Hantavirus causes severe and sometimes fatal respiratory infections, but how they infect lung cells has become a mystery. In today's edition NaturalInternational teams including researchers at the Albert Einstein College of Medicine report that hantavirus enters lung cells by "opening" a cell surface receptor called protocadherin-1 (PCDH1). Removal of these receptors makes laboratory animals very resistant to infection. The findings suggest that targeting PCDH1 could be a useful strategy against deadly Hantavirus Pulmonary Syndrome (HPS).
The study was led by Kartik Chandran, Ph.D. Thijn R. Brummelkamp, Ph.D., at the Netherlands Cancer Institute; 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.
HPS was first identified in 1993. A total of 728 cases have so far been reported in the United States, especially in rural western countries. "While rare hantavirus infections, they are expected to increase in the coming decades when temperatures around the world increase due to climate change. And we are not at all ready for this possibility," said Dr. Chandran, professor of microbiology & immunology and Harold and Muriel Block Faculty Scholar at Virology at Einstein.
Hantavirus is transmitted to humans who breathe viruses from urine, feces, or saliva from infected mice. Early symptoms of HPS include fatigue, fever and muscle aches, followed after a week or more by coughing and shortness of breath. HPS has a mortality rate of around 40 percent, according to the Centers for Disease Control and Prevention. There are no treatments or vaccines available. "Our findings provide new insights into how these infections develop and how they can be prevented or treated," Dr. Chandran added.
Detect Viral Entry Points
In searching for host factors that allow infection with hantavirus, the researchers conducted a genetic screen of "loss of function" to see whether dropping certain cellular genes could block the entry of hantavirus. The screen highlights the PCDH1 gene, which encodes the PCDH1 protein receptor found on cell membranes. Strikingly, PCDH1 has previously been involved in human respiratory function and lung disease but is not known to play a role in infection by hantavirus or other viruses.
To confirm that PCDH1 plays a role in infection with hantavirus, the researchers removed it from human lung endothelial cells (i.e. the cells lining the lungs). These cells become very resistant to infection by the two main HPS sets that cause hantavirus found in North and South America: Sin Nombre virus and Andes virus. Importantly, Syrian golden hamsters (the main mouse model for the study of hantavirus) are engineered to lack PCDH1 receptors which are largely resistant to lung infections and injuries caused by the Andes virus. In contrast, most control animals, which have receptors, succumb to the virus. "Our findings establish a key role for PCDH1 in lung infections caused by hantavirus in animal models that capture the main features of HPS," said senior author Dr. Dye, head of viral immunology at USAMRIID.
The researchers also pointed to a specific part of the PCDH1 protein that is directly recognized by hantavirus, making this region of the protein a promising target for drug development. Indeed, the team produced high-affinity monoclonal antibodies for the PCDH1 region that can bind pulmonary endothelial cells and protect them from infections by the Andes virus and Nombre Sin. Ongoing studies are evaluating these antibodies against hantavirus infections and diseases in animals.
Interestingly, different hantavirus groups that cause severe kidney disease in Europe and Asia and sometimes in the US do not need PCDH1 receptors for infection. "These viruses have other ways to attack cells that still have to be found," said Rohit Jangra, Ph.D., assistant research professor at Einstein and first research author.
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Material provided by Albert Einstein College of Medicine. Note: Content can be edited for style and length.