Written by Becky Gullberg, a 2016-2017 Sustainability Leadership Fellow and Ph.D. student in the Department of Microbiology, Immunology, and Pathology
We’ve all experienced those annoying guests that overstay their welcome. They take up your time and eat your food. Now imagine one 10 times worse, who trashes your house and wrecks havoc. You need to get rid of this guest before everything is ruined. You turn off the heat and crank up the air conditioning to encourage them to leave. Luckily the guest leaves, but they stole your coat and tried to get to your neighbor’s house. You just want them to take your old and tattered jacket rather than your nice one. Perhaps this will prevent them from bothering your neighbor.
Unwelcome houseguests can be parasites. They are very successful at ruining your life and difficult to get rid of. The cells in your body are like little homes for your genetic material and viruses are the unwelcome houseguests. In fact, viruses are completely dependent on host cells. Without the cell, the virus cannot make more viruses and will fall apart without passing on its genetic material.
Viruses are also minimalists. When a virus shows up in a cell to replicate itself, it doesn’t bring much with it. Instead it relies on the cell for its building blocks and energy source to make new viruses – just like an unwelcome houseguest raiding the fridge. Additionally, the virus takes its jacket from part of the cellular membrane and uses that to get into a new cell. If we can trick the virus and change these building blocks, perhaps give them a defective jacket so they freeze when they leave the house; we can stop the spread of the virus to your neighbor.
My lab studies dengue virus (see video) and how it interacts with the cell to make the building blocks it requires. This virus is transmitted from one human to another through the bite of a mosquito. Dengue virus causes a painful fever, quite similar to the flu, but often much worse. In some cases the disease can progress to hemorrhaging, (excessive bleeding, as seen in this picture). This often leads to death. Currently, there isn’t a way to treat this disease and so many people, often babies, suffer unnecessarily.
It has been very difficult to find good treatment options for this disease. It can take a drug 10-20 years to go from a research setting to being used in clinical trials. Along with this comes millions of dollars in research funds. Dengue virus evolves quickly and can gain resistance to drugs that directly impact the replication of the virus. This quickly renders the drug useless and requires starting from square one to find another antiviral treatment. A better option is to use drugs that the virus cannot adapt to so quickly. These drugs could be useful in the clinic for many more years and save the time and money of developing something new.
An attractive approach to making more robust antivirals is using host-targeted drugs. These are drugs that act to change the host cell rather than directly inactivating the virus. Meaning, they change the building blocks of the house that the virus is trying to use for its replication and energy needs. These types of drugs are thought to be more effective for a few reasons.
First, they are less likely to make resistant viruses since it is much harder for viruses to mutate and overcome these drugs. It is very difficult for the virus to adapt to new building materials - thus it won’t be able to assemble and spread.
Second, the cellular proteins that are impacted by these drugs are quite stable meaning the cell isn’t likely to mutate in response to the drug. It is likely that these types of drugs can be used in a clinical setting longer and treat many more people.
Third, since these drugs act to change the host, they may be effective against different types of viruses that have common needs. Many viruses use the same building blocks or energy sources and could be treated with the same drug that depletes these resources.
Since host-targeted drugs impact our cells, it is important to consider their safety. We need to be sure that we aren’t changing the cells irreversibly or unnecessarily. Importantly, a viral infection is an acute and relatively short-lived condition. People wouldn’t have to take these drugs for very long, and thus they can avoid some of the potential toxicity. Additionally, many of these drugs have already been developed to treat other diseases. Some are FDA approved and currently being used, but not against viruses.
It is predicted that global range of dengue virus will continue to grow due to climate change and subsequent spread of mosquitoes that harbor the virus. More cases of this infection without good treatment options means continued loss of productivity and unnecessary suffering. It is important that we find new ways to interrupt these viruses with sustainable treatment options. Changing the energy source or building blocks viruses use to replicate and assemble, may be an effective strategy.
Society may continue to struggle with the challenge of in-laws that overstay their welcome, but we are on the cusp of important breakthroughs in making our cells less hospitable to viruses such as dengue viruses.
Figure 1: A virus won't make it very far to bother other cells if it has a tattered jacket like this.
Figure 2: Dengue virus can cause hemorrhagic fever, with no approved antivirals.