November 21, 2018
A human protein associated with asthma is key to how hantaviruses infect the lungs and sometimes cause a life-threatening pulmonary condition known as hantavirus pulmonary syndrome (HPS), according to researchers supported by the National Institutes of Health. They say the most prevalent hantaviruses in North America (Sin Nombre virus) and South America (Andes virus) can recognize the protein, protocadherin-1 (PCDH1), and exploit it to infect the lungs. They hope that disrupting that recognition event could lead to a therapeutic against HPS.
The findings from the study, a collaboration among nearly a dozen research groups, appear in Nature. Scientists from Albert Einstein College of Medicine, the U.S. Army Medical Research Institute of Infectious Diseases, Utah State University, and The Netherlands Cancer Institute led the project. NIH’s National Institute of Allergy and Infectious Diseases was among the entities providing project funding.
Their study involved creating cells that had no PCDH1 on their surfaces. Those cells were not susceptible to infection by four New World hantaviruses (those found in the Americas). They also investigated precisely how the viruses infect cells in which PCDH1 is present and identified protein residues that appear to facilitate infection. The researchers then developed a monoclonal antibody (mAb-3305) against those residues and confirmed that mAb-3305 stopped the virus from entering cells.
Next, using Syrian golden hamsters as a study model for HPS caused by Andes virus, the scientists confirmed that the hamster version of PCDH1 was needed for infection of hamster lung cells, and that mAb-3305 could block that infection. They then developed 21 hamsters without PCDH1 and exposed them to Andes virus. About 85 percent of the animals lacking PCDH1 survived, whereas only about 15 percent of the hamsters bearing PCDH1 did. This high level of protection indicates that PCDH1 plays a major role in hantavirus infection of lung cells. However, not all of the animals lacking PCDH1 were protected, suggesting that additional routes of infection also exist.
The researchers plan to seek out those additional infection pathways as well as investigate therapeutics that might prevent New World hantaviruses from exploiting PCDH1.
This research was supported by NIH research grants AI101436, AI132633, and AI125462; NIH T32 training grants GM007491, AI070117, and AI007501; and NCI center grant P30CA013330.
R Jangra et al. Protocadherin-1 is essential for cell entry by New World hantaviruses. Nature DOI: 10.1038/s41586-018-0702-1 (2018).
Rodolfo Alarcon, Ph.D., and Patricia Repik, Ph.D., NIAID program officers familiar with this project, are available for comment.