Toxoplasma Co-opts Host Cells It Does Not Invade

Anita A Koshy,Christopher A Hunter,Hans K Dietrich,Anjali J Shastri,Jason H Melehani,David A Christian,John C Boothroyd,George S Yap

doi:10.1371/journal.ppat.1002825

Anita A Koshy, Christopher A Hunter + Show 6 more

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https://doi.org/10.1371/journal.ppat.1002825

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Journal: PLoS Pathogens	Publication Date: Jul 26, 2012
Citations: 183	License type: CC BY 4.0

Affiliation: Stanford University, University of Pennsylvania

Abstract

Like many intracellular microbes, the protozoan parasite Toxoplasma gondii injects effector proteins into cells it invades. One group of these effector proteins is injected from specialized organelles called the rhoptries, which have previously been described to discharge their contents only during successful invasion of a host cell. In this report, using several reporter systems, we show that in vitro the parasite injects rhoptry proteins into cells it does not productively invade and that the rhoptry effector proteins can manipulate the uninfected cell in a similar manner to infected cells. In addition, as one of the reporter systems uses a rhoptry:Cre recombinase fusion protein, we show that in Cre-reporter mice infected with an encysting Toxoplasma-Cre strain, uninfected-injected cells, which could be derived from aborted invasion or cell-intrinsic killing after invasion, are actually more common than infected-injected cells, especially in the mouse brain, where Toxoplasma encysts and persists. This phenomenon has important implications for how Toxoplasma globally affects its host and opens a new avenue for how other intracellular microbes may similarly manipulate the host environment at large.

Highlights

Obligate intracellular organisms, from viruses to eukaryotic pathogens, modify the microenvironment of the infected host cell to avoid clearance by host-cell-intrinsic mechanisms as well as to block the immune system from recognizing the host cell as infected
A priori, these uninfected green cells observed during Toxoplasma-Cre infections could arise by several possible mechanisms: (a) the reporter cells exhibit a background leakiness, (b) the reporter cells take up either plasmid DNA or the Cre fusion protein from the extracellular environment; (c) after invasion, the host cells clear the parasites by cell-intrinsic mechanisms, (d) a host cell undergoes cell division after invasion and only one daughter acquires the parasitophorous vacuole (PV), and/or (e) invasion is initiated, including injection of the rhoptry proteins, but the process is aborted
The results presented here show that Toxoplasma gondii tachyzoites can inject effector proteins into cells that they do not

Summary

Introduction

From viruses to eukaryotic pathogens, modify the microenvironment of the infected host cell to avoid clearance by host-cell-intrinsic mechanisms (e.g., autophagy, phago-lysosomal fusion) as well as to block the immune system from recognizing the host cell as infected. The presumption has been that invasion or uptake is required in order to initiate injection or secretion of these effector proteins but two recent reports on Toxoplasma gondii, an obligate intracellular parasite related to Plasmodium, have challenged this notion [6,7]. All the details are not yet known, recent studies have shown that a significant portion of this manipulation is initiated less than one minute into the invasion process [11], during which time Toxoplasma injects effector proteins into the host cell. Many of these effector proteins originate from specialized, apically-localized organelles called rhoptries [12]. Recent reports have provided evidence that some injected rhoptry proteins affect host transcription factors and block cell-intrinsic defense mechanisms [3,13]

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