Toxoplasma Hypervirulence in the Rat Model Parallels Human Infection and Is Modulated by the Toxo1 Locus

Abstract

Toxoplasmosis is considered as an opportunistic parasitic disease. If post-natally acquired in children or adults, it may pass unnoticed, at least with strains of European origin. However, in the wild biotopes especially in South America, Toxoplasma gondii strains display a greater genetic diversity, which correlates to higher virulence for humans, particularly along the Amazon River and its tributaries. In French Guiana, several atypical strains have been associated with severe clinical forms: ocular toxoplasmosis and acute respiratory distress syndrome both of which can result in death. Among these, the GUY008-ABE strain was responsible for an epidemic of severe disseminated toxoplasmosis in Suriname, which led to the death of one immunocompetent individual. To better understand the mechanism underlying the hypervirulence of the GUY008-ABE strain, we have tested the rat model which compared to the mouse, better reflects the immune resistance of humans to Toxoplasma infection. Here we compare the outcome of toxoplasmosis in F344 rats infected either by the GUY008-ABE strain or the type II Prugniaud strain. We show that the GUY008-ABE strain displays a higher virulence phenotype leading to the death of all infected rats observed in this study. GUY008-ABE infection was characterized by an increase of the parasite load in several organs, especially the heart and lung, and was mainly associated with severe histological changes in lungs. Moreover, correlating with its hypervirulence trait, the GUY008-ABE strain was able to form cysts in the LEW rat model otherwise known to be refractory to infection by other Toxoplasma strains. Together, these results show that the rat is a discriminating experimental model to study Toxoplasma virulence factors relevant to the pathogenesis of human infection and that the degree of virulence is linked to the Toxo1 locus.

Unifying Virulence Evaluation in Toxoplasma gondii: A Timely Task

“…Real-time PCR was used to monitor the distribution of T. gondii in different murine tissues during the infection with 10 2 or 10 6 tachyzoites (IP) of the RH strain, or 10 cysts (PO) of the ME49 strain ( Djurković-Djaković et al., 2012 ); this study concluded that the level of parasite burden in the lungs seemed to be critical for mice survival/parasite virulence. This result agrees perfectly with what was observed previously ( Loeuillet et al., 2019 ), where pneumomegaly, and the greater parasitic load and tissue destruction in the lungs were strongly associated with the hypervirulence of the non-canonical GUY008-ABE isolate (haplogroup 5, ToxoDB # unknown). On the other hand, some studies pointed out ocular tropism as a virulence related trait, with a more frequent parasite DNA detection in ocular tissues from mice infected with more virulent strains ( Hamilton et al., 2019 ; Chiebao et al., 2021 ; Fernández-Escobar et al., 2021 ).…”

“…Complementarily, parasite proliferation was evaluated in vitro in primary rat peritoneal macrophages. Final findings in this model demonstrated the hypervirulent phenotype of the South American (French Guiana) GUY008-ABE strain in contrast to the avirulent profile of PRU laboratory strain ( Loeuillet et al., 2019 ). Recently, guinea pigs were also proposed as a suitable model for human congenital toxoplasmosis in experimental infections of pregnant guinea pigs being administered 10, 100 or 500 oocysts of T. gondii strain ME49 at different time points during gestation ( Grochow et al., 2021 ).…”

“…In contrast to laboratory mice, which are highly susceptible to toxoplasmosis ( Zenner et al., 1998 ), rats have been repeatedly demonstrated to be resistant to acute infection, remaining asymptomatic or even resistant to chronic infection by preventing tissue cysts formation in the case of some rat breeds ( Sergent et al., 2005 ; Cavaillès et al., 2006 ). Therefore, it is considered that the laboratory rat infection model represents a better system for studying the immune resistance of humans to T. gondii infection than the mouse model ( Loeuillet et al., 2019 ). In an experiment carried out in the USA, chronic toxoplasmosis was induced in Sprague Dawley female rats after oral inoculation with oocysts of 11 T. gondii strains of seven different genotypes.…”

“…In vitro models are considered also suitable first approaches to phenotypically characterize apicomplexan parasite strains ( Regidor-Cerrillo et al., 2011 ; Dellarupe et al., 2014 ; Frey et al., 2016 ; Jiménez-Pelayo et al., 2017 ; García-Sánchez et al., 2019 ). However, only a small proportion of the publications addresses the virulence characterization of non-laboratory T. gondii isolates in vitro ( Loeuillet et al., 2019 ; Sánchez-Sánchez et al., 2019 ; Bernstein et al., 2020 ; Uzelac et al., 2020 ; Fernández-Escobar et al., 2021 ; Salman et al., 2021 ).…”

Influence of the Host and Parasite Strain on the Immune Response During Toxoplasma Infection

“…This locus contains a nucleotide-binding oligomerization domain, leucine-rich repeat protein 1 ( NLRP1 ), which encodes for the NLRP1 inflammasome sensor that causes rapid cell death and disruption of the replicative niche of the parasite upon activation (Cirelli et al, 2014 ). One exception is the South American strain GUY008-ABE, which can establish a chronic infection in Lewis rats and is fatal to F334 rats (Loeuillet et al, 2019 ). Thus, although it is in the parasite's best interest to cause a lifelong chronic infection, it is clear that not every parasite strain can produce an optimal infection in every animal.…”