bacteria's proliferation, thus initiating a new potential treatment against deadly Streptococcal infections. These findings were first published today in the prestigious scientific journal Cell.
The research programme is funded by the National Research Foundation, Prime Minister's Office, Singapore, under its Campus for Research Excellence and Technological Enterprise (CREATE) programme. The NUS-HUJ-CREATE Inflammation Research Programme was established in 2011, and is focused on advancing an understanding of cellular and molecular mechanisms of inflammation of diseases prevalent in Asia, a field that is currently under-studied.
GAS is a strict human pathogen that causes a wide range of infections, from mild to deadly. It can colonise the host without causing any symptoms, or cause mild infections of skin and trough such as pharyngitis. On the invasive end of the spectrum, GAS can cause life-threatening infections such as bacteremia, necrotising fasciitis (commonly known as flesh-eating disease), and streptococcal toxic shock syndrome. Annually, disseminated GAS infections cause approximately 160,000 deaths globally and severe injuries to those infected.
The flesh-eating bacterium, in particular, causes an extremely vicious infection which progresses rapidly throughout the soft tissues of the body, often leaving doctors with little time to stop or delay the progress of the infection. The main treatments include administration of antibiotics and surgical removal of infected tissues. Despite prompt treatments, bacteria succeed to proliferate and cause death in approximately 25% of patients.
Deciphering how GAS regulates its virulence
How GAS converts from benign coloniser of the human to a deadly one has intrigued many researchers in the field. To decipher this mystery, an international research team led by Professor Emanuel Hanski of HUJ, together with NUS Research Fellows Dr Catherine Cheng Youting and Dr Zhou Yiting, discovered a novel mechanism that influences GAS virulence at the early steps of the infection.
Prof Hanski and the NUS-HUJ-CREATE team found that GAS is able to directly alter the host's metabolism for its own benefit. When GAS adheres and infects the host's cells, it delivers two streptolysin toxins – streptolysin O and streptolysin S – into these cells. These toxins impair the mechanism responsible in the host for quality control of protein synthesis. This in turn triggers a stress response, which among other things also increases the production of the amino acid asparagine. GAS senses the increased asparagine level and alters its gene expression profile. GAS also utilises this amino acid to increase its rate of proliferation.
The research team further discovered that asparaginase, a widely-used chemotherapeutic agent, arrests GAS growth in human blood and in an animal model of human bacteremia, thus suggesting the potential use of asparaginase as a new therapeutic agent against GAS. Asparaginase is an FDA approved drug for lymphoblastoid leukemia, and has never before been applied to treat GAS infections.
The findings of this study constitute a major advance of the concept that understanding the metabolic changes occurring between the pathogen and its host during infection can lead to development of effective treatments against infectious diseases. Prof Hanski said, “We predict that other Gram-positive bacterial pathogens, such as Staphylococcus aureus, and Clostridium botulinium, which possess toxins similar to streptolysin O and streptolsin S, may use similar mechanism to obtain metabolite from the host.”
The NUS-HUJ-CREATE team intends to further their research in the GAS pathogen. Dr Catherine Cheng elaborated, “The next step for us would be to elucidate the mechanism responsible for the sensing of asparagine by Group A Streptococcus.”