Redefining Chronic Toxoplasmosis—A T Cell Exhaustion Perspective

Abstract

Toxoplasmosis caused by Toxoplasma gondii (T. gondii), an obligate intercellular protozoan, is considered to be a leading cause of foodborne mortality in the United States (www.cdc.gov). Even in the post-HAART era, fatal toxoplasmic encephalitis (TE) due to reactivation of chronic Toxoplasma infection remains a major problem in Toxoplasma-seropositive AIDS patients in developing countries [1]. In warm-blooded intermediate hosts (including humans), the parasite undergoes stage conversion between the rapidly proliferating tachyzoite, which is considered to be responsible for acute toxoplasmosis, and the relatively quiescent, slowly replicating, encysted bradyzoite that can persist for life. However, in the immunocompromised such as AIDS patients, the parasite converts from a bradyzoite to a tachyzoite stage, leading to TE [2]. Similarly, repeated reactivations can also occur in congenitally infected individuals [3]. Tachyzoite– bradyzoite interconversion is believed to play a central role not only in establishing the chronic infection but also in disease recrudescence [2]. However, factors responsible for the reactivation of chronic infection in vivo remain poorly understood [2,4]. Studies in murine models of chronic toxoplasmosis have demonstrated that CD8 T cells are pivotal for long-term protection [3]. Paradoxically, despite a robust CD8 T cell response during the acute phase of infection, long-term immunity against this pathogen is compromised in susceptible mouse strains, leading to reactivation and host mortality. Differential susceptibility to T. gondii reactivation in AIDS patients was also noted in a study conducted during the pre-HAART era, which reported that only 30% of AIDS patients with low CD4 T cell count and Toxoplasma seropositivity, who were not on effective prophylaxis, developed reactivated toxoplasmosis [5]. Why does a modest subset of this high-risk group develop TE? Considering that memory CD8 T cells can persist for a lifetime and can mediate protective recall responses upon antigen reencounter in other infectious diseases [6], it remains to be addressed whether this differential outcome is a consequence of potential attrition of T. gondii–specific memory CD8 T cells due to genetic polymorphisms or other microenvironment-associated factors. Recent studies from our group, which utilized a susceptible mouse model (C57BL/6), have demonstrated that CD8 T cells during the later phase of chronic toxoplasmosis exhibit progressive attrition of functionality, increased apoptosis, and poor recall response along with elevated expression of PD-1, an inhibitory receptor-a phenomenon referred to as CD8 exhaustion [7]. Concomitant with graded CD8 exhaustion, parasites undergo reactivation resulting in the mortality of the infected host (Figure 1). While the paradigm of CD8 exhaustion has been extensively explored in chronic viral models, it is just beginning to unfold in parasitic infections. Unlike chronic viral models of CD8 exhaustion, which are characterized by persistent high viremia, the T. gondii model represents a unique situation where, despite initial control of parasitemia, CD8 T cells eventually become exhausted [7,8]. Considering that current drugs against T. gondii are toxic and inefficacious against the encysted bradyzoite stage of the parasite [2,3], a thorough understanding of T cell exhaustion during chronic toxoplasmosis is critical for the development of improved immunotherapeutics against this pathogen. Significantly, our laboratory has demonstrated that a blockade of PD-1 interaction with its receptor PDL1, via anti-PD-L1 antibody treatment of chronically infected animals, not only reinvigorates CD8 response and controls parasite reactivation but also prevents host mortality [7].