According to some estimates, mosquito-borne diseases could be responsible for nearly half of all deaths throughout human history: approximately 50 billion people. While advances in modern medicine have cut this number to about 1 million deaths a year, a lack of effective antiviral drugs and vaccines for numerous mosquito-related viral infections continues to be a problem.
Hans-Heinrich Hoffmann is looking to change that. A postdoctoral fellow in Charles Rice’s virology lab at Rockefeller University, Hoffmann recently published a paper in Cell Host and Microbes identifying a protein in human cells critical for the later stages of the viral life cycle. This protein, calcium pump SPCA1, is required for the manufacturing of new viruses in both respiratory and mosquito-borne diseases, making it an attractive target for potential therapies.
“If you think about [diseases like] Zika, which came out in the past two years, there are other viruses we don’t even know about yet,” Hoffmann said. “We will have something in hand that could be a broad antiviral.”
Hoffmann discovered SPCA1 in a genome-wide knockout screen, which turns off selected genes in cells to test their function. Normally, SPCA1 acts as a transporter, transporting calcium ions through the Golgi Apparatus, which is a structure within the cell involved in the packaging and exporting of proteins. When Hoffmann knocked the SPCA1 gene out, thus eliminating its protein product, certain proteins within the Golgi Apparatus that depended on the influx of calcium ions showed reduced function.
Now, one might wonder how this mechanism relates to viruses. Viruses replicate by hijacking a normal cell’s machinery so that the cell does nothing but produce more copies of the virus. One part of this machinery is the Trans-Golgi Network (TGN), located within the Golgi Apparatus, which in certain types of viruses packages and processes viral proteins. This is akin to a postal worker labeling a package to be shipped. Viruses require this label to be functional, so if the postal worker fails to label the package (the virus), it will never arrive at its destination. SPCA1’s calcium specifically activates these postal worker proteins, called proteases. Thus, without SPCA1, these proteases will not work.
Hoffmann found that removal of SPCA1 most strongly impairs respiratory and mosquito-borne viruses, both of which are heavily dependent on cellular proteases. The study originally focused only on the human respiratory syncytial virus (RSV), a disease that kills an average of 66,000 children under five each year. However, once Hoffmann realized the far-reaching potential of SPCA1, he expanded his experiments to test viruses like measles, dengue, West Nile, and Zika.
In the future, Hoffmann wants to test this mechanism on Ebola and the avian flu. Both are heavily dependent on furin, a postal worker protease, so it is likely that removal of the calcium transporter will limit these diseases. Although Hoffmann does not have access to these extremely dangerous viruses, he hopes collaborations with other labs will progress this research.
One concern with targeting SPCA1 therapeutically is potential side effects. Does removing SPCA1 prevent the Golgi from packaging normal human proteins as well? Not so, says Hoffmann. “We know you can reduce the protein level and people are still fine,” Hoffmann said. “We can screen small molecules that have the potential to reduce the activity of this pump.”
Hoffmann’s research paves the way for a new antiviral drug targeting SPCA1, one that theoretically would limit a number of common and dangerous diseases. In respiratory and mosquito-borne diseases, effective treatments are scarce, but initial experiments suggest Hoffmann’s potential drug could be both tolerable and effective. Science is continuing its long fight against the mosquito, man’s greatest killer.