Determination of a Key Antigen for Immunological Intervention To Target the Latent Stage of Toxoplasma gondii

Abstract

Toxoplasma gondii , an obligate intracellular protozoan parasite, establishes a chronic infection by forming cysts preferentially in the brain, and up to one third of human population worldwide is estimated to be chronically infected with this parasite. However, there are currently no drugs effective against the cyst form of the parasite. In addition, the protective immunity against the cysts remains largely unknown. We analyzed the molecular mechanisms by which the immune system detects host cells harboring the cysts to eliminate the latent stage of the parasite using mice with the H-2d haplotype, which are genetically resistant to the infection. Our study revealed that CD8+ immune T cells bearing T cell receptor Vβ8.1, 8.2 chain have a potent activity to remove T. gondii cysts from the brain. Our studies also uncovered that the H-2Ld is the major antigen-presenting molecule to CD8+ T cells for initiating the cyst elimination, and that the CD8+Vβ8.1, 8.2+ immune T cells recognize the amino-terminal region (amino acids 41 to 152) of dense granule protein 6 (GRA6Nt) of the parasite presented by the H-2Ld molecule. Furthermore, CD8+ immune T cells induced by immunization with recombinant GRA6Nt were eventually capable of removing the cysts from the brain when transferred to infected immunodeficient mice lacking T cells. Thus, GRA6Nt is a novel and potent antigen to activate CD8+ T cells capable of removing T. gondii cysts. These observations offer the basis for immunological intervention to combat the chronic infection with T. gondii by targeting the persistent cysts of the parasite.

Toxoplasma gondii: isolation, biological and molecular characterisation of samples from free-range Gallus gallus domesticus from countryside Southeast Brazil

“…The present study was developed in the mountainous region of the state (Venda Nova do Imigrante) for which no previous data on avian toxoplasmosis were available. In Venda Nova do Imigrante, 38% of the evaluated birds exhibited specific antibodies against T. gondii, our results were similar compared to results from backyard chickens in the metropolitan area of Recife (FERNANDES et al, 2016) and in the semiarid region of the state of Pernambuco (SÁ et al, 2017). Venda Nova do Imigrante also has a high prevalence of ocular toxoplasmosis, with 11.27% positive cases (ABREU et al, 1998), and is likely a favourable site for the presence and transmission of the parasite, as the mean prevalence of ocular toxoplasmosis in Brazil is 1.6% (ZANETTI & PLETSCH, 2007).…”

Penetration of CD8+ Cytotoxic T Cells into Large Target, Tissue Cysts of Toxoplasma gondii, Leads to Its Elimination

“…Therefore, CD8 þ cytotoxic T cells first need to recognize T. gondii antigen(s) presented by the major histocompatibility complex class I molecules on the surface of the cyst-harboring cells. Our recent studies identified that the N-terminus region of dense granule protein 6 of the T. gondii, presented by the H-2L d molecule, is a key target for CD8 þ T cells to display their cytotoxic activity 31 ; and that N-terminus region of dense granule protein 6eprimed CD8 þ T cells are able to reduce numbers of cysts in the brain when transferred to infected SCID mice that had already established large numbers of cysts. 31 Therefore, it is most likely that the recognition of the N-terminus region of dense granule protein 6 presented by the H-2L d molecule on the surface of cyst-containing cells by CD8 þ cytotoxic T cells plays a critical role for their attachment to initiate their invasion into the cysts.…”

“…Our recent studies identified that the N-terminus region of dense granule protein 6 of the T. gondii, presented by the H-2L d molecule, is a key target for CD8 þ T cells to display their cytotoxic activity 31 ; and that N-terminus region of dense granule protein 6eprimed CD8 þ T cells are able to reduce numbers of cysts in the brain when transferred to infected SCID mice that had already established large numbers of cysts. 31 Therefore, it is most likely that the recognition of the N-terminus region of dense granule protein 6 presented by the H-2L d molecule on the surface of cyst-containing cells by CD8 þ cytotoxic T cells plays a critical role for their attachment to initiate their invasion into the cysts. Figure 7 Both cysts formed within neurons and astrocytes were destroyed by CD8 þ immune T cells, and the destruction of the cysts was associated with accumulation of Iba1 þ microglia and Ly6C þ inflammatory macrophages.…”

Presence of Toxoplasma gondii infection in brain as a potential cause of risky behavior: a report of 102 autopsy cases

“…This is directly related with the complex adaptable nature of this parasite, which is associated with its determinants of high virulence and transmission mode [33]. Insights afforded by ongoing studies and literature reports indicate the significance of the potential negative consequences of latent toxoplasmosis occurring in immunocompetent population, a group which was previously considered to be asymptomatic and uncomplicated [34]. Therefore, latent infection by T. gondii was linked to several diseases and states that impair the complex functioning of the brain [35].…”