Adriana Lima Vallochi

Genetic Divergence of Toxoplasma gondii Strains Associated with Ocular Toxoplasmosis, Brazil

Brazilian strains of T. gondii differ from lineages in North America and Europe; these differences may underlie severe ocular disease.

Discrimination between Patients with Acquired Toxoplasmosis and Congenital Toxoplasmosis on the Basis of the Immune Response to Parasite Antigens

Many persons infected with Toxoplasma gondii develop ocular lesions. Immunologic parameters in the response to T. gondii were evaluated in infected persons with and without ocular lesions and in noninfected controls. Subjects were divided into groups on the basis of presence of serum antibodies to T. gondii, presence of ocular lesions, and clinical history. Production of interleukin-2 and interferon-gamma by peripheral blood mononuclear cells from patients with probable congenital toxoplasmosis was decreased, compared with that in persons with presumed acquired infection. Cell proliferation and delayed-type skin reaction induced by soluble toxoplasma tachyzoite antigen followed the same pattern. Asymptomatic persons showed high levels of interleukin-12 and interferon-gamma, whereas persons with ocular lesions had high interleukin-1 and tumor necrosis factor-alpha responses toward soluble toxoplasma tachyzoite antigen. These data suggest that patients with ocular disease due to congenital infection show tolerance toward the parasite. Furthermore, susceptibility to ocular lesions after acquired toxoplasmosis is associated with high levels of interleukin-1 and tumor necrosis factor-alpha, whereas resistance is associated with high levels of interleukin-12 and interferon-gamma.

The role of polymorphonuclear leukocytes in the resistance to cutaneous Leishmaniasis

The massive infiltration by polymorphonuclear leukocytes (PMN) soon after skin infection with Leishmania major suggests that PMN could participate in reducing parasite load and controlling the spreading of leishmanial infection. Yet, direct evidence for the participation of PMN in host defense against L. major was lacking. We investigated L. major infection in susceptible and resistant mice treated with the monoclonal (mAb) antibody RB6-8C5 that depletes the population of mature neutrophils and eosinophils. Both BALB/c and C57BL/6 mice depleted of PMN show accelerated parasite spreading and more severe footpad swelling than similarly infected untreated mice. In addition, significant higher parasite numbers were found in the lesion draining lymph nodes from PMN-depleted C57BL/6 mice. Histopathological analysis of the paw confirmed neutrophils containing ingested parasites as the dominant cell type in the infiltrate of the first days after infection and the nearly absolute neutrophil depletion in mAb-treated mice. Our data show the importance of PMN in early control of parasite load and parasitism spreading in cutaneous leishmaniasis.

Toxoplasma gondii in the peripheral blood of patients with acute and chronic toxoplasmosis.

Background and aims Toxoplasmic retinochoroiditis may recur months or years after the primary infection. Rupture of dormant cysts in the retina is the accepted hypothesis to explain recurrence. Here, the authors present evidence supporting the presence of Toxoplasma gondii in the peripheral blood of immunocompetent patients. Methods Direct observation by light microscopy and by immunofluorescence assay was performed, and results were confirmed by PCR amplification of parasite DNA. Results The authors studied 20 patients from Erechim, Brazil, including acute infected patients, patients with recurrent active toxoplasmic retinochoroiditis, patients with old toxoplasmic retinal scars, and patients with circulating IgG antibodies against T gondii and absence of ocular lesions. Blood samples were analysed, and T gondii was found in the blood of acutely and chronically infected patients regardless of toxoplasmic retinochoroiditis. Conclusions The results indicate that the parasite may circulate in the blood of immunocompetent individuals and that parasitaemia could be associated with the reactivation of the ocular disease.

Ocular toxoplasmosis: more than just what meets the eye.

