**2. Mechanisms of protective immunity against toxoplasmosis**

Immune responses during the early stages of *T. gondii* infection are characterized by activation of innate mechanisms mediated by macrophages and dendritic cells (DC) (Gazzinelli *et al*. 1996; Pifer and Yarovinsky 2011). These cells are activated in mice (not yet known how in humans) after parasite internalization, by engagement of endosomal toll-like receptor 11 (and probably others) with tachyzoite products, which drives subsequent production of interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-α). In turn, IL-12 activates natural killer (NK) cells (Denkers *et al*. 1993) to secrete gamma interferon (IFN-γ) (Gazzinelli *et al*. 1994), which then acts as stimulus for T-cell activation and, in synergy with TNF-α, mediates killing of tachyzoites by macrophages through enhanced production of free oxygen radicals and nitric oxide (NO).

Acquired immunity against *T. gondii* develops afterward, and is characterized by strong CD4+ and CD8+ T cell activity (Gazzinelli *et al*. 1992). The cytokine IFN-γ continues to be central in resistance to the parasite during the successive acute and chronic stages of infection, driving the differentiation of CD4+ T lymphocytes specific for parasite antigens to a helper T cell type (Th1) cytokine profile. More important, the newly generated CD8+ T

will grow unabated and cause tissue destruction, which can be severe and even fatal. However, the inflammatory immune response induced by tachyzoites can cause immunemediated tissue destruction. Therefore, a subtle balance between inducing and evading the

The success of *Toxoplasma* as a widespread pathogen is due to the ease in which it can be transmitted between intermediate hosts. Humans do not play a major role in transmission; consequently, pathogenesis in humans is the indirect result of adaptations to infection in other hosts and treatment of human infections is unlikely to lead to the

Once inside a host, the parasite develops powerful tools to modulate its host cell and develop into a chronic infection that can evade the host's immune system as well as all known anti-toxoplasmatic drugs. The ability of the parasite to replicate within a host cell, evade immune responses and undergo bradyzoite development requires the parasite to

Toxoplasmosis remains a major health concern in pregnancy, where it causes severe birth defects or miscarriage, and in immunocompromised hosts. Thus, new toxoplasmosis control strategies are needed. The development of effective human and veterinary vaccines against toxoplasmosis is a relevant goal for Public Health (Gazzinelli *et al*. 1996; Pifer and Yarovinsky 2011). Even if new therapeutic drugs, with less hypersensitivity and toxicityrelated events, are developed, not only for acute *T. gondii* infection but also for the currently untreatable latent bradyzoite form of the parasite, a prophylactic vaccine against the disease would still be the best option from the financial, epidemiological, and social points of view. A vaccine would decrease the enormous costs of diagnosis/treatment, the premature loss of lives, the extensive rates of dissemination as well as the social impact of the disease. One major fact that suggests the possibility of vaccination against toxoplasmosis is that primary infection with the *T. gondii* parasite elicits protective immunity against re-infection in most

Immune responses during the early stages of *T. gondii* infection are characterized by activation of innate mechanisms mediated by macrophages and dendritic cells (DC) (Gazzinelli *et al*. 1996; Pifer and Yarovinsky 2011). These cells are activated in mice (not yet known how in humans) after parasite internalization, by engagement of endosomal toll-like receptor 11 (and probably others) with tachyzoite products, which drives subsequent production of interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-α). In turn, IL-12 activates natural killer (NK) cells (Denkers *et al*. 1993) to secrete gamma interferon (IFN-γ) (Gazzinelli *et al*. 1994), which then acts as stimulus for T-cell activation and, in synergy with TNF-α, mediates killing of tachyzoites by macrophages through enhanced production of

Acquired immunity against *T. gondii* develops afterward, and is characterized by strong CD4+ and CD8+ T cell activity (Gazzinelli *et al*. 1992). The cytokine IFN-γ continues to be central in resistance to the parasite during the successive acute and chronic stages of infection, driving the differentiation of CD4+ T lymphocytes specific for parasite antigens to a helper T cell type (Th1) cytokine profile. More important, the newly generated CD8+ T

immune response is crucial for *Toxoplasma* to establish a chronic infection.

**2. Mechanisms of protective immunity against toxoplasmosis** 

free oxygen radicals and nitric oxide (NO).

spread of drug resistance.

effectively modulate its host.

individuals.

cells become crucial to control parasite replication, not only by serving as additional sources of IFN-but also by developing cytotoxic activity against infected cells, eliminating parasite factories and thus preventing reactivation of infection (Denkers *et al*. 1993; Denkers and Gazzinelli 1998; Bhopale 2003). Whether B cells also play a role in protection against this parasite is not clear, but studies have generated indirect evidences that IgG antibodies may be important for protection (Kang *et al*. 2000). B cell-deficient mice have shown increased susceptibility to brain inflammatory pathology in chronic infections with the parasite, despite presenting similar levels of serum and tissue pro-inflammatory cytokines, such as IFN-γ. Furthermore, adoptive transfer of polyclonal anti- *T. gondii* IgG antibodies to these mice prevented both pathology and mortality.
