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Blocking a cell receptor may provide protection against fatal disease in the southwest US – ScienceDaily


Hantaviruses cause severe and sometimes fatal respiratory infections, but how they infect lung cells has been a mystery. In today's edition NatureAn international team, including researchers at Albert Einstein College of Medicine, reports that hantaviruses provide access to lung cells by "unlocking" a cell surface receptor called protocadherin-1 (PCDH1). The deletion of this receptor made high-resistance laboratory animals against infection. The findings show that targeting PCDH1 may be a useful strategy against lethal hantavirus pulmonary syndrome (HPS).

Working in Kartik Chandran, Ph.D. Thijn R. Brummelkamp, ​​Ph.D., The Netherlands Cancer Institute; US Army Medical Research Institute Infectious Disease Institute (ABDAMRIID) John M. Dye; and Ph.D. in Utah State University.

A New Developing Threat

HPS was first described in 1993. In the United States, a total of 728 cases have been reported so far, mostly in rural areas of western states. Iyor Although hantavirus infections are rare, they are expected to increase in the coming decades due to climate change as temperatures in the world rise. And we're completely unprepared for this possibility, bu said Dr. Dr. Chandran is a professor of microbiology and immunology. Harold and Muriel Block Faculty Academy at Virology in Einstein.

Hantavirus is transmitted to humans from the urine, feces or saliva of infected rodents. Early HPS symptoms are followed by fatigue, fever and muscle aches, coughing and shortness of breath one week later. According to HPS Disease Control and Prevention Centers, it has a mortality rate of about 40 percent. No treatments or vaccines are available. "Our findings provide new information on how these infections develop and how to prevent or treat them."

Detection of Viral Entry Point

When investigating host factors for hantavirus infection, researchers performed a "loss of function" genetic screening to see if knockout of certain cellular genes could block hantavirus entry. The screen illuminated the PCDH1 gene encoding the protein receptor PCDH1 found in cell membranes. Strikingly, PCDH1 had previously played a role in human respiratory function and lung diseases, but it was not known to play a role in infection by hantaviruses or other viruses.

To confirm that PCDH1 plays a role in hantavirus infection, the researchers deleted it from human pulmonary endothelial cells (ie, cells aligning the lung). These cells became highly resistant to infection by hantavirus, the Sin Nombre virus and the Andes virus, which caused the two major HPS found in North and South America. Importantly, Syrian gold hamsters (the primary rodent model for hantavirus studies) are designed to be devoid of PCDH1 receptor and are largely resistant to infection and lung damage caused by the Andes virus. In contrast, most of the control animals with the receptor have succumbed to the virus. Dr. Dr. Ar Our findings play an important role for PCDH1 in hantavirus-induced lung infections in an animal model that captures the key features of HPS. “

The researchers also identified a specific part of the PCDH1 protein directly recognized by the hantaviruses, making it a promising target for drug development. Indeed, the team produced high affinity monoclonal antibodies for this PCDH1 region that could bind to lung endothelial cells and protect it from infection by the Andes and Sin Nombre viruses. Ongoing studies have evaluated these antibodies against hantavirus infection and disease in animals.

Interestingly, a different group of hantaviruses causing serious kidney disease in Europe and Asia and sometimes in the United States did not require infection for the PCDH1 receptor. "These viruses have other ways of being discovered," said Rohit Jangra, a research assistant at Einstein and one of the first authors of the study.

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Materials supplied by Albert Einstein School of Medicine. Note: Content can be edited for style and length.

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