Research
Research Institutes & Horseshoe crab holds secret to protein that fights infection
"Using an ancient species, the horseshoe crab, we demonstrated that CRP does not act alone, but it must be in an ensemble, collaborating with other blood proteins in order to bind bacteria. This combined action of CRP with other blood proteins constitutes a strong 'pathogen-recognition assembly', which boosts frontline immune defense to kill the invading bacteria."
Prof Ding Jeak Ling, Department of Biological Sciences
Prof Ding Jeak Ling, Department of Biological Sciences
BREAKTHROUGH: Prof Ding (above) and team make significant discovery on how C-reactive protein works, with the help of horseshoe crabs.
Scientists have observed that high levels of the C-reactive protein (CRP) are always present during septicaemia (blood poisoning) and other forms of infection. So they know that CRP is an important clinical marker for acute inflammation and infection in patients. From experiments where mice were given human CRP, scientists also knew that CRP helps fight infection, protecting the mice from bacteria. But they could not understand how CRP functions in the human body -- their experiments using purified CRP had not been able to reveal the secret of this protein which is also found in the blood of the horseshoe crab.
Red-blood cells are fighters too
Our red blood cells do more than just transporting oxygen, they are also a fighting force that can take down disease-causing bacteria. Haemoglobin, a protein that gives the blood its colour, was found to produce free radicals that may kill bacteria.
This discovery, by Prof Ding Jeak Ling and Ms Jiang Naxin of Department of Biological Sciences; Prof Ho Bow, Department of Microbiology; and Dr Tan Nuan Soon of anyang Technological University, was recently published in scientific journal, Nature Immunology (August 2007).
The team found that when bacteria break open a red blood cell, the haemoglobin molecule releases chemicals called free radicals which will bind on to the invading bacteria. The radicals will then break their cell walls and effectively destroy them.
Prof Ding said the disease-fighting ability of haemoglobin was first discovered in her earlier studies on haemolyain, the equivalent of oxygen-carrying protein in horseshoe crabs' blood. "We first saw this in our studies on horseshoe crabs ... when invaded by bacteria, the haemocyanin releases free radicals aggressively. So we wanted to study how haemoglobin in humans would respond too."
This faster alternative way of combating against disease challenges the accepted paradigm of immune response -- a multi-stepped process whereby the immune system first recognises the invading bacteria or virus, before sending out signals to direct immune cells to fight the intruders. The team is currently doing further investigation of this defence mechanism to discover new avenues into the development of antibacterial strategies, which can potentially benefit patients suffering from immunodeficiency disorders. "We aim to identify the hotspots in haemoglobin where bacteria bind to help us come up with novel strategies and drugs to fight microbes," said Prof Ding.
But now, a team comprising Prof Ding Jeak Ling from the Department of Biological Sciences; Profs Ho Bow and Lu Jinhua, Department of Microbiology, has shed light on how CRP can fight infection. Their findings in the paper, C-reactive protein collaborates with plasma lectins to boost immune response against bacteria' were published by the European Molecular Biology Organization journal (June 2007).Our red blood cells do more than just transporting oxygen, they are also a fighting force that can take down disease-causing bacteria. Haemoglobin, a protein that gives the blood its colour, was found to produce free radicals that may kill bacteria.
This discovery, by Prof Ding Jeak Ling and Ms Jiang Naxin of Department of Biological Sciences; Prof Ho Bow, Department of Microbiology; and Dr Tan Nuan Soon of anyang Technological University, was recently published in scientific journal, Nature Immunology (August 2007).
The team found that when bacteria break open a red blood cell, the haemoglobin molecule releases chemicals called free radicals which will bind on to the invading bacteria. The radicals will then break their cell walls and effectively destroy them.
Prof Ding said the disease-fighting ability of haemoglobin was first discovered in her earlier studies on haemolyain, the equivalent of oxygen-carrying protein in horseshoe crabs' blood. "We first saw this in our studies on horseshoe crabs ... when invaded by bacteria, the haemocyanin releases free radicals aggressively. So we wanted to study how haemoglobin in humans would respond too."
This faster alternative way of combating against disease challenges the accepted paradigm of immune response -- a multi-stepped process whereby the immune system first recognises the invading bacteria or virus, before sending out signals to direct immune cells to fight the intruders. The team is currently doing further investigation of this defence mechanism to discover new avenues into the development of antibacterial strategies, which can potentially benefit patients suffering from immunodeficiency disorders. "We aim to identify the hotspots in haemoglobin where bacteria bind to help us come up with novel strategies and drugs to fight microbes," said Prof Ding.
Prof Ding explained that so far, research groups worldwide have only investigated CRP in its purified form of a single protein. They found that the protein in this form, would not bind to bacteria in the test tube. However, her team, using purified human CRP, has shown that the protein does indeed bind to Salmonella enterica (a bacterium that causes food poisoning) -- and that binding is enhanced in the presence of plasma factors.
The protein works by rallying other proteins in the bloodstream into a colony to attach themselves to the cell walls of bacteria. Together, they manage to make the bacteria irresistible to white blood cells which are soldier cells fighting off infection.
The team first noticed the CRP's behaviour in the blood of horseshoe crabs. "Using an ancient species, the horseshoe crab, we demonstrated that CRP does not act alone, but it must be in an ensemble, collaborating with other blood proteins in order to bind bacteria. This combined action of CRP with other blood proteins constitutes a strong 'pathogen-recognition assembly', which boosts frontline immune defense to kill the invading bacteria."
The team used the protein partner (found in the horseshoe crab) of the human CRP -- and found that this phenomenon of host protein-protein interaction in bacterial recognition and antibacterial action is conserved from horseshoe crab to the human. "Between horseshoe crab and human, the evolutionary distance is several hundred million years!" said Prof Ding. Such an evolutionary conservation therefore indicates the crucial importance of this immune defense mechanism in human, she said. Profs Ding and Ho, a husband-and-wife team, are known for their research on horseshoe crabs, an endangered species. They successfully cloned the enzyme that clots the blood of the horseshoe crab, making it one of the nature's most sensitive sensors for toxic contaminants. For the last several decades, pharmaceutical companies have been bleeding the horseshoe crabs to extract the enzyme, Factor C, which initiates clotting of the crab's blood. This is used to test for contaminants in human healthcare products, including medical equipment, fluids and other sterile products.
