Abstract
Toxoplasmosis is a prevalent parasitic disease caused by Toxoplasma gondii (T. gondii). Under the control of the host immune system, T. gondii persists as latent bradyzoite cysts. Immunosuppression leads to their reactivation, a potentially life-threatening condition. Interferon-gamma (IFN-γ) controls the different stages of toxoplasmosis. Here, we addressed the role of the parasite surface antigen P18, belonging to the Surface-Antigen 1 (SAG-1) Related Sequence (SRS) family, in a cyst-forming strain. Deletion of P18 gene (KO P18) impaired the invasion of parasites in macrophages and IFN-γ-mediated activation of macrophages further reduced the invasion capacity of this KO, as compared to WT strain. Mice infected by KO P18, showed a marked decrease in virulence during acute toxoplasmosis. This was consequent to less parasitemia, accompanied by a substantial recruitment of dendritic cells, macrophages and natural killer cells (NK). Furthermore, KO P18 resulted in a higher number of bradyzoite cysts, and a stronger inflammatory response. A prolonged survival of mice was observed upon immunosuppression of KO P18 infected BALB/c mice or upon oral infection of Severe Combined Immunodeficiency (SCID) mice, with intact macrophages and natural killer (NK) cells. In stark contrast, oral infection of NSG (NOD/Shi-scid/IL-2Rγnull) mice, defective in macrophages and NK cells, with KO P18, was as lethal as that of the control strain showing that the conversion from bradyzoites to tachyzoites is intact and, suggesting a role of P18 in the response to host IFN-γ. Collectively, these data demonstrate a role for P18 surface antigen in the invasion of macrophages and in the virulence of the parasite, during acute and chronic toxoplasmosis.
Highlights
Toxoplasma gondii is an obligate intracellular parasite that infects all warm-blooded animals
The successful genetic modification was verified by PCR (Figure 1B) and the P18 expression level was assessed in tachyzoites and upon in vitro switch from tachyzoites to bradyzoites, by immunoblot using specific anti-P18 antibodies [38]
Trace levels of P18 were detected in tachyzoites of this strain as they required a higher exposure of the nitrocellulose membrane with Luminol (Figure 1C)
Summary
Toxoplasma gondii is an obligate intracellular parasite that infects all warm-blooded animals. Tachyzoites use innate immune cells, namely monocytes, macrophages and dendritic cells, to spread into various organs, and subsequently form bradyzoite cysts in the brain and in skeletal muscles [5] These slow-growing bradyzoites are responsible for a persistent disease known as chronic toxoplasmosis (CT). Despite the availability of prophylactic and treatment options, reactivation of CT can still occur, imposing a life-threatening situation [10,11,12,13,14,15] These include Human Immunodeficiency Virus (HIV)-infected patients, cancer patients after chemotherapy, or following bone marrow or organ transplantation [11,12,13,14,15]. The interconversion between acute and CT is controlled by the host immune system [16]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
