CD39 and immune regulation in a chronic helminth infection: The puzzling case of Mansonella ozzardi

Abstract

BackgroundChronic helminth infections typically induce an immunoregulatory environment, with markedly reduced immune responses to both parasite-specific and unrelated bystander antigens. Here we tested whether these changes are also observed in human infections with Mansonella ozzardi, a neglected filarial nematode widely distributed across Latin America.MethodsCD4+ T cell populations from microfilaremic (Fil+) and uninfected (Fil-) inhabitants in M. ozzardi-endemic riverine communities in Brazil were characterized by flow cytometry analysis. Plasma concentrations of a wide range of cytokines and chemokines were measured. We examined whether M. ozzardi infection is associated with suppressed in vitro lymphoproliferative and inflammatory cytokine responses upon stimulation with filarial antigen, unrelated antigens or mitogens.Principal findings/ConclusionsFil+ subjects had lower plasma levels of selected inflammatory cytokines, such as TNF-α, IL-8, and IL-6, than their Fil- counterparts. However, we found no evidence for attenuated T-cell responses to filarial antigens or co-endemic pathogens, such as malaria parasites and Toxoplasma gondii. CD4+ T cells expressing CD39, an ectonucleosidase involved in the generation of the anti-inflammatory molecule adenosine, were increased in frequency in Fil+ subjects, compared to uninfected controls. Significantly, such an expansion was directly proportional to microfilarial loads. Surprisingly, CD39 blocking with a neutralizing antibody suppressed antigen-driven lymphoproliferation in vitro, while decreasing inflammatory cytokine responses, in Fil+ and Fil- individuals. These findings suggest that circulating CD4+ CD39+ T cells comprise subsets with both regulatory and stimulatory roles that contribute to the immune homeostasis in chronic M. ozzardi infection.

Detection of Mansonella ozzardi among blood donors from highly endemic interior cities of Amazonas state, northern Brazil

“…In our study, Boca do Acre showed the second highest prevalence while high M. ozzardi prevalence (24%) was previously described in the neighboring municipalities of Boca do Acre and Pauiní . A recent study combining thick smear microscopy and PCR in six villages by the Purus river basin in the municipality of Boca do Acre detected 14.3% prevalence . In our study, the three transfused M. ozzardi contaminated blood units were from Lábrea, Piauiní, and Boca do Acre.…”

“…28 A recent study combining thick smear microscopy and PCR in six villages by the Purus river basin in the municipality of Boca do Acre detected 14.3% prevalence. 19 In our study, the three transfused M. ozzardi contaminated blood units were from Lábrea, Piauiní, and Boca do Acre. So far M. ozzardi infections have been reported mainly in small cities located along major Amazonian rivers with sporadic cases from urban areas of the Amazon.…”

“…[15][16][17][18] However, a recent study showed similar lymphoproliferative responses to filarial and unrelated antigens and similar regulatory cytokine responses in M. ozzardi infected and uninfected controls from the same area. 19 The involvement of inflammatory and regulatory cytokines has also been demonstrated in M. ozzardi infection. 20 M. ozzardi transmission occurs through the bite of infected female hematophagous arthropod vectors from the insect family Diptera (Simulium or Culicoides) by depositing third stage larvae onto skin, which after two molts transform into adult worms.…”

“…Chronic helminthic infections usually modulate immunity leading to a marked decrease in responses to parasite‐specific and unrelated co‐infecting pathogens, a phenomenon known as “spillover suppression.” Studies with other filarial nematodes as Wuchereria bancrofti , Brugia mala yi, and M. perstans have shown reduced immune responses to malaria parasites and to other pathogens . However, a recent study showed similar lymphoproliferative responses to filarial and unrelated antigens and similar regulatory cytokine responses in M. ozzardi infected and uninfected controls from the same area . The involvement of inflammatory and regulatory cytokines has also been demonstrated in M. ozzardi infection …”

In Silico Identification of Novel Biomarkers and Development of New Rapid Diagnostic Tests for the Filarial Parasites Mansonella perstans and Mansonella ozzardi

“…ozzardi LAMP assay was evaluated using 83 samples from Brazilian individuals whose infection status regarding M . ozzardi was previously determined by microscopy or qPCR using an ITS-2 based assay 60 . All 51 patients that were reported to be M .…”