Why birds don't spread Lassa fever
04 July 2014
An international group of researchers examined a 30-year old riddle why birds aren't susceptible to Lassa virus, leading to a better understanding of how it infects humans. To their surprise, the virus needs a second receptor on the inside of cells to infect them. Their findings are published in Science.
The Lassa virus is a dangerous virus that is endemic to West Africa. It is spread by a rodent, and infection of humans causes a severe and often deadly haemorrhagic fever. Over 30 years ago, researchers discovered that the virus can infect a broad range of cells from different species, but doesn't affect chicken cells. What makes this even more surprising is that bird cells do have the exact same cell surface receptor, a protein that the virus uses to hook onto cells and enter them, as cells from other species. So why can birds still not be infected?
An international research team, under supervision of Dr. Thijn Brummelkamp from the Netherlands Cancer Institute (NKI), used genetic screens to find that a protein called LAMP1 is essential for the virus to properly infect cells. It turns out that when Lassa virus hooks onto its receptor on the cell surface, it is first transported to a structure inside the cell called a lysosome. Lysosomes are the 'garbage cans' of cells in whose hostile interior all kinds of molecules are broken down. To infect the cell, Lassa virus needs to escape the lysosome. It does so by hooking onto LAMP1, which appears to be an unknown type of in-cell receptor for the virus.
"From a virology point of view, this second part of our discovery is the most interesting", comments Lucas Jae, who also works at the NKI and is the first author of a paper in Science that appeared on 26 June. "The identity of the receptor on the cell surface has been known for 15 years. Nobody expected there to be a second receptor, inside of the cell." Brummelkamp adds, "Three years ago we found a similar two step mechanism for the entry of Ebola virus into cells. We now suspect that more viruses may require multiple receptors to reach the cytoplasm. If this turns out to be true, the process by which viruses infect cells is more complicated than currently stated in the text books."
Brummelkamp and Jae also discovered that the critical difference between the avian version of the LAMP1 protein and its human counterpart lies within a single additional sugar structure, present in humans but absent in birds.
Their genetic discoveries were validated in vivo with the help of research groups from Harvard, the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) and the University of Kiel in Germany. They engineered mice that completely lack the LAMP1 protein. These mice turn out to be insusceptible to the Lassa virus.