X-ray Research at Diamond Paves Way for Lassa Fever Vaccine and Drug Development
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Scientists from the University of St Andrews in Scotland, and their international collaborators from Emory University, USA, and Sun Yat-sen University, China, have discovered how the Lassa virus, which causes Lassa fever, remains invisible to the human defence system and causes thousands of deaths each year. The research, which centered around the collection of X-ray data at Diamond Light Source, the UK’s national synchrotron facility, was published in Nature this week.
Treatment for Lassa fever is currently limited and there is no effective vaccine against the virus. In addition, the virus is a biological threat agent, as Lassa fever could transmit from person to person. This latest research has been partly funded by the Wellcome Trust, the Southeast Regional Center of Excellence of Emerging Infections and Biodefense, and the National Institutes of Health in the USA.
It had been known that the nucleoprotein (NP) of Lassa virus has an essential role in immune suppression in sufferers but how this protein worked on a molecular level was still a mystery. By focusing on the Lassa virus NP protein during their experiments at Diamond, where protein crystal samples were exposed to finely tuned pinpoint X-ray beams, the group has succeeded in building up an atom by atom 3D picture of the protein's structure and how it operates in the body.
Lassa virus, which is spread by the "multimammate rat" of the genus Mastomys, was first identified in 1969 and today it causes up to 500 000 cases of the acute viral haemorrhagic fever and some 5000 deaths each year across West Africa. Various degrees of deafness occur in approximately one-third of cases, and in many cases hearing loss is permanent. The onset of the disease is usually gradual, starting with fever, general weakness and malaise. Other symptoms such as sore throat, chest pain, vomiting and diarrhoea may follow. Severe multi-system disease will develop in about 20% of cases, where the virus affects several organs in the body, such as the liver, spleen and kidneys.
Fears that the virus may be spreading were sparked just last week as a third person died of Lassa Fever in northern Sierra Leone, an area which has not known of any prevalence of the disease in recent times. Lassa fever cases have also been found in Britain, Germany, USA and Japan due to travel to areas of West Africa where Lassa virus infection is endemic.
Dr Changjiang Dong, a Wellcome Trust Career Development Fellow, the group leader for the research project at University of St. Andrews, says, "The research hugely relies on the very close collaboration among my group, Dr. Yuying Liang and Dr. Hinh Ly groups at Emory University, and Dr. Wenjiang Wang group at Sun Yat-sen University. Our findings are really exciting and provide great potential for vaccine and drug development. In solving the structure of the Lassa virus NP protein, we have revealed its unexpected functions and shown the unique workings of viral replication and immune evasion.
This totally unexpected knowledge will make designing a vaccine and drug treatments much easier. Trying to design a vaccine or drug without this kind of information is a bit like trying to make a chair cover when the chair’s shape is a total unknown, in all likelihood it won't fit, or do its job properly. By understanding how virus proteins attack the body at the molecular level, we stand a much better chance of designing a vaccine or drug whose shape and function will successfully block the virus from developing into the acute viral illness."
The Lassa virus NP structural information obtained in this research revealed amino (N) - and carboxy (C) - terminal domains with structures unlike any of the reported viral NPs. The N domain folds into a novel structure with a deep cavity for initiating the virus RNA synthesis; whereas the C domain contains exoribonuclease activity, which removes special viral RNAs recognized by cellular receptors and is involved in suppressing the non-specific immune system response that would normally be induced at an early stage in viral infection.
These findings also have implications for the other known 27 viruses in the arenavirus family, some of which result in severe haemorrhagic fevers. New arenaviruses have been discovered on average every one to three years. Particularly Lymphocytic choriomeningitis virus, a worldwide distributed arenavirus, which has been identified as a causative agent for fatal central nervous system disease for children and fatal multi-organ failure for the elderly and organ transplant patients.
Treatment for Lassa fever is currently limited and there is no effective vaccine against the virus. In addition, the virus is a biological threat agent, as Lassa fever could transmit from person to person. This latest research has been partly funded by the Wellcome Trust, the Southeast Regional Center of Excellence of Emerging Infections and Biodefense, and the National Institutes of Health in the USA.
It had been known that the nucleoprotein (NP) of Lassa virus has an essential role in immune suppression in sufferers but how this protein worked on a molecular level was still a mystery. By focusing on the Lassa virus NP protein during their experiments at Diamond, where protein crystal samples were exposed to finely tuned pinpoint X-ray beams, the group has succeeded in building up an atom by atom 3D picture of the protein's structure and how it operates in the body.
Lassa virus, which is spread by the "multimammate rat" of the genus Mastomys, was first identified in 1969 and today it causes up to 500 000 cases of the acute viral haemorrhagic fever and some 5000 deaths each year across West Africa. Various degrees of deafness occur in approximately one-third of cases, and in many cases hearing loss is permanent. The onset of the disease is usually gradual, starting with fever, general weakness and malaise. Other symptoms such as sore throat, chest pain, vomiting and diarrhoea may follow. Severe multi-system disease will develop in about 20% of cases, where the virus affects several organs in the body, such as the liver, spleen and kidneys.
Fears that the virus may be spreading were sparked just last week as a third person died of Lassa Fever in northern Sierra Leone, an area which has not known of any prevalence of the disease in recent times. Lassa fever cases have also been found in Britain, Germany, USA and Japan due to travel to areas of West Africa where Lassa virus infection is endemic.
Dr Changjiang Dong, a Wellcome Trust Career Development Fellow, the group leader for the research project at University of St. Andrews, says, "The research hugely relies on the very close collaboration among my group, Dr. Yuying Liang and Dr. Hinh Ly groups at Emory University, and Dr. Wenjiang Wang group at Sun Yat-sen University. Our findings are really exciting and provide great potential for vaccine and drug development. In solving the structure of the Lassa virus NP protein, we have revealed its unexpected functions and shown the unique workings of viral replication and immune evasion.
This totally unexpected knowledge will make designing a vaccine and drug treatments much easier. Trying to design a vaccine or drug without this kind of information is a bit like trying to make a chair cover when the chair’s shape is a total unknown, in all likelihood it won't fit, or do its job properly. By understanding how virus proteins attack the body at the molecular level, we stand a much better chance of designing a vaccine or drug whose shape and function will successfully block the virus from developing into the acute viral illness."
The Lassa virus NP structural information obtained in this research revealed amino (N) - and carboxy (C) - terminal domains with structures unlike any of the reported viral NPs. The N domain folds into a novel structure with a deep cavity for initiating the virus RNA synthesis; whereas the C domain contains exoribonuclease activity, which removes special viral RNAs recognized by cellular receptors and is involved in suppressing the non-specific immune system response that would normally be induced at an early stage in viral infection.
These findings also have implications for the other known 27 viruses in the arenavirus family, some of which result in severe haemorrhagic fevers. New arenaviruses have been discovered on average every one to three years. Particularly Lymphocytic choriomeningitis virus, a worldwide distributed arenavirus, which has been identified as a causative agent for fatal central nervous system disease for children and fatal multi-organ failure for the elderly and organ transplant patients.
