Image_1_Praziquantel Reduces Maternal Mortality and Offspring Morbidity by Enhancing Anti-Helminthic Immune Responses.tiff

Alongside the wide distribution throughout sub Saharan Africa of schistosomiasis, the morbidity associated with this chronic parasitic disease in endemic regions is often coupled with infection-driven immunomodulatory processes which modify inflammatory responses. Early life parasite exposure is theorized to drive immune tolerance towards cognate infection as well as bystander immune responses, beginning with in utero exposure to maternal infection. Considering that 40 million women of childbearing-age are at risk of infection worldwide, treatment with Praziquantel during pregnancy as currently recommended by WHO could have significant impact on disease outcomes in these populations. Here, we describe the effects of anthelminthic treatment on parasite-induced changes to fetomaternal cross talk in a murine model of maternal schistosomiasis. Praziquantel administration immediately prior to mating lead to clear re-awakening of maternal anti-parasite immune responses, with persistent maternal immune activation that included enhanced anti-schistosome cytokine responses. Clearance of parasites also improved capacity of dams to endure the additional pressure of pregnancy during infection. Maternal treatment also drove lasting functional alterations to immune system development of exposed offspring. Prenatal anthelminthic treatment skewed offspring immune responses towards parasite clearance and reduced morbidity during cognate infection. Maternal treatment also restored offspring protective IgE antibody responses directed against schistosome antigens, which were otherwise suppressed following exposure to untreated maternal infection. This was further associated with enhanced anti-schistosome cytokine responses from treatment-exposed offspring during infection. In the absence of cognate infection, exposed offspring further demonstrated imprinting across cellular populations. We provide further evidence that maternal treatment can restore a more normalized immune profile to such offspring exposed in utero to parasite infection, particularly in B cell populations, which may underlie improved responsiveness to cognate infection, and support the WHO recommendation of anthelminthic treatment during pregnancy.</p

Image_4_Praziquantel Reduces Maternal Mortality and Offspring Morbidity by Enhancing Anti-Helminthic Immune Responses.tiff

Alongside the wide distribution throughout sub Saharan Africa of schistosomiasis, the morbidity associated with this chronic parasitic disease in endemic regions is often coupled with infection-driven immunomodulatory processes which modify inflammatory responses. Early life parasite exposure is theorized to drive immune tolerance towards cognate infection as well as bystander immune responses, beginning with in utero exposure to maternal infection. Considering that 40 million women of childbearing-age are at risk of infection worldwide, treatment with Praziquantel during pregnancy as currently recommended by WHO could have significant impact on disease outcomes in these populations. Here, we describe the effects of anthelminthic treatment on parasite-induced changes to fetomaternal cross talk in a murine model of maternal schistosomiasis. Praziquantel administration immediately prior to mating lead to clear re-awakening of maternal anti-parasite immune responses, with persistent maternal immune activation that included enhanced anti-schistosome cytokine responses. Clearance of parasites also improved capacity of dams to endure the additional pressure of pregnancy during infection. Maternal treatment also drove lasting functional alterations to immune system development of exposed offspring. Prenatal anthelminthic treatment skewed offspring immune responses towards parasite clearance and reduced morbidity during cognate infection. Maternal treatment also restored offspring protective IgE antibody responses directed against schistosome antigens, which were otherwise suppressed following exposure to untreated maternal infection. This was further associated with enhanced anti-schistosome cytokine responses from treatment-exposed offspring during infection. In the absence of cognate infection, exposed offspring further demonstrated imprinting across cellular populations. We provide further evidence that maternal treatment can restore a more normalized immune profile to such offspring exposed in utero to parasite infection, particularly in B cell populations, which may underlie improved responsiveness to cognate infection, and support the WHO recommendation of anthelminthic treatment during pregnancy.</p

Image_3_Praziquantel Reduces Maternal Mortality and Offspring Morbidity by Enhancing Anti-Helminthic Immune Responses.tiff

Alongside the wide distribution throughout sub Saharan Africa of schistosomiasis, the morbidity associated with this chronic parasitic disease in endemic regions is often coupled with infection-driven immunomodulatory processes which modify inflammatory responses. Early life parasite exposure is theorized to drive immune tolerance towards cognate infection as well as bystander immune responses, beginning with in utero exposure to maternal infection. Considering that 40 million women of childbearing-age are at risk of infection worldwide, treatment with Praziquantel during pregnancy as currently recommended by WHO could have significant impact on disease outcomes in these populations. Here, we describe the effects of anthelminthic treatment on parasite-induced changes to fetomaternal cross talk in a murine model of maternal schistosomiasis. Praziquantel administration immediately prior to mating lead to clear re-awakening of maternal anti-parasite immune responses, with persistent maternal immune activation that included enhanced anti-schistosome cytokine responses. Clearance of parasites also improved capacity of dams to endure the additional pressure of pregnancy during infection. Maternal treatment also drove lasting functional alterations to immune system development of exposed offspring. Prenatal anthelminthic treatment skewed offspring immune responses towards parasite clearance and reduced morbidity during cognate infection. Maternal treatment also restored offspring protective IgE antibody responses directed against schistosome antigens, which were otherwise suppressed following exposure to untreated maternal infection. This was further associated with enhanced anti-schistosome cytokine responses from treatment-exposed offspring during infection. In the absence of cognate infection, exposed offspring further demonstrated imprinting across cellular populations. We provide further evidence that maternal treatment can restore a more normalized immune profile to such offspring exposed in utero to parasite infection, particularly in B cell populations, which may underlie improved responsiveness to cognate infection, and support the WHO recommendation of anthelminthic treatment during pregnancy.</p

