A Praziquantel Treatment Study of Immune and Transcriptome Profiles inSchistosoma haematobium-Infected Gabonese Schoolchildren

Abstract

Background Although Schistosoma haematobium infection has been reported to be associated with alterations in immune function, in particular immune hyporesponsiveness, there have been only few studies that have used the approach of removing infection by drug treatment to establish this and to understand the underlying molecular mechanisms. Methods Schistosoma haematobium-infected schoolchildren were studied before and after praziquantel treatment and compared with uninfected controls. Cellular responses were characterized by cytokine production and flow cytometry, and in a subset of children RNA sequencing (RNA-Seq) transcriptome profiling was performed. Results Removal of S haematobium infection resulted in increased schistosome-specific cytokine responses that were negatively associated with CD4+CD25+FOXP3+ T-cells and accompanied by increased frequency of effector memory T-cells. Innate responses to Toll like receptor (TLR) ligation decreased with treatment and showed positive association with CD4+CD25+FOXP3+ T-cells. At the transcriptome level, schistosome infection was associated with enrichment in cell adhesion, whereas parasite removal was associated with a more quiescent profile. Further analysis indicated that alteration in cellular energy metabolism was associated with S haematobium infection and that the early growth response genes 2 and 3 (EGR 2 and EGR3), transcription factors that negatively regulate T-cell activation, may play a role in adaptive immune hyporesponsiveness. Conclusions Using a longitudinal study design, we found contrasting effects of schistosome infection on innate and adaptive immune responses. Whereas the innate immune system appears more activated, the adaptive immunity is in a hyporesponsive state reflected in alterations in CD4+CD25+FOXP3+ T-cells, cellular metabolism, and transcription factors involved in anergy.

Immunological Considerations for Schistosoma Vaccine Development: Transitioning to Endemic Settings

“…Clearance of infection following PZQ administration results in increased effector T cell frequency, increased Schistosome-specific cytokine response and decreased levels of T reg. This contrasts with the immune suppressive profile during infection such as antigen specific hypo-responsiveness, T cell memory pool distortion and increased CD4+CD25+FOXP3+T cell numbers ( 177 ). Consequently, in a randomized trial in Entebbe, Uganda, PZQ treatment significantly, although transiently, improved vaccine response to measles immunization in S. mansoni infected pre-school children ( 169 ).…”

Evaluation of IL-35, as a Possible Biomarker for Follow-Up after Therapy, in Chronic Human Schistosoma Infection

“…Several studies have focused on the Th1 and Th2 cytokines [ 24 , 31 , 32 , 33 ]. In contrast, the behavior of cytokines from the Treg and Breg lymphocyte subsets during infections caused by the main Schistosoma species has not been fully investigated.…”

“…The proliferation of Treg and Breg during chronic infection is associated with suppressed development of pathology [ 19 ] and down-modulated Th1 and Th2 responses [ 20 , 21 ], promoting parasite survival within the host [ 22 , 23 ]. Treatment with the anti-schistosomal drug praziquantel (PZQ) leads to clearance of infection [ 24 ], elevated antigen-specific T-cell proliferation [ 15 ], and cytokine production [ 10 , 16 ]. However, after PZQ treatment, it an increase in effector T-cell frequencies (Th1 and Th2) with increased antigen-specific cytokine production was observed, with a concurrent decrease in the levels of the Treg subpopulation and their secreted specific cytokines [ 24 ].…”

“…Treatment with the anti-schistosomal drug praziquantel (PZQ) leads to clearance of infection [ 24 ], elevated antigen-specific T-cell proliferation [ 15 ], and cytokine production [ 10 , 16 ]. However, after PZQ treatment, it an increase in effector T-cell frequencies (Th1 and Th2) with increased antigen-specific cytokine production was observed, with a concurrent decrease in the levels of the Treg subpopulation and their secreted specific cytokines [ 24 ].…”

Systems Biology Analysis of the Radiation-Attenuated Schistosome Vaccine Reveals a Role for Growth Factors in Protection and Hemostasis Inhibition in Parasite Survival

“…Similar experiments have not been performed with NK cells, but lymph node NK cells stimulated by IL-12 shortly after vaccination are believed critical to the subsequent development of antigen-specific Th1 cells (73). Recently, a PBMC transcriptomic study in schoolchildren revealed that infection with S. hematobium is associated with reduced gene signatures for natural killer (NK) cells, DCs, monocytes and T-cell activation (74). There is also a suggestion from an experiment in pigs immunized with one dose of UV-attenuated Schistosoma japonicum, that Granzyme B increase in skin-draining lymph nodes was associated with protection (25).…”