How The Immune System Detects One of the World's Most Common Parasites

In reference to a new publication in Nature Immunology authored by researchers at the University of Rochester Medical Center and the University of Pennsylvania.

Toxoplasma gondii (TG) isn’t as well-known as its cousin malaria, but this protozoan parasite is estimated to infect up one billion people worldwide (Xiao et al. 2015). In immunocompromised and pregnant individuals TG may cause symptomatic toxoplasmosis, a condition which can be fatal to these more susceptible populations. The good news is that, unlike malaria, the human body’s immune system is very adept at detecting TG and establishing long term immunity against any sort of symptoms it may cause. Healthy adults very rarely experience any noticeable symptoms from the infection. However, for such a prevalent infection little is known about how the immune system responds to TG and creates such long-lasting tolerance.

In a recent publication, Safronova et al. describe a possible mechanism by which human immune cells detect and respond to a TG infection. The tricky part of this study is that humans and mice (the default test subjects for TG research in the past) (Saraf et al. 2017) respond to TG very differently. Mice immune cells are known to secrete IL-12, a chemical messenger which promotes an inflammatory response, when exposed to TG. In humans, though, there is no such inflammation or IL-12 production. Instead, the main messenger molecule produced in response to TG is a chemokine called CCL2. Chemokines are small molecules that direct cells of the immune system to move in a particular direction. So rather than trigger an inflammatory response similar to the mouse response, humans first recruit other cells of the immune system to the site of the TG infection.

The researchers also found that human immune cells don’t make CCL2 in response to profilin, the TG infection-associated protein that mice immune cells recognize. In fact, the actual presence of TG within the cells isn’t what directly triggers the CCL2 production either. To find the mystery molecule, the authors decided to separate an infected cell’s proteins by anion exchange chromatography, a technique that allows for proteins to be extracted and grouped together based on similar electrical charges. By adding each fraction individually to live cells, they found a fraction containing the protein S100A11 to stimulate CCL2 production.

So then the question remained: if S100A11 wasn’t responding to profilin, how does it recognize a TG infection? As it turns out, cellular damage from the TG parasite breaking into the cell is necessary for S100A11 release. The broken elements of the cell trigger the activity of caspase-1, an enzyme that normally functions in programmed cell death. When a cell is diseased, caspase-1 helps form a protein complex called the inflammasome which digests materials of the cell into smaller elements which can be “recycled” and reused by surrounding cells. This is a highly inflammatory process, characterized by activation of molecules similar to the IL-12 that mice produce during TG infection. One of these molecules appears to be S100A11, which serves as an alarm signal that TG is causing cell damage and immune cells (specifically monocytes) must be recruited to the area via CCL2 release. The monocytes then attack the TG parasites and prevent disease symptoms from developing.

This research, while a valuable insight into a poorly understood mechanism of a highly common infection, leaves many questions unanswered. For instance, the S100A11 “alarm” signal functions in recruiting monocytes to the infected area. However, monocytes are a part of the innate immune system which generally serves as the first line of defense during infection. Over a longer period of time, the adaptive immune system (composed of different types of immune cells like B and T cells) kicks in and establishes immune memory to prevent the same type of pathogen from infecting the body again. TG infections are long term and can often last for the duration of a patient’s lifetime. This sort of chronic response would likely involve adaptive immune cells, and yet that scenario is not commented upon in this paper. There is also no mention of how S100A11 is specifically triggered by TG infection. If S100A11 is only responding to the cellular damage and not the presence of the parasite itself, then you would think that it would be well-characterized in plenty of cell damage or cell death pathways. The actual damaged material that triggers S100A11 is never specified, and so we don’t know what makes TG-related damage unique in comparison to other pathogens that break open cells. While the authors don’t address these questions, their work is undoubtedly useful in understanding how parasites like TG and malaria can be detected and fought off by our immune system.

References

Saraf, P., Shwab, E. K., Dubey, J. P., & Su, C. (2017). On the determination of Toxoplasma gondii virulence in mice. Experimental parasitology, 174, 25-30.

Xiao, J., & Yolken, R. H. (2015). Strain hypothesis of Toxoplasma gondii infection on the outcome of human diseases. Acta Physiologica, 213(4), 828-845.