Survival of the tolerant: the role of metabolism in overcoming malaria

Written by: Padmini Pillai

Original Article: Cumnock et al. Current Biology 2018
The Gist of It:
We all know the symptoms we feel when we have a cold or the flu: not wanting to get out of bed, decreased appetite, and that pesky fever. These symptoms are known as “sickness behavior”. What you may not know is that sickness behavior is caused by your immune system responding to the pathogen, not by the infection itself. In fact, your symptoms are independent of the amount of virus, bacteria, or parasite present, and how quickly they go away depends on how well your body can tolerate infection. We generally treat disease by boosting resistance, our ability to kill invading pathogens, through the use of antibiotics or vaccines. In contrast, we know very little about boosting disease tolerance, the capacity to maintain health and minimize damage during infection. Imagine if we could carry on as normal while fighting an infection! To figure out how to boost disease tolerance, we need to understand how changes in our bodies during infection make us “feel sick.”
One example of an infectious disease that makes us “feel sick” is malaria. Malaria affects hundreds of millions of people each year and is characterized by sickness behaviors including lethargy and loss of appetite. This mosquito-borne disease is typically caused by the parasite Plasmodium falciparum, which enters and reproduces in red blood cells (RBCs), the cells responsible for carrying oxygen throughout the body. After the parasite has reproduced in the RBC, it causes the cell to pop so it can escape and move on to a new one, killing the RBC in its wake.
A research team at Stanford sought to determine how malaria impacts metabolism and disease tolerance. To do this, they measured behavioral and physiological changes in mice with malaria. Just as in human malarial infection, parasites were found in the blood, RBC counts dropped (in other words, the mice become anemic), and mice exhibited sickness behavior, including decreased appetite (or anorexia). During anorexia, your body produces energy by burning fat stores through a process that requires oxygen. But malaria causes anemia by killing RBCs, limiting the number of cells to carry the oxygen needed to burn the fat. Therefore, the researchers hypothesized that a shift to a form of energy production that doesn’t require oxygen would lend an advantage to handling the infection. Glycolysis, which turns sugar (glucose) into energy, doesn’t require oxygen and even triggers the production of RBCs.
The researchers tested this hypothesis by giving mice with malaria either 2-deoxyglucose (2-DG), which blocks glycolysis, or glucose, which sparks glycolysis. Infected mice that were given 2-DG had high parasite levels, severe anemia, and weight loss, leading to death. In contrast, glucose-treated mice had much better survival, but did not have lower parasite levels. In other words, glucose promoted disease tolerance without affecting resistance to the pathogen. This work further supports the established idea that nutrition and metabolism can affect the outcome of disease.
Disclaimer: Depending on the type of infection, consuming food can have beneficial or detrimental effects on fighting an infection. Although glucose induces tolerance in this scenario, fasting has been shown to boost tolerance during other infections.

In this mouse model of malaria, glucose boosts tolerance and survival after malaria infection!

The Nitty Gritty:
Mice were infected with P. chabaudi, and the parasite density and mouse body temperature, food and water intake, activity, respiratory quotient (RQ), energy expenditure, and RBC count were monitored over time. Compared to controls, infected mice exhibited hypothermia, weight loss, anorexia, and RBC loss.  Significant decreases in activity correlated with ketosis and fat burn, based on RQvalues. Infection-induced anemia led to a 90% reduction in oxygen availability. Infected mice treated with 5 mg of 2-DG exhibited decreased body temperature, weight, and RBC counts between days 11-14 and typically succumbed to disease by day 15. Conversely, infected mice treated with 20 mg of glucose had body temperatures closer to normal and improved survival. Overall, no difference in parasite density was observed between the different treatment groups.
Original Research Article:  Cumnock, Katherine, et al. “Host energy source is important for disease tolerance to malaria.” Current Biology 28.10 (2018): 1635-1642.


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