Circulating inflammatory mediators as biomarkers of ocular toxoplasmosis in acute and in chronic infection

Abstract

Toxoplasmosis is highly endemic worldwide. In Brazil, depending on the geographical region and socioeconomic status, 40-70% of individuals become seropositive at some point in their lives. A significant proportion of Toxoplasma gondii-chronically infected individuals who are otherwise immunocompetent develop recurrent ocular lesions. The inflammatory/immune mechanisms involved in development of ocular lesion are still unknown and, despite previous investigation, there are no reliable immune biomarkers to predict/follow disease outcome. To better understand the impact of the immune response on parasite control and immunopathology of ocular toxoplasmosis, and to provide insights on putative biomarkers for disease monitoring, we assessed the production of a large panel of circulating immune mediators in a longitudinal study of patients with postnatally acquired toxoplasmosis stratified by the presence of ocular involvement, both at the early acute stage and 6 months later during chronic infection, correlating them with presence of ocular involvement. We found that T. gondii-infected patients, especially during the acute stage of the disease, display high levels of chemokines, cytokines, and growth factors involved in the activation, proliferation, and migration of inflammatory cells to injured tissues. In particular, major increases were found in the IFN-induced chemokines CXCL9 and CXCL10 in T. gondii-infected patients regardless of disease stage or clinical manifestations. Moreover, a specific subgroup of circulating cytokines and chemokines including GM-CSF, CCL25, CCL11, CXCL12, CXCL13, and CCL2 was identified as potential biomarkers that accurately distinguish different stages of infection and predict the occurrence of ocular toxoplasmosis. In addition to serving as predictors of disease development, these host inflammatory molecules may offer promise as candidate targets for therapeutic intervention.

Murine Model of Primary Acquired Ocular Toxoplasmosis: Fluorescein Angiography and Multiplex Immune Mediator Profiles in the Aqueous Humor

“…61 Here, the postinfection serum IFN-γ and IL-12(p40) levels were very low. The serum IFN-γ level has been reported to increase during the acute phase of toxoplasmosis but decrease during the chronic phase, 22,44,[62][63][64][65][66] although elevated serum IFN-γ and IL-12 levels have also been reported in the chronic phase. 63,64 TNF-α is a proinflammatory cytokine that plays a crucial protective role during T. gondii infection.…”

“…65 Here, the TNFα levels in the AH and CSF were undetectable or very low compared with that in the serum for both uninfected and T. gondii-infected mice, although the postinfection CSF TNF-α level was significantly increased. Many reports have described that the serum TNF(-α) level increases during the acute phase of T. gondii infection 22,23,44,62,63,66,67 and decreases thereafter. 44,62,66 However, increased serum TNFα levels in the chronic phase have also been reported.…”

“…Many reports have described that the serum TNF(-α) level increases during the acute phase of T. gondii infection 22,23,44,62,63,66,67 and decreases thereafter. 44,62,66 However, increased serum TNFα levels in the chronic phase have also been reported. 63 Here, the T-cell growth factor IL-2 68 was undetectable in all samples.…”

“…However, some prior studies reported different findings. [36][37][38][41][42][43][44][45]47,48,63 In patients infected with type I/III T. gondii strains, a Th2 response was associated with more severe clinical characteristics. 37 IL-4 and IL-13 levels have been positively correlated with the number and size of active lesions, and IL-5 has been described as a predictor of OT recurrence.…”

“…However, there are few reports concerning such molecules in the AH of OT patients, and these details remain unknown. [36][37][38][39][40][41][42][43][44] Although there are anatomic, biochemical, and immunological differences between mice and humans, a murine model of OT can provide key information about human OT 6 and would expedite an exact evaluation of the immunopathogenesis of this disease. Some active experimental murine research on immune profiles in the AH of OT has been performed via intravitreal or peritoneal injections of the parasite, which are unnatural infection routes.…”