Role of Serotonin in SIV-associated Enteropathogenesis

Irina Grishina
University of California, Davis
Basic Biomedical Sciences

The gastrointestinal tract is home to a majority of the body’s immune cells and also houses the enteric nervous system (ENS), the only branch of our nervous system that operates independently from the central nervous system (CNS). Both the CNS and ENS send signals via small molecules called neurotransmitters than are exchanged between two nerve cells. Interestingly, neurotransmitters can also be exchanged between nerve cells and those not related to the nervous system. Such interactions can occur between the immune and nervous system, potentially changing the way the immune system responds to infections. These changes are mediated by proteins called neurotransmitter receptors present on the surface of immune cells. Human/Simian Immunodeficiency Virus (HIV/SIV) is a virus that rapidly infects and eliminates specific immune cells called CD4+ T-cells. The loss of these cells can cause extreme dysfunction in the immune system, but currently it is not known how CD4+ T-cell depletion results in gut complications that are routinely seen in HIV-infected individuals. One common gut complication is diarrhea, a dysfunction that is associated with increased intestinal motility. It has already been shown that diarrhea can be a result of altered neurotransmitter activity, specifically serotonin. This neurotransmitter can stimulate and increase the rate of solids passing through the gut but can also affect immune system activity. Unfortunately, the role of serotonin has not been extensively studied in context of HIV/SIV infection of the gut. In this study we test the idea that SIV infection increases serotonin levels and alters the presence of serotonin receptors in the gastrointestinal tract. This altered environment could possibly contribute to a long-lasting intestinal condition called SIV-induced chronic immune activation, of which diarrhea is a common symptom. To perform this study, we will characterize changes in serotonin’s availability and the abundance of its receptor in intestinal tissue infected with SIV. Next, we will determine if the serotonin receptor profiles are related to altered gut functions that are thought to be linked to the presence of serotonin; including chronic immune activation. Finally, we will explore the direct effects inflammatory molecules and SIV have on serotonin regulators and receptors using cells from the immune system. By using both the non-human primate SIV model and laboratory cell cultures it will be possible to explore when and how changes in serotonin availability and signaling occur in the gut during SIV infection. This study also presents to opportunity to better describe the intimate relationship between the immune and nervous systems in the gut. A better understanding of the serotonin-related system in the gastrointestinal tract during infection is crucial and could lead to the development of therapeutic interventions that would greatly improve management and treatment of disease in HIV-positive patients.