Placental resistance and response to the teratogenic pathogen Toxoplasma gondii

PROJECT SUMMARY/ABSTRACT:
Toxoplasma gondii can have devastating consequences in the developing fetus if it is acquired during
pregnancy. A significant number of congenital T. gondii infections occur yearly (~4000 in the U.S. and over
200,000 worldwide), making T. gondii among the most important teratogenic pathogens. To date it is not possible
to predict whether infection of a T. gondii-naïve pregnant woman will ultimately transmit to the fetus. Congenital
toxoplasmosis occurs only after T. gondii breaches the placental barrier, yet very little is known about the cellular
and molecular events that occur during this host-pathogen interaction, nor how these events affect infection
outcome. In this proposal we outline a series of complementary experiments aimed at understanding what
happens when Toxoplasma gondii encounters cells of the placenta and how this might impact infection
outcome in the developing fetus. A major focus of our work is on placental trophoblasts which form the primary
interface between the developing fetus and maternal blood. Our extensive preliminary and published data firmly
establish that placental syncytiotrophoblasts (SYNs) but not cytotrophoblasts (CYTs) resist Toxoplasma
infection, and that Toxoplasma infection of trophoblasts induces a transcriptional response that is unique
compared to most cell types studied to date. In Aim 1 we exploit multiple genetically tractable models of SYN
function and development to identify SYN resistance mechanisms and validate them at the molecular level.
Significance of this aim derives from the fact that SYNs are unique in being the only cell type studied to date
that is intrinsically resistant to T. gondii infection. In Aim 2 we address the importance of innate immune signaling
at the maternofetal interface during congenital transmission. In Subaim 2.2. we will do this by quantifying
multiple immunomodulatory cytokines in a unique set of human serum samples that longitudinally cover
gestational seroconversion events during pregnancy, and then use multivariate analyses to link immune
signaling profiles to different infection outcomes. In Subaim 2.2. we will genetically ablate multiple host-targeting
effectors in T. gondii (including one that alters the immunoregulatory landscape specifically in placental cells),
and link congenital transmission dynamics to the immunomodulatory landscape in a well-established mouse
model of congenital transmission. Impact of the proposed studies derives from (1) the use of primary placental
tissues and tractable cell line models of CYTs and SYNs to decode critical molecular mechanisms of resistance
and susceptibility, (2) the use of serum samples before, during and after T. gondii infection to robustly quantify
changes in the host response during congenital exposure events and (3) the synergistic and well-established
collaboration of the co-PI team (Coyne and Boyle) which leverages their expertise in the molecular biology of
Toxoplasma host-pathogen interactions (Boyle) and the cellular and molecular basis of placental development
and pathogen resistance (Coyne).

Grant Number: 5R01HD106247-05
NIH Institute/Center: NIH
Principal Investigator: Jon Boyle