Abstract
The initiation of immune responses is thought to occur more slowly in the brain than in other tissues, owed to the blood brain barrier and the challenge of a lack of circulating immune cells to sense pathogens and other forms of danger. Thus, it is of great interest to understand how brain cells sense invading pathogens in order to initiate signals which bring immune cells into the brain. In this thesis work, we have used the parasite Toxoplasma gondii as a model pathogen to better understand these early sensing mechanisms. T. gondii reliably traffics to the brain of its hosts and persists there for the host’s lifetime, kept in constant check by the immune system. Therefore, T. gondii infection is an excellent model for better understand the process of initiating immunity in the brain. We hypothesized that recognition of damage to brain tissue caused by T. gondii plays a significant role in sounding the alarm to recruit immune cells. This was based on histological evidence of brain cell loss in areas where parasite was quickly replicating. We focused on the role of one candidate damage signal, IL-33, which is highly expressed in the brain and spinal cord at baseline. We found that during T. gondii brain infection, IL-33
can signal locally – it is released into the CSF, it induces chemokine within brain tissue, and it can bring immune cells into brain tissue and support their anti-parasitic function. Importantly, we found that IL-33 signals on astrocytes, and not on immune cells, to achieve these effects. Therefore, IL-33 is one local signal by which brain resident cells can sense T. gondii and promote blood-derived cells to enter the brain and control parasite. In addition, our work highlights an important role for astrocytes in promoting immunity, as we found they are chief producers of the chemokine Ccl2 during chronic infection. When we removed this chemokine from astrocytes alone, it resulted in significant impacts on immune cell recruitment and parasite burden. This work opens new doors to better understanding the importance of astrocytes in controlling T. gondii, and other infections that impact the CNS.
