Biology subjects

Dubey, J. P.

Publications and source records attributed to Dubey, J. P..

3 recordsLinked to original sources

bioRxiv2019

Intestinal delta-6-desaturase activity determines host range for Toxoplasma sexual reproduction

Many eukaryotic microbes have complex lifecycles that include both sexual and asexual phases with strict species-specificity. While the asexual cycle of the protistan parasite Toxoplasma gondii can occur in any warm-blooded mammal, the sexual cycle is restricted to the feline intestine1. The molecular determinants that identify cats as the definitive host for T. gondii are unknown. Here, we defined the mechanism of species specificity for T. gondii sexual development and break the species barrier to allow the sexual cycle to occur in mice. We determined that T. gondii sexual development occurs when cultured feline intestinal epithelial cells are supplemented with linoleic acid. Felines are the only mammals that lack delta-6-desaturase activity in their intestines, which is required for linoleic acid metabolism, resulting in systemic excess of linoleic acid2, 3. We found that inhibition of murine delta-6-desaturase and supplementation of their diet with linoleic acid allowed T. gondii sexual development in mice. This mechanism of species specificity is the first defined for a parasite sexual cycle. This work highlights how host diet and metabolism shape coevolution with microbes. The key to unlocking the species boundaries for other eukaryotic microbes may also rely on the lipid composition of their environments as we see increasing evidence for the importance of host lipid metabolism during parasitic lifecycles4, 5. Pregnant women are advised against handling cat litter as maternal infection with T. gondii can be transmitted to the fetus with potentially lethal outcomes. Knowing the molecular components that create a conducive environment for T. gondii sexual reproduction will allow for development of therapeutics that prevent shedding of T. gondii parasites. Finally, given the current reliance on companion animals to study T. gondii sexual development, this work will allow the T. gondii field to use of alternative models in future studies.

microbiology↗

bioRxiv2019

Parasite manipulation of the host cell cycle as a means to block inflammatory signaling and promote intracellular replication

Toxoplasma gondii and Hammondia hammondi are closely-related coccidian intracellular parasites that differ in their ability to cause disease in animal and (likely) humans. The role of the host response in these phenotypic differences is not known and to address this we performed a transcriptomic analysis of a monocyte cell line (THP-1) infected with these two parasite species. The pathways altered by infection were shared between species ~95% the time, but the magnitude of the host response to H. hammondi was significantly higher compared to T. gondii. Accompanying this divergent host response was an equally divergent impact on the cell cycle of the host cell. In contrast to T. gondii, H. hammondi infection induces cell cycle arrest via pathways linked to DNA-damage responses and cellular senescence and robust secretion of multiple chemokines that are known to be a part of the senescence associated secretory phenotype (SASP). Remarkably T. gondii-conditioned media can suppress the SASP response during H. hammondi infection, and this suppression is accompanied by a corresponding increase in the replication rate of H. hammondi in recipient cells. Taken together our data suggest that T. gondii manipulation of the host cell cycle provides a novel mechanism to avoid stress and/or DNA-damage induced responses by the host cell, and that this ability has a direct impact on parasite replication rate both within the host cell as well as in bystander cells.

cell biology↗

bioRxiv2017

Hammondia hammondi has a developmental program in vitro that mirrors its stringent two host life cycle

Hammondia hammondi is the nearest relative of Toxoplasma gondii, but unlike T. gondii is obligately heteroxenous. We have compared H. hammondi and T. gondii development in vitro and identified multiple H. hammondi-specific growth states. Despite replicating slower than T. gondii, H. hammondi was resistant to pH-induced tissue cyst formation early after excystation. However, in the absence of stress H. hammondi spontaneously converted to a terminally differentiated tissue cyst stage while T. gondii did not. Cultured H. hammondi could infect new host cells for up to 8 days following excystation, and this period was exploited to generate stably transgenic H. hammondi. Coupled with RNAseq analyses, our data clearly show that H. hammondi zoites grow as stringently regulated life stages that are fundamentally distinct from T. gondii tachyzoites and bradyzoites.

microbiology↗