Toxoplasma gondii is an intracellular parasite whose life cycle may include the man as an intermediate host. Close to a billion people are infected with this parasite worldwide. Ocular lesions may occur in up to 25% of those individuals infected. The infection may occur intra‐uterus, through the placenta when the mother is infected during pregnancy. The parasite may also infect adults after the ingestion of contaminated food products, most notably meats or water. We have shown that although congenital and post‐natal (acquired) infection results in similar ocular lesions, the immunological mechanisms behind the development of disease are different. On the other hand, contrary to published data obtained in mice, we were unable to find evidence that the T. gondii express superantigen activity for human lymphocytes. Our findings are important because they suggest that superantigen activity is not important as a pathological mechanism in human disease. Our data also suggest that, whereas the ocular lesion caused by infection after birth is the result of an excessive or dysfunctional immune response, the lesions caused by congenital infection may be due to a lack of an appropriate response to the parasite.

Molecular markers of susceptibility to ocular toxoplasmosis, host and guest behaving badly.

Infection with Toxoplasma gondii results in retinochoroiditis in 6% to 20% of immunocompetent individuals. The outcome of infection is the result of a set of interactions involving host genetic background, environmental, and social factors, and the genetic background of the parasite, all of which can be further modified by additional infections or even reinfection. Genes that encode several components of the immune system exhibit polymorphisms in their regulatory and coding regions that affect level and type of expression in response to stimuli, directing the immune response into different pathways. These variant alleles have been associated with susceptibility to immune-mediated diseases and with severity of pathology. We have investigated polymorphisms in several of these genes, identified as candidates for progression to retinochoroiditis caused by toxoplasmosis, namely chemokine (C-C motif) receptor 5 (CCR5), toll-like receptor-2 (TLR2), and TLR4. Furthermore, because interleukin-12 (IL-12) has been shown to be fundamental both in mice and in man to control a protective response against T. gondii, molecules that have a key function in IL-12 production will be emphasized in this review, in addition to discussing the importance of the genetic background of the parasite in the establishment of ocular disease.

Cytokine profile in response to Cytomegalovirus associated with immune recovery syndrome after highly active antiretroviral therapy.

BACKGROUND Several changes have occurred in the presentation and course of cytomegalovirus (CMV) retinitis in patients with AIDS since the introduction of HAART (highly active antiretroviral therapy). In some individuals who take HAART, retinitis is kept under control even after the discontinuation of anti-CMV therapy. However, many of these patients develop intraocular inflammation. Uveitis, cataract, vitreitis, cystoid macular edema, epiretinal membrane, and disc edema may occur in patients with immune recovery syndrome (IRS). METHODS We evaluated the CMV-specific immune response in 55 patients by assessing CMV-specific lymphocyte proliferation, cytotoxicity, and cytokine production and correlated it with the clinical outcome. RESULTS Our data suggest that control of CMV retinitis is associated with acquisition of cytotoxic and lymphoproliferative responses to CMV. In addition, the upsurge of macular and disc edema seems associated with the production of interleukin-4 and tumor necrosis factor-alpha, whereas vitreitis is associated with the production of interleukin-2 and interferon-gamma. INTERPRETATION The type of T-cell response that develops after HAART may determine the side effects of immune recovery and these effects are predictable based on the lymphokine profile produced by CMV-specific cells.

Lack of evidence for superantigen activity of Toxoplasma gondii towards human T cells

Toxoplasma gondii is an obligatory intracellular parasite whose life cycle may include man as an intermediate host. More than 500 million people are infected with this parasite worldwide. It has been previously reported that T. gondii contains a superantigen activity. The purpose of the present study was to determine if the putative superantigen activity of T. gondii would manifest towards human T cells. Peripheral blood mononuclear cells (PBMC) from individuals with no previous contact with the parasite were evaluated for proliferation as well as specific Vbeta expansion after exposure to Toxoplasma antigens. Likewise, PBMC from individuals with the congenital infection were evaluated for putative Vbeta family deletions in their T cell repertoire. We also evaluated, over a period of one year, the PBMC proliferation pattern in response to Toxoplasma antigens in patients with recently acquired infection. Some degree of proliferation in response to T. gondii was observed in the PBMC from individuals never exposed to the parasite, accompanied by specific Vbeta expansion, suggesting a superantigen effect. However, we found no specific deletion of Vbeta (or Valpha) families in the blood of congenitally infected individuals. Furthermore, PBMC from recently infected individuals followed up over a period of one year did not present a reduction of the Vbeta families that were originally expanded in response to the parasite antigens. Taken together, our data suggest that T. gondii does not have a strong superantigen activity on human T cells.