{"id":9325,"date":"2016-07-14T11:05:36","date_gmt":"2016-07-14T11:05:36","guid":{"rendered":"http:\/\/revoscience.com\/en\/?p=9325"},"modified":"2016-07-14T11:05:36","modified_gmt":"2016-07-14T11:05:36","slug":"uw-purdue-scientists-solve-structure-of-cold-virus-linked-to-childhood-asthma","status":"publish","type":"post","link":"https:\/\/www.revoscience.com\/en\/uw-purdue-scientists-solve-structure-of-cold-virus-linked-to-childhood-asthma\/","title":{"rendered":"UW, Purdue scientists solve structure of cold virus linked to childhood asthma"},"content":{"rendered":"
\"<\/a>

The atomic resolution structure of a strain of rhinovirus C. The structure was determined by cryo-electron microscopy. The image colors are depth-cued to highlight protein structure variations on the surface of the virus particle.<\/figcaption><\/figure>\n

The atomic structure of an elusive cold virus linked to severe asthma and respiratory infections in children has been solved by a team of researchers at the University of Wisconsin\u2013Madison and Purdue University.<\/span><\/p>\n

The findings are published this in the\u00a0Proceedings of the National Academy of Sciences<\/span><\/a>\u00a0(PNAS) and provide the foundation for future antiviral drug and vaccine development against the virus, rhinovirus C.<\/span><\/p>\n

\u201cRhinovirus C has been the \u2018missing link\u2019 in explaining illness caused by the common cold,\u201d says Michael Rossmann, Hanley Distinguished Professor of Biological Science at Purdue and co-lead of the study with UW\u2013Madison\u2019s\u00a0Ann Palmenberg<\/span><\/a>, professor of biochemistry and with the\u00a0Institute for Molecular Virology<\/span><\/a>. \u201cThis is sure to spark major new efforts toward the development of vaccines and antiviral drugs, particularly for the prevention of asthma.\u201d<\/span><\/p>\n

\"Michael<\/a>
Michael Rossmann<\/figcaption><\/figure>\n

Asthma affects an estimated 24 million people in the U.S. and asthmatic children infected with rhinovirus C have been shown in previous studies to have more severe asthma symptoms.Rhinovirus C is resistant to current antiviral drugs and no vaccines exist. It was discovered just 10 years ago and health experts believe it is responsible for 50 to 85 percent of all childhood hospitalizations for asthma.In fact, multiple pharmaceutical companies have been waiting for the data, Palmenberg says.<\/span><\/p>\n

Rhinovirus C infections are also a major contributor to poor outcomes for people with chronic lung conditions like cystic fibrosis, and early exposure to the virus can cause lifelong lung scarring leading to persistent respiratory difficulties later, says Palmenberg.<\/span><\/p>\n

Last fall, using a rhinovirus C preparation grown in the Palmenberg lab \u2014 currently one of the few places in the world capable of culturing the virus \u2014 and an imaging technology new to Purdue, Rossmann\u2019s graduate student, Yue Liu, first author of the study, was able to map the full atomic structure of a rhinovirus C particle.<\/span><\/p>\n

Discerning the structure of microscopic biological agents like viruses allows them to be studied and understood in ways not possible by other means. For instance, Liu uncovered physical features of rhinovirus C that help explain why it is resistant to standard antiviral treatments, how it interacts with cells to cause infection, and why it behaves as a different disease from other members of the enterovirus family.<\/span><\/p>\n

This and other virus surface changes help explain why clinical rhinovirus drug trials, which rely on different virus surfaces, have generally failed when tested against rhinovirus C isolates over the last four to five years, says Palmenberg.\u201cWe found some interesting things,\u201d says Palmenberg. \u201cUnlike normal rhinoviruses, this one has spikes on the surface of the particles. We had not anticipated that.\u201d<\/span><\/p>\n

\"Ann<\/a>
Ann Palmenberg<\/figcaption><\/figure>\n

However, the spikes present new binding sites for the human immune response to infection and as such, may present promising new targets for the development of different types of drugs. Or, they may contain structure elements that could be leveraged for effective vaccines.<\/span><\/p>\n

\u201cAnother new finding is that 30 percent of the virus particles were empty and do not contain genetic material,\u201d Palmenberg says.<\/span><\/p>\n

The \u201cempty\u201d particles are not capable of causing infection, but like tiny molecular mimics, they present virus-specific information to the immune system.<\/span><\/p>\n

\u201cThey could be immune decoys,\u201d says Palmenberg, luring the body to fight off noninfectious viral particles, leaving infectious virus free to do its dirty work. \u201cNo other rhinoviruses seem to do this naturally.\u201d<\/span><\/p>\n

They could potentially be used for vaccines.<\/span><\/p>\n

The virus was among the first samples analyzed with a new cryo-electron microscopy system at Purdue, which was designed to operate at vastly higher resolution than previous instruments. The system allows for multiple imaging of single virus particles, rather than relying on a composite of images from thousands of individual viruses. Therefore, the system is faster, more accurate and gives higher resolution structures from less virus material.<\/span><\/p>\n

While the rhinovirus C structure determination was certainly accelerated by this new technology, it was also dependent upon Rossmann\u2019s many years of expertise, Liu\u2019s efforts, and years of work by Palmenberg\u2019s experienced team in order to get the virus to grow under laboratory conditions.<\/span><\/p>\n