Image_2_Praziquantel Reduces Maternal Mortality and Offspring Morbidity by Enhancing Anti-Helminthic Immune Responses.tiff

Alongside the wide distribution throughout sub Saharan Africa of schistosomiasis, the morbidity associated with this chronic parasitic disease in endemic regions is often coupled with infection-driven immunomodulatory processes which modify inflammatory responses. Early life parasite exposure is theorized to drive immune tolerance towards cognate infection as well as bystander immune responses, beginning with in utero exposure to maternal infection. Considering that 40 million women of childbearing-age are at risk of infection worldwide, treatment with Praziquantel during pregnancy as currently recommended by WHO could have significant impact on disease outcomes in these populations. Here, we describe the effects of anthelminthic treatment on parasite-induced changes to fetomaternal cross talk in a murine model of maternal schistosomiasis. Praziquantel administration immediately prior to mating lead to clear re-awakening of maternal anti-parasite immune responses, with persistent maternal immune activation that included enhanced anti-schistosome cytokine responses. Clearance of parasites also improved capacity of dams to endure the additional pressure of pregnancy during infection. Maternal treatment also drove lasting functional alterations to immune system development of exposed offspring. Prenatal anthelminthic treatment skewed offspring immune responses towards parasite clearance and reduced morbidity during cognate infection. Maternal treatment also restored offspring protective IgE antibody responses directed against schistosome antigens, which were otherwise suppressed following exposure to untreated maternal infection. This was further associated with enhanced anti-schistosome cytokine responses from treatment-exposed offspring during infection. In the absence of cognate infection, exposed offspring further demonstrated imprinting across cellular populations. We provide further evidence that maternal treatment can restore a more normalized immune profile to such offspring exposed in utero to parasite infection, particularly in B cell populations, which may underlie improved responsiveness to cognate infection, and support the WHO recommendation of anthelminthic treatment during pregnancy.</p

Key cellular and humoral effectors associated with parenchymal and extraparenchymal NCC.

Key cellular and humoral effectors associated with parenchymal and extraparenchymal NCC.</p

Schematic diagram of <i>T</i>. <i>solium</i> infection showing the different steps of human and porcine cysticercosis including human NCC. NCC, neurocysticercosis.

Schematic diagram of T. solium infection showing the different steps of human and porcine cysticercosis including human NCC. NCC, neurocysticercosis.</p

Cyst involution in brain parenchyma and associated immunopathogenesis.

The presence of viable vesicular cysts (A) is usually asymptomatic and associated with suppression of the host immune responses through induction of anti-inflammatory cytokines. Upon successful attack of the host immune system, the cyst passes through a series of involuting stages (B–D). The BBB is disrupted, and granuloma, mainly composed of macrophages, granulocytes, and lymphocytes, encompasses the cyst that contracts (colloidal stage) (B) and becomes nodular and the scolex granulated (granular-nodular stage) (C); this is followed by the formation of collagenous and fibrotic structures and calcification of the cyst (calcified stage) (D). Each involuting stage of the cyst releases material (ES and Ag) and elicits an inflammatory reaction and release of mediators in the brain that lead to the development of pathology and symptoms (pale orange box). Ag, cyst antigen; B, lymphocyte B; BBB, blood–brain barrier; EO, eosinophil; ES, excretory–secretory; EV, extracellular vesicle; IFN, interferon; IL, interleukin; M, macrophage; Mi, microglia/dendritic cell; NE, neutrophil; TGF-ß, transforming growth factor beta; Th, T helper cell; TNF, tumor necrosis factor.</p

Host immune regulation during parenchymal NCC.

Viable cyst releases ES products and EVs that interact with resident brain cells (microglia and DCs) and induce AAMs, which suppress adhesion molecules and local Th1 response via TGF-ß and IL-10. Excreted products reach peripheral system where they drive the expansion of suppressive Tregs from CD4+ cells through the alteration of the maturation of DCs. Furthermore, cyst products inhibit complement C1q activity and prevent the infiltration and migration of neutrophils, eosinophils and MO from the peripheral system into the brain via production of immunomodulatory cytokines and blocking of chemokines and adhesion molecules. AAM, alternatively activated macrophages; B, ; BBB, blood–brain barrier; CCL, chemokine C-C ligand; CD4, cluster of differentiation 4; C1q, complement first component; CTLA-4, cytotoxic T-lymphocyte associated protein 4; CXCL, chemokine C-X-C ligand; DC, dendritic cell; EO, eosinophil; ES, excretory–secretory; EV, extracellular vesicle; ICAM-1, intercellular adhesion molecule 1; iDC, immature DC; IL, interleukin; Mi, microglia; MO, monocytes; NCC, neurocysticercosis; TGF-ß, transforming growth factor beta; Th, T helper; Treg, regulatory T cell; VCAM-1, vascular cell adhesion protein 1.</p