Researchers at Indiana University School of Medicine have discovered how a dangerous parasite maintains a steady supply of nutrients while replicating inside of its host cell: it calls for delivery.
Toxoplasma gondii is a single-celled parasite capable of infecting any animal, including humans.
Up to one-third of infections in people happen through contact with cat waste or contaminated food or water.
Although the parasite only causes acute disease in immune compromised persons, the infection is permanent and has been associated with neurological diseases such as schizophrenia and rage disorder.
The parasite can invade virtually all types of cells in the body. Once inside, it begins to divide exponentially, a process that requires a great deal of resources.
The parasite extracts most of the nutrients it needs for replication from its host cell, including essential amino acids like arginine.
Because arginine is quickly depleted from the host cell, researchers wanted to learn where the parasite gets more of the amino acid to fuel its expansion into the hundreds.
In a collaborative study funded by the National Institutes of Health, microbiology and immunology professor Bill Sullivan, Ph.D. and biochemistry and molecular biology professor Ronald Wek, Ph.D. identified a cellular starvation stress response that occurs within two hours after Toxoplasma infection.
The study was led by Leo Augusto, a postdoctoral fellow in the Sullivan and Wek laboratories, who used a variety of mutant host cells to discern that a protein called GCN2 becomes activated as parasites consume the host cell’s arginine supply.
Augusto mapped out the cascade of events following GCN2 activation, leading him to discover that host cells infected with Toxoplasma express more of an arginine transporter called CAT1 at their cell surface. CAT1 brings more arginine into the infected cell so Toxoplasma can continue to binge.
These findings suggest infected host cells can sense their nutrients being depleted.
Oblivious to the parasites growing inside them, the host cells unwittingly gear up to bring in more arginine to compensate for the loss.
The identification of proteins like GCN2 that are important for parasite growth and replication may serve as promising new drug targets to treat intracellular pathogens.
“Pathogens that live and grow inside of cells face special challenges,” Sullivan said. “Intracellular pathogens have to replicate without raising alarms, but in order to grow they need to pilfer nutrients from the host.
Our study shows that Toxoplasma gets additional nutrients simply by hijacking a starvation response already built into the host cell.”
Whether the parasite does this on purpose or if it is a happy accident is still a lingering question. Augusto’s work appears to suggest the latter, as parasites deficient in arginine uptake did not elicit a strong starvation response in host cells.
The study was recently published in the journal PLOS Pathogens.
The protozoan parasite Toxoplasma gondii can infect nearly all warm-blooded animals, including humans (Robert-Gangneux and Darde, 2012; Liu et al., 2015). Approximately 30% of the world’s population is estimated to be infected with T. gondii (Montoya and Liesenfeld, 2004).
Humans become primarily infected by ingesting raw or undercooked meat containing viable tissue cysts, or by ingesting water or food contaminated with oocysts from infected cat feces (Baldursson and Karanis, 2011; Meireles et al., 2015).
In healthy humans, the infection with T. gondii is usually asymptomatic, but it can be fatal in the immunocompromised individuals, such as HIV/AIDS patients, cancer patients, and organ transplant recipients (Da Cunha et al., 1994; Pott and Castelo, 2013; Agrawal et al., 2014; Lu et al., 2015).
Toxoplasmosis of immunosuppressed individuals is most often the result of reactivation of latent infection, which presents neurological signs, including headache, disorientation, drowsiness, hemiparesis, reflex changes, and convulsions (Barratt et al., 2010; Robert-Gangneux and Darde, 2012).
Acute acquired T. gondii infection in immunocompromised patients may also occur and involve multiple organs. Pneumonia, retinochoroiditis, and other disseminated systemic diseases, can also be seen, but are not as common as encephalitis in immunocompromised patients (Machala et al., 2015).
An increased frequency of Toxoplasma encephalitis has been reported in AIDS patients, especially those with significant immunosuppression when CD4 T lymphocyte cell counts is <200 cells/μL, and T. gondii infection is regarded as an important opportunistic pathogen that lead to the death of AIDS patients (Luft et al., 1993; Jones et al., 1996).
The cancer can also reactivate latent T. gondii infection during antitumor treatment process (Frenkel et al., 1978).
Transplantation of an organ from seropositive donor can activate latent infection in a seronegative recipient receiving immunotherapy (Chehrazi-Raffle et al., 2015).
Transplantation of an organ from seronegative donor can also initiate fatal infection by activation of the latent infection in a seropositive recipient receiving immunosuppressive therapy.
It seems that danger of transplanting an infected organ into a seronegative recipient is greater than that of transplanting a non-infected organ into a seropositive recipient (Chehrazi-Raffle et al., 2015).
Fatal toxoplasmosis has been reported in heart, liver and bone marrow, haematopoietic stem cell transplant recipients (Castagnini et al., 2007; Caner et al., 2008; Stajner et al., 2013; Gajurel et al., 2015).
Toxoplasmosis can be complicated and is considered a serious disease in immunocompromised patients, in which the reactivation of a latent infection can be fatal.
The incidence of reactivated toxoplasmosis may rely on the prevalence and concentration of IgG antibodies (Robert-Gangneux and Darde, 2012).
It is necessary to obtain information concerning the prevalence of T. gondii infection in different special populations worldwide.
We conducted a global meta-analysis to assess the seroprevalence and odds ratios (ORs) of T. gondii infection in immunocompromised patients compared with those in control individuals.
More information: Leonardo Augusto et al, Regulation of arginine transport by GCN2 eIF2 kinase is important for replication of the intracellular parasite Toxoplasma gondii, PLOS Pathogens (2019). DOI: 10.1371/journal.ppat.1007746
Journal information: PLoS Pathogens
Provided by Indiana University