Phosphatidylserine Exposure by Toxoplasma gondii Is Fundamental to Balance the Immune Response Granting Survival of the Parasite and of the Host

Abstract

Phosphatidylserine (PS) exposure on the cell surface indicates apoptosis, but has also been related to evasion mechanisms of parasites, a concept known as apoptotic mimicry. Toxoplasma gondii mimics apoptotic cells by exposing PS, inducing secretion of TGF-beta1 by infected activated macrophages leading to degradation of inducible nitric oxide (NO) synthase, NO production inhibition and consequently persisting in these cells. Here PS+ and PS− subpopulation of tachyzoites were separated and the entrance mechanism, growth and NO inhibition in murine macrophages, and mice survival and pathology were analyzed. Infection index in resident macrophages was similar for both PS subpopulations but lower when compared to the total T. gondii population. Growth in resident macrophages was higher for the total T. gondii population, intermediate for the PS+ and lower for the PS− subpopulation. Production of NO by activated macrophages was inhibited after infection with the PS+ subpopulation and the total populations of tachyzoites. However, the PS− subpopulation was not able to inhibit NO production. PS+ subpopulation invaded macrophages by active penetration as indicated by tight-fitting vacuoles, but the PS− subpopulation entered macrophages by phagocytosis as suggested by loose-fitting vacuoles containing these tachyzoites. The entrance mechanism of both subpopulations was confirmed in a non-professional phagocytic cell line where only the PS+ tachyzoites were found inside these cells in tight-fitting vacuoles. Both subpopulations of T. gondii killed mice faster than the total population. Clear signs of inflammation and no tachyzoites were seen in the peritoneal cavity of mice infected with the PS− subpopulation. Moreover, mice infected with the PS+ subpopulation had no sign of inflammation and the parasite burden was intense. These results show that PS+ and PS− subpopulations of T. gondii are necessary for a successful toxoplasma infection indicating that both subpopulations are required to maintain the balance between inflammation and parasite growth.

Apoptotic-likeLeishmaniaexploit the host´s autophagy machinery to reduce T-cell-mediated parasite elimination

“…Santos et al already showed that phosphatidylserine exposure by Toxoplasma gondii is fundamental for granting survival of the parasite in murine macrophages. 7 In concordance, phagocytosis of apoptotic cells by macrophages plays a role in Trypanosoma cruzi persistence. 6 Indeed, we have also found that during Leishmania infection, disease development relies on the presence of apoptotic-like promastigotes as infection of mice with only viable Leishmania promastigotes does not result in disease development.…”

“…5 In agreement, apoptotic cells exacerbate parasite growth in Trypanosoma cruzi infection and phosphatidylserine exposure by Toxoplasma gondii is fundamental for granting intracellular survival, in macrophages. 6,7 Macrophages also serve as host cell for Leishmania parasites and act as antigenpresenting cells, in which phagosomal and autophagosomal maturation are involved in major histocompatibility complex (MHC) loading. In addition to the well-known endogenous MHC loading pathway, recent efforts have shed light on the involvement of autophagy-related proteins in antigen presentation.…”

Transmission and Epidemiology of Zoonotic Protozoal Diseases of Companion Animals

“…Once within the PV, T. gondii continues its stealth-like state by inducing the production of the antiinflammatory cytokines interleukin 10 (IL-10) and transforming growth factor beta (TGF-␤), inhibiting the production of the proinflammatory cytokines interleukin 12 (IL-12) and tumor necro- sis factor alpha (TNF-␣), and slowing its recognition by blocking major histocompatibility complex class II (MHC-II) expression (24)(25)(26)(27)(28). Apoptotic body mimicry through the parasite surface expression of phosphatidylserine may facilitate the production of TGF-␤ and the degradation of induced nitric oxide synthase (iNOS) (29). Additionally, T. gondii maintains a favorable host cell state by inhibiting the programmed cell death of infected cells and inducing leukocyte apoptosis (30)(31)(32).…”

Tissue Plasminogen Activator Activates NF-κB through a Pathway Involving Annexin A2/CD11b and Integrin-Linked Kinase

“…Primary peritoneal macrophages were isolated from CD11b knockout (CD11b 2/2 ) and wild-type (CD11b +/+ ) mice using the method modified from a previous report. 41 Briefly, mouse peritoneal macrophages were isolated by peritoneal lavage and purified by removing nonadherent cells after 1 hour of culture in complete medium with 10% fetal bovine serum. Macrophages were maintained in Dulbecco's modified Eagle's medium containing 4 mM L-glutamine, 4500 mg/L glucose, 1 mM sodium pyruvate, 1500 mg/L sodium bicarbonate, and 10% fetal bovine serum.…”