HI Scientists Publish Nature Communications Paper Revealing First Atomic-Resolution CryoEM Structures of authentic, infectious parvovirus of humans

Susan web

Austin, Minn. — A team of researchers led by Susan Hafenstein, PhD, Professor and CryoEM Director at The Hormel Institute, University of Minnesota, recently published a paper entitled “Infectious parvovirus B19 circulates in the blood coated with active host protease inhibitors,” in the leading scientific journal Nature Communications. The paper reveals the first  3D structure of human parvovirus B19 (B19V) at the atomic level. B19V infections are on the rise in the United States, and these new insights offer vital perspectives for vaccine development, the improvement of intravenous immunoglobulin treatment, and the possibility for discovering additional solutions to treating and preventing B19V infection.

B19V is a small virus that infects erythroid progenitor cells (stem cells that can become red blood cells). Infection with B19V can cause a mild rash in children (known as erythema or “fifth disease”), but leads to more severe conditions in adults, including joint diseases like arthritis and transient aplastic crisis (TAC), when bone marrow stops producing red blood cells that can lead to severe anemia. In pregnant women, B19V also poses the risk for hydrops fetalis (buildup of fluid in a fetus’s or newborn’s body) or stillbirth due to severe fetal anemia. 

Vaccines to protect against B19V using virus-like particles (VLPs) are currently under development, and intravenous immunoglobulin treatment is used when needed. However, studies of infectious virions have been limited, and existing structures (3D maps) have remained at low resolution until Hafenstein’s study.

With that in mind, the lab’s research project began with a simple idea: to solve (or map) a structure of B19V in higher resolution to understand how the virus operates so that researchers can explore possible avenues for treatment and prevention.

The researchers prepared samples of purified virions derived from a patient infected with B19V, and using cryoEM (cryogenic-sample electron microscopy) technology, solved the first atomic-level structure of the virus.

Doing so led to some serendipitous findings.

“The findings in this paper were a structure-driven discovery. We began with a simple idea: to solve a higher-resolution structure of the authentic B19V. This led to unexpected observations—something on the viral capsid that we had never seen before,” described Assistant Research Professor Hyunwook Lee, PhD, who is listed as first author of the publication. “From there, all the new findings emerged.” 

Among the research team’s new findings:

  •  B19V circulating in patient blood has distinct surface structures and features compared to VLPs.
  •  B19V’s capsid (shell) was bound to 2 human proteins: serpinA3 and inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4). Both proteins are protease inhibitors and acute-phase reactants (APRs).
  • The above phenomenon, where large host proteins coat the virions, creating a “disguise” that allows them to go undetected by the immune system.
  •  Most antigenic sites (areas on the virus surface to which antigens or antibodies bind) were covered by APRs, which don’t bind to VLPs.
  •  Furthermore, and perhaps most importantly, the virus uses the bound host proteins to protect itself.

In light of these discoveries, new questions have been unlocked.

“As shown in the figures of the paper, the virus appears to be ’cloaked’ by human proteins, decorating the capsid surface,” said Dr. Lee. “The presence of the two protease inhibitors binding to B19V was confirmed in samples from ten different patients, including one sample with B19V genotype 2, which is considered an ancient genotype. This suggests that the binding of these host proteins is a general and evolutionarily conserved feature of B19V infection. It implies that the virus may be utilizing host proteins to its advantage during viremia. The question of how and why this small virus acquired the ability to bind human proteins is particularly intriguing.

“Another question is whether this phenomenon is specific to B19V, or if other parvoviruses, and even other animal viruses, might also exhibit similar strategies. The key difference from a previous study of B19V, which was also purified from human plasma, lies in the virus purification protocol: we used an isotonic solution without EDTA, whereas the previous study used a hypertonic solution containing EDTA—simply to put, a milder and harsher condition. Could it be that critical information is being overlooked in the study of many viruses?”

“This represents a new chapter in understanding B19V infection mechanisms. While the exact role of the bound protease inhibitors in B19V infection remains unclear, their protease inhibitory functions may play a role in viral entry. As we continue to investigate these details, we are likely to uncover more insights into the virus’s interaction with the host.

“With the installation of more advanced microscopes and equipment here at The HI, we will be able to explore even more details at the molecular level,” said Dr. Lee.

The Hormel Institute authors included Dr. Hafenstein, Dr. Lee, and CryoEM Specialist Carol Bator. The project was in collaboration with the lab of Dr. Carlos Ros at the University of Bern, Switzerland. 

The findings are already garnering significant attention. The editors at Nature Communications, for example, selected the paper as an Editor's Highlights item, which showcases the "50 best papers recently published in an area." It was also broadcast on the podcast This Week in Virology.

You can read the paper here: https://www.nature.com/articles/s41467-024-53794-1

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