A Family of Toxoplasma gondii Genes Related to GRA12 Regulate Cyst Burdens and Cyst Reactivation

Abstract

If host immunity weakens, Toxoplasma gondii cysts recrudesce in the central nervous system and cause a severe toxoplasmic encephalitis. Current therapies target acute stage infection but do not eliminate chronic cysts.

Dense granule biogenesis, secretion, and function in Toxoplasma gondii

“…Parasite proteins that alter the host immune response can be broadly categorized into two groups: Those found at the PVM that limit PV destruction by both host immunity‐related GTPases (IRGs) and guanylate‐binding proteins (GBPs; Guevara, et al, 2021); and those that are secreted into the host nucleus and cytosol to influence immune signaling and transcriptional pathways (Hakimi et al, 2017; Tomita et al, 2021).…”

“…During the tachyzoite‐to‐bradyzoite transition, many IVN‐associated GRA proteins including GRA1, GRA2, GRA4, GRA6, GRA9, and GRA12 relocalize from the IVN to the cyst wall early in differentiation (Guevara et al, 2019; Tu et al, 2020). GRA2 expression is necessary for GRA4 and GRA6 localization to the cyst periphery (Guevara et al, 2019) and deletions of all but GRA1 resulted in slower cyst maturation (Guevara et al, 2019, 2021). The localization of SFP1 and GRA29 also exhibit distinct localizations in tachyzoites compared to bradyzoites.…”

Functional Characterization of 15 Novel Dense Granule Proteins in Toxoplasma gondii Using the CRISPR-Cas9 System

“…To further characterize the location of GRAs in the in vitro -induced cyst, tachyzoites were allowed to differentiate into bradyzoites by shifting the pH of medium to 8.2 for 2 days. Cysts were detected by DBA staining, which specially recognizes N-acetylgalactosamine on the bradyzoite-specific cyst wall ( 42 , 43 ), and targeted GRA proteins were detected by anti-HA antibody. By 48 h postdifferentiation ( 44 , 45 ), 15 GRAs were localized to the cyst wall or matrix, which were colocalized or partly colocalized with DBA ( Fig.…”

Importance of aspartyl protease 5 in the establishment of the intracellular niche during acute and chronic infection of Toxoplasma gondii

“…In the tachyzoite stage, many GRAs are restricted to the PV and participate in the elaboration of an intravacuolar network (IVN) embedding parasites and shaping the vacuole (Mercier & Cesbron‐Delauw, 2015). In addition, several GRAs localize to the PVM, at the interface with the host cell cytosol, where they modulate host cell signaling pathways (GRA6 [Ma et al, 2014]; GRA7 [Alaganan et al, 2014]; GRA12 [Guevara et al, 2021]; GRA15 [Jensen et al, 2011; Rosowski et al, 2011]; GRA60 [Nyonda et al, 2021]) or mediate the recruitment of host organelles to the vicinity of the PVM notably via MAF1 (Pernas et al, 2014). Finally, a category of GRAs containing intrinsically disordered domains are exported beyond the PVM and reside in the host cytosol such as GRA18 (He et al, 2018) or are imported into the host cell nucleus i.e., GRA16 (Bougdour et al, 2013), GRA24 (Braun et al, 2013), GRA28 (Nadipuram et al, 2016), IST (Gay et al, 2016; Olias et al, 2016), and TEEGR (Braun et al, 2019; Panas, Naor, et al, 2019) to remodel the host transcriptome in favor of parasite long‐term persistence.…”