Saturday, December 21, 2024
12/21/2024
Toxoplasma gondii is a widespread protozoan parasite that can cause life-threatening disease in immunocompromised individuals and the developing fetus. While drugs are available to treat acute toxoplasmosis, they are frequently discontinued due to severe adverse effects. The development of new, better- tolerated drugs requires an improved understanding of the biology of T. gondii and the mechanisms underlying its virulence so that critical points of vulnerability in its life cycle can be identified and targeted. T. gondii belongs to a group of related human pathogens, the Apicomplexa, which also includes the causative agents of malaria (Plasmodium) and cryptosporidiosis (Cryptosporidium). Apicomplexan parasites must invade into cells of their hosts in order to survive and multiply. During the early stages of invasion, proteins are exocytosed from apical organelles known as the rhoptries. After their release, these proteins are delivered into the host cell cytosol where they participate in parasite internalization, inactivate host innate immune defenses, and manipulate host gene expression to the parasite’s advantage. Because the injected effector proteins play such critical roles in parasite invasion and intracellular survival, they are among the most important of the parasite’s virulence factors. While we know a great deal about the functions of these effector proteins, we know virtually nothing about the process by which they are delivered into the host cell. The goal of this project is to fill in this important gap in our understanding of host cell invasion by apicomplexan parasites. We have previously shown that when T. gondii first contacts a host cell, it causes a transient (~200msec) disruption in the barrier integrity of the host cell plasma membrane. The central hypothesis of this project is that this transient perforation of the host cell membrane, which we can detect using high-speed multiwavelength fluorescence microscopy, serves as the conduit through which rhoptry proteins are injected into the host cell. The major Aims of the project are to: (1) Determine the physical nature and proximate cause of host cell perforation during invasion and (2) Determine how the perforating agent is delivered to the host cell membrane and the function of the breach it creates. How rhoptry proteins are injected into the host cell during invasion is a fascinating cell biological problem, and current evidence suggests that the underlying mechanisms are novel. A greater understanding of these mechanisms may lead to new approaches to treating or preventing toxoplasmosis, since targeting the injection process will simultaneously disrupt the delivery into the host cell of many of the parasite’s most critical virulence factors. In addition, because rhoptry protein injection into the host cell occurs in all apicomplexans examined, the results of this project are likely to be directly applicable to related human pathogens such as Plasmodium and Cryptosporidium.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).