To kill or to transmit: changing a host’s behaviour benefits pathogen survival

If you think back to the last time you were quite sick, you will likely remember how miserable you felt. All you probably wanted to do was lie in bed and sleep, while avoiding anything that required any effort—even eating and socializing was most likely hard.

And while these shifted behaviour patterns do not make you feel much better in the short term, they are actually evolutionarily advantageous. These so called ‘sickness behaviours’ increase your chances of surviving the illness while limiting the spread of the pathogen that has infected you. Not eating, technically termed ‘sickness-induced anorexia’, likely limits the amount of nutrients available for the pathogen inside you. Social withdrawal prevents the pathogen from spreading to people around you. However, there is a tug-of-war happening between you and the bug that has infected you. While you change your behaviour and your immune system tries to eliminate the pathogen inside you, the pathogen itself responds by hiding, resisting and fighting back against the host. The fight, however, has a delicate balance—if a pathogen is too virulent it may damage the host too much and make it no longer able to provide a home for the pathogen, decreasing the likelihood of the pathogen to spread. On the other hand, if the pathogen is too tame the host may quickly kill it. The perfect balance between virulence and spread, therefore, has to be maintained and, as a new research shows, sometimes a pathogen can achieve this balance by directly modulating the behaviour of its host.

Salmonella Typhimurium is a bacterium which typically infects the intestinal lining of various animals, including humans. In an effort to identify microbial factors that decrease pathogen virulence, a group led by Janelle S. Ayres from the Salk Institute have noted that a Salmonella protein called SlrP decreases the virulence of the bacterium in mice. Namely, mice infected with Salmonella strains lacking SlrP (dSlrP) succumbed to infection and died much faster than the mice infected with a wild-type Salmonella strain. As it turns out, the lack of SlrP during infection caused a change in the metabolism of the mice. dSlrP infection led to the use of fat as the primary energy resource in mice and consequently, a significant decrease in their body mass. Both the wild-type and the dSlrP Salmonella infections caused weight loss in mice, however, the weight loss in the dSlrP-infected mice was so quick and severe that it led to premature mouse death. Interestingly, dSlrP-infected mice, which were given additional food to compensate for the weight loss, survived more often than the mice without the additional food, suggesting that the reduced nutrient intake in the infected mice might be the main cause of death. The pertinent question after this initial study was the precise way in which the SlrP protein changed the eating habits of mice.

Since the brain controls all animal behaviour, scientists involved in this research hypothesized that there must exist a link between the SlrP protein in the mouse intestines and the behaviour control centres in the brain. By analyzing changes in the expression of various inflection-related factors in the Salmonella infected mice, they found that the production of an immune-system-modulating molecule called IL-1β was significantly increased in mice infected with the dSlrP strain. Interestingly, previous research had found that IL-1β is not only involved in regulating the immune system, but is also important for communication between the gut and the brain. IL-1β is capable of inducing signalling via the vagus nerve leading to excitations in the part of the brain responsible for regulating eating behaviour, called the hypothalamus. Indeed, mice infected with dSlrP had increased expression of food-intake-related factors in the hypothalamus. By contrast, if the connection between gut and brain via the vagus nerve was disrupted, the expression of these factors in the hypothalamus decreased and the mice did not exhibit such severe infection-induced anorexia, even though the levels of IL-1β remained high.

So why would a bacterium encode a factor, SlrP, which reduces its virulence? It might be obvious that a pathogen should avoid starving its host to a point at which nutrients become limited for the pathogen itself. However, during the course of this study scientists also noted that the dSlrP strain is able to disseminate and infect other organs than the intestine better than the wild-type Salmonella strain can. Therefore, would it not be more beneficial for the bacterium in this case to be more virulent, so that within its host it could reach the resources available outside the intestinal tract? Well, evolution is often a trade-off. A successful replication in one host does not predict a successful transmission to another one. Indeed, the lack of SlrP in bacteria during infection negatively affected the transmission of the bacteria to the secondary hosts. Uninfected mice, co-housed with dSlrP-infected mice, were 65% less likely to become infected with Salmonella. It therefore appears that SlrP in Salmonella acts as the keeper of balance between virulence and transmission. While the dissemination within a host may provide some benefits, if it limits the ability to spread to another host it also limits the long-term survival of the pathogen. By limiting the sickness-induced anorexia in its host, Salmonella allows the host to better tolerate an infection, which in turn increases its chances of transmission, and ultimately prolongs its survival.

Source:

Rao, Sheila, et al. “Pathogen-Mediated Inhibition of Anorexia Promotes Host Survival and Transmission.” Cell 168.3 (2017): 503-516

(featured image courtesy of nasamarshall on Flickr)