\u201cIf you can\u2019t grow it, you can\u2019t do experiments,\u201d says Palmenberg. \u201cThat was the linchpin for this structure \u2026 it took us two-and-a-half years of work to figure out how to put sufficient virus into a tube so we could give it to Purdue.\u201d<\/span><\/p>\n

[pullquote]While learning how to culture rhinovirus C, Palmenberg\u2019s research team discovered the virus only infects certain lung cells that express a particular genetic form of a cell-surface molecule called cadherin-related protein 3 (CDHR3).[\/pullquote]<\/p>\n

That process has now been licensed by the Wisconsin Alumni Research Foundation, a private nonprofit that manages intellectual property at UW\u2013Madison.<\/span><\/p>\n

While learning how to culture rhinovirus C, Palmenberg\u2019s research team discovered the virus only infects certain lung cells that express a particular genetic form of a cell-surface molecule called cadherin-related protein 3 (CDHR3).\u00a0The team published those results<\/span><\/a>\u00a0last year in PNAS.<\/span><\/p>\n

When a rhinovirus C particle encounters a cell bearing the right CDHR3 protein, it can lock onto and gain entry into the cell. During the ensuing infection, it makes many copies of its genetic material, using the cell\u2019s machinery, and this reassembles into many more virus particles that are then released to infect more cells.<\/span><\/p>\n

When CDHR3 is expressed on cells deep in the lungs, the virus infections can wreak havoc, says Rossmann. \u201cIt creates the perfect storm for the severest type of asthma-inducing, lung-scarring events.\u201d<\/span><\/p>\n

But \u201cknowing how to grow it doesn\u2019t tell you what it looks like,\u201d says Palmenberg. Multiple types of rhinovirus C exist and they are part of a larger group of illness-causing viruses, including cold viruses rhinovirus A and B. \u201cWe knew it would be different from rhinovirus A and B: It didn\u2019t respond to drugs, it used a different receptor, it had different biological properties. So the question was, what was going on?\u201d<\/span><\/p>\n

With the new structure data, the team is much closer to finding answers. In fact, mapping the rhinovirus C particles also showed where on these surfaces the virus likely makes contact with the CDHR3 molecules, presenting yet another opportunity to design drugs which may prevent infection.<\/span><\/p>\n

Palmenberg and Rossmann have collaborated for 34 years, ever since her former mentor, UW\u2013Madison professor emeritus\u00a0Roland Rueckert<\/span><\/a>, and Rossmann collaborated to become the first to determine the structure of rhinovirus B.<\/span><\/p>\n

Once Palmenberg worked out how to grow rhinovirus C, she, too, partnered with Rossmann. Her research technician and co-author of the paper, Marchel Hill, delivered a crude test sample of the virus to Purdue on a Friday morning last fall. Liu performed some of the imaging that same day and a preliminary structure was mostly ready by Saturday.<\/span><\/p>\n

The results were unexpectedly quick and remarkable but Rossmann did not call Palmenberg that Saturday. He knows her fall Saturdays are reserved for one thing: Badger football. Asked whether she would have taken his call anyway, the prominent virologist and avid sports fan vigorously shook her head.<\/span><\/p>\n

\u201cNo. I never bring my phone to games.\u201d<\/span><\/p>\n

The study was also co-authored by UW\u2013Madison\u2019s Kelly Watters; Purdue\u2019s Thomas Klose, Zhenguo Chen and Wen Jiang; and Yury Bochkov of the UW\u2013Madison School of Medicine and Public Health. It was funded by the National Institutes of Health.<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"

The atomic structure of an elusive cold virus linked to severe asthma and respiratory infections in children has been solved by a team of researchers at the University of Wisconsin\u2013Madison and Purdue University.<\/p>\n","protected":false},"author":6,"featured_media":9326,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[16,17],"tags":[],"class_list":["post-9325","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-biology","category-research"],"featured_image_urls":{"full":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427.png",500,427,false],"thumbnail":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427-150x150.png",150,150,true],"medium":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427-300x256.png",300,256,true],"medium_large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427.png",500,427,false],"large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427.png",500,427,false],"1536x1536":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427.png",500,427,false],"2048x2048":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427.png",500,427,false],"ultp_layout_landscape_large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427.png",500,427,false],"ultp_layout_landscape":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427.png",500,427,false],"ultp_layout_portrait":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427.png",500,427,false],"ultp_layout_square":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427.png",500,427,false],"newspaper-x-single-post":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427.png",500,427,false],"newspaper-x-recent-post-big":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427.png",422,360,false],"newspaper-x-recent-post-list-image":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427.png",76,65,false],"web-stories-poster-portrait":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427.png",500,427,false],"web-stories-publisher-logo":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427.png",96,82,false],"web-stories-thumbnail":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2016\/07\/Rhinovirus-C15a-full-500x427.png",150,128,false]},"author_info":{"info":["Amrita Tuladhar"]},"category_info":"Biology<\/a> Research<\/a>","tag_info":"Research","comment_count":"0","_links":{"self":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts\/9325","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/users\/6"}],"replies":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/comments?post=9325"}],"version-history":[{"count":0,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts\/9325\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/media\/9326"}],"wp:attachment":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/media?parent=9325"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/categories?post=9325"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/tags?post=9325"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}