Hantaviruses cause severe and sometimes fatal respiratory infections, but how they infect the lungs is a mystery. In today's issue of nature, an international team including researchers from the Albert Einstein College of Medicine, reported that hantaviruses gain access to the lungs by "unlocking" a cell surface receptor called Protocon-1 (PCDH1). Deletion of this receptor makes the laboratory animals highly resistant to infection. The findings suggest that targeting of PCDH1 may be a useful strategy against Hantavirus lethal pneumonia (HPS).
The study was jointly led by Kartik Chandran, Ph.D. Thijn R. Brummelkamp, PhD, at the Dutch Cancer Institute; John M. Dye, Ph.D., at the US Institute of Medical Research on Infectious Diseases (USAMRIID); and Dr. Jong Wang, State University of Utah.
HPS was first identified in 1993. So far, a total of 728 cases have been reported in the United States, mainly in rural areas of Western countries. "While hantaviral infections are rare, they are expected to increase over the coming decades as temperatures around the globe are rising due to climate change," said Dr Chandran, professor of microbiology, who is totally unprepared for this option. and Immunology Harold and Muriel Block Faculty of Frontiers in Einstein.
Hantavirus is transmitted to people who breathe the virus from the urine, feces or saliva of infected rodents. Early symptoms of HPS include fatigue, fever, and muscle aches, followed after about a week of coughing and shortness of breath. HPS has a mortality rate of about 40%, according to the Centers for Disease Control and Prevention. No treatments or vaccines. "Our findings provide new insights into how these infections develop and how they can be prevented or treated," said Dr. Chandran.
Detection of a viral entry point
In search of host factors that allow Hantavirus infection, the researchers performed a "loss of functionality" genetic screen to see if the killing of certain cell genes could block hantavirus infestation. The screen noticed the PCDH1 gene encoding the PCDH1 protein receptor found on the cell membranes. Remarkably, PCDH1 has previously been implicated in human respiratory function and pulmonary disease but is not known to play a role in infection with hantaviruses or other viruses.
To confirm that PCDH1 plays a role in hantavirus infection, researchers are deleting it from human lung endothelial cells (ie, cells that line the lung). These cells become very resistant to infection by the two major HPS-causing hantaviruses found in the North and South America: Sin Nombre Virus and Andes Virus. Significantly, Syrian golden hamsters (the main rodent model for hantavirus testing) designed to have no PCDH1 receptor are largely resistant to infections and lesions of the lungs caused by the Andes virus. Conversely, most of the control animals that have the receptor delivered to the virus. "Our findings set a key role for PCDH1 in lung infections caused by hantaviruses in an animal model that captures the key features of HPS," said co-author Dr. Dye, head of viral immunology at USAMRIID.
Researchers also identify a specific portion of the PCDH1 protein that is directly recognized by hantaviruses, making this protein region a promising target for drug development. Indeed, the team generates highly affinity monoclonal antibodies to this area of PCDH1 that can bind to lung endothelial cells and protect them from infection by the Andes and Sin Nombre viruses. Current studies evaluate these antibodies against hantavirus infection and animal disease.
Interestingly, a different group of hantaviruses that cause severe kidney disease in Europe and Asia and sometimes in the United States do not require PCDH1 receptor for infection. "These viruses also have other ways to invade cells that remain to be detected," said Robbit Jangra, Ph.D., a research scientist at Einstein, and co-author of the study.
Materials provided by Albert Einstein College of Medicine, Note: Content can be edited for style and length.