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Hantaviruses cause severe and sometimes fatal respiratory infections, but the way they infect lung cells was a mystery. In today's show a The nature, an international team, including researchers from the Albert Einstein College of Medicine, reports that hantaviruses gain entry into lung cells by unlocking a cell-cell receptor called protocadherin-1 (PCDH1). Deleting this receiver has made laboratory animals extremely resistant to infections. The results show that targeting PCDH1 could be a useful strategy against deadly Hantavirus Syndrome (HPS).
The study was co-led by Kartik Chandran, Ph.D. Thijn R. Brummelkamp, Ph.D., at the Cancer Institute in the Netherlands; John M. Dye, Ph.D., at the US Army Medical Research Institute for Infectious Diseases (USAMRIID); and Zhongde Wang, Ph.D., at Utah State University.
An emerging threat
HPS was first identified in 1993. A total of 728 cases have been reported so far in the United States, particularly in rural areas in Western states. While hantavirus infections are rare, they are expected to increase over the next decades, as temperatures around the world are rising due to climate change. And we are totally inappropriate for this possibility, "said Dr. Chandran, Professor of Microbiology and Immunology, and Harold and Muriel Block Scholar of the Faculty of Virology at Einstein.
Hantavirus is transmitted to people who inject the virus from the urine, faeces or saliva of infected rodents. Early HPS symptoms include fatigue, fever and muscle aches followed by a coughing week and shortness of breath. HPS has a mortality rate of about 40 percent, according to Centers for Disease Control and Prevention. No treatments or vaccines are available. "Our findings provide new insights into how these infections develop and how they could be prevented or treated," Dr. Chandran added.
Detecting a viral entry point
In search of host factors that allow for a hantavirus infection, the researchers performed a "loss of function" genetic screen to see if beating in special cell genes could block access to hantavirus. The screen highlighted the PCDH1 gene encoding the PCDH1 protein receptor found on cell membranes. Clearly, PCDH1 has previously been implicated in respiratory and lung disease in humans but was not known to have a role in infection with hantaviruses or other viruses.
To confirm that PCDH1 plays a role in hantavirus infection, researchers have removed it from human lung endothelial cells (ie cells that align the lung). These cells became extremely resistant to infections by the two HPS major Hantaviruses found in North and South America: the Sin Nombre virus and the Andes virus. Crucially, Syrian golden hamsters (the primary rodent model for hantavirus studies) designed for lack of the PCDH1 receptor were largely resistant to infections and pulmonary lesions caused by the Andes virus. Instead, most control animals, possessing the receptor, yielded to the virus. "Our findings establish a key role for PCDH1 in lung infections caused by hantaviruses in an animal model that captures the key features of HPS," said co-senior author Dr. Dye, chief of viral immunology at USAMRIID.
The researchers also identified a specific part of the PCDH1 protein, which is recognized directly by hantaviruses, which makes this protein region a promising target for drug development. Indeed, the team generated monoclonal antibodies with a high affinity for this region of PCDH1 that could bind to lung endothelial cells and protect them from infections with the Andes and Sin Nombre viruses. Studies underway are the evaluation of these antibodies against hantavirus infection and animal disease.
Interestingly, another group of hantaviruses that cause severe kidney disease in Europe and Asia and occasionally in the U.S. did not require the PCDH1 receptor for infection. "These viruses have other methods of invading cells that remain to be discovered," said Rohit Jangra, Ph.D., research assistant professor at Einstein and co-author of the study.
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Materials provided by Albert Einstein College of Medicine. Note: content can be edited for style and length.
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