Ann C. Palmenberg

Photo of Ann C. Palmenberg
Professor (also Institute for Molecular Virology)
B.S.: St. Lawrence University
Ph.D.: University of Wisconsin-Madison
Phone: (608) 262-7519
Email: acpalmen@wisc.edu

Biology and biochemistry of RNA picornaviruses

Figure 1. A phylogram
Fig 1. A phylogram, derived from aligned sequences determined by our program defines the relationships among all known RV genotypes.

Almost everyone has suffered at one time or another, from the sneezing, sniffling, watery-eyed misery of a good old-fashioned common cold. The culpable agent in many cases is a rhinovirus (RV), one of the small, positive-sense RNA-containing picornaviruses, whose very name evokes images of a runny nose. The 100+ genotypes in the RV-A&B species (Fig 1) are canonically linked to the common cold, but many studies have established that some of these viruses aggressively infect the lower airways as well. This is especially true for isolates of the recently described RV-C species (55 genotypes).

Our research focuses the molecular mechanisms, virus structures, biochemistry and cell biology by which such deep-lung virus infections, specifically with human rhinoviruses, contribute and shape episodes of asthma. Collectively, the RV contribute to 50-85% of all asthma exacerbations, but by far, the RV-C are the strongest and most frequently isolated virus components, of any type, leading to the most severe respiratory infections and hospitalizations among children. Asthma is a highly complex disease because individual etiologies may result from composite elements of genetic susceptibility, nuanced personal medical histories and a myriad of environmental factors. Our program, synergizing biochemistry directions with UW hospital clinical units, is at the forefront in the collection and evaluation of extensive virology structure data relevant to each of these components (Fig 2).

Figure 2. The cryo-EM structure of RV-C15a
 

 

 

Fig 2. The cryo-EM structure of RV-C15a
was determined in a collaboration with
Michael Rossmann, at Purdue.

Click for movie

 

Model highlights the EC5-6 protein junction where the human allele dichotomy occurs
Fig 3. The cryo-EM structure of CDHR3 is underway. This model made by our program was a recent cover for the Journal of Virology and highlights the EC5-6 protein junction where the human allele dichotomy occurs.

 

We discovered that unlike the RV-A&B, the RV-C require cadherin-related family member 3 (CDHR3), a deep-lung localized protein, as their cell-entry receptor (Fig 3). The “A” allele of this gene (Tyr529 protein variant) is among the strongest known genetic correlates for childhood asthma susceptibility. Conversely, Cys529, encoded by the high prevalence “G” allele genotype in most modern human lineages, is not an asthma correlate. We are studying why the CDHR3 Cys529 variant fails at the biochemical level, to display this protein properly or extensively on cell surfaces, making their carriers more refractive to RV-C infections and virus-induced asthma-exacerbations. Initial paleo genetics meta analyses suggests the frequency of the asthma-protective Cys529 variant in ancient human lineages may have increased in parallel with the predicted emergence of primordial RV-C genotypes from the RV-A about 3000 years ago. Essentially, modern kids who still maintain the more ancient “A” genetic legacy, are programmed to display more of the CDHR3 receptor on their pulmonary surfaces, marking them as 2-5 times more susceptible to devastating virus-triggered asthma episodes.

The forte of our program is our unique and extensive technical, genetic engineering and computational resources for describing the structures and biochemistry of the virus (RV-C), its receptor (CDHR3), their precise interactions, cell-receptor display parameters, required cellular functions for RV infection, and consequent therapeutic implications to asthma-treatment therapies, which we now predict, may need to discriminate among specific human genetic lineages. We are the only laboratory in the world with these experimental RV-C capabilities and at the technical forefront of advanced RV-A&B&C molecular biology.