EDCTP Alumni Network

Fostering excellence and collaboration in the next generation of researchers

Call Career Development Fellowship (CDF)
Programme EDCTP2
Start Date 2018-07-01
End Date 2021-06-30
Project Code TMA2016CDF1571
Status Active

Title

Identification of host regulators of tissue fibroproliferative pathology in schistosomiasis-diseased children in Africa

Objectives

The overall aim of the present study is to unequivocally establish a gene expression profile that trigger / promote tissue fibrosis during schistosomiasis and in so doing generate a comprehensive database of druggable fibrosis-regulating factors and build a solid capacity in clinical genomics in the applicant. The present project proposes to address the differential gene expression profile of blood cells from schistosomiasis-diseased patients presenting with a differential grade of liver fibrosis. The overall goal of the study is to define in the most informed manner possible cohorts of schistosomiasis-diseased children that present a differential fibrotic profile following an infection with S. mansoni and evaluate thereafter changes in their blood gene expression profiles that might associate with the observed differential fibroproliferative responses.

Host Organisation

Institution Country
University of Cape Town (UCT) South Africa

Participants

Name Institution Country
Justin Komguep Nono University of Cape Town South Africa

Study Design

Cross-sectional, observational, case-control study.

Sites

Bokito, Cameroon

Phd Study

Title University Start Date End Date
Immunomodulation through Excretory/Secretory Products of the parasitic Helminth Echinococcus multilocularis University of Wuerzburg, Germany 2009-01-15 2013-07-17

Students Supervised

Type Name Title University Start Date End Date
PhD Severin Donald Kamdem Mr University of Cape Town 2018 2020
MSc Erve Kuekom Mr Catholic University of Central Africa 2018 2020
MSc Josephine Ntankheuh Ms Catholic University of Central Africa 2018 2020
MSc Francis Konhawa Mr Catholic University of Central Africa 2018 2020
PhD Fungai Musaigwa Mr University of Cape Town 2019 2021
PhD Thabo Mpotje Mr University of Cape Town 2018 2021
MSc Elvis Leonel Kamguia Meyo Mr Protestant University of Central Africa 2020 2021

Publications

Sci Rep. 2020 Feb 17;10(1):2773. doi: 10.1038/s41598-020-59613-z
Front Immunol. 2019 Dec 3;10:2827.
Front Immunol. 2018 Nov 28;9:2781.
Front Immunol. 2018 Oct 9;9:2295.
Trends in Parasitology DOI:https://doi.org/10.1016/j.pt.2021.07.009

Current Organisation

University of Cape Town and Ministry of Scientific Research of Cameroon

Current Job Title

Senior Research Officer

Awards

2019 Flair Award of the UK Royal Society and the African Academy of Sciences

Students Supervised

Type Name Title University Start Date End Date
PharmD Marie laure Mefang Dr Universite des Montagnes, Cameroon 2017 2018
MSc Josephine Ntankheuh Ms Catholic University of Central Africa 2018 2020
MSc Francis Konhawa Mr Catholic University of Central Africa 2018 2020
MSc Thabo Mpotje Mr University of Cape Town, South Africa 2016 2017
PhD Paballo Mosala Ms University of Cape Town, South Africa 2017 2019
PhD Thabo Mpotje Mr University of Cape Town, South Africa 2018 2020
PhD Severin Donald Kamdem Mr University of Cape Town, South Africa 2018 2020
MSc Martial Kuekom Sielinou Mr Catholic University of Central Africa, Cameroon 2018 2019
PhD Fungai Musaigwa Mr University of Cape Town 2019 2021
MSc Elvis Kamguia Leonel Meyo Mr Protestant University of Central Africa 2020 2021

Memberships

Role Committee/board Start Date End Date
Member Animal Ethics Committee of the Faculty of Health Science of the University of Cape Town, South Africa 2017 2020
Research Working Group Co-Chair Global Schistosomiasis Alliance 2019 Ongoing
Member Executive Committee of the Division of Immunology of the University of Cape Town 2019 Ongoing

Education

Institution Degree Year
University of Wuerzburg, Germany PhD 2013-07-01
University of Yaounde 1, Cameroon MSc 2008-10-01

Areas Of Specialisation

Neglected Infectious Diseases (NID)

Grants

Grant Code:
CT/MER/17 & CT/MER/18
Source of funding:
Merck Master Service Agreement.
Amount:
200000
Role:
Researcher
Start Date:
2017-01-01
End Date:
2019-05-01
Grant Code:
2018-1DEV26-FBR01
Source of funding:
NHLS, South Africa
Amount:
6000
Role:
Researcher
Start Date:
2018-11-01
End Date:
2020-10-31
Grant Code:
CRP/CMR15-05
Source of funding:
ICGEB CRP Research Grant
Amount:
40000
Role:
Principal Investigator
Start Date:
2016-01-04
End Date:
2018-12-28
Grant Code:
PRF KOMGUEP 18/19
Source of funding:
Poliomyelitis Research Foundation Research Grant
Amount:
18750
Role:
Principal Investigator
Start Date:
2018-07-01
End Date:
2021-02-01
Grant Code:
FLR\R1\191058
Source of funding:
UK Royal Society (GCRF) and African Academy of Sciences (AAS)
Amount:
209970
Role:
Principal Investigator
Start Date:
2019-01-01
End Date:
2021-01-01
Grant Code:
TMA2016-CDF1571
Source of funding:
European and Developing Countries Clinical Trials Partnership (EDCTP)
Amount:
140000
Role:
Principal Investigator
Start Date:
2018-07-01
End Date:
2021-06-30
Grant Code:
DST UID 92627
Source of funding:
NRF & Nacosti (RSA-KENYA) Research Grant
Amount:
18750
Role:
Researcher
Start Date:
2017-01-01
End Date:
2018-06-30

Publications

Authors:
Date:
2020-05-08
Journal:
Frontiers in Immunology
Content:
Identifiers:
DOI: 10.3389/fimmu.2020.00798
Part of ISSN: 1664-3224
Authors:
Brombacher TM., Nono JK., De Gouveia K.S., Makena N., Darby M., J. Womersley, Tamgue O and Frank Brombacher
Date:
2017-04-01
Journal:
Journal of Immunology
Content:

The role of proinflammatory cytokines in cognitive function has been investigated with both beneficial and possible detrimental effects, depending on the cytokine. More recently, the type 2 IL-4 has been demonstrated to play a role in cognition. In this study, using the Morris water maze task, we demonstrate that IL-13–deficient mice are significantly impaired in working memory as well as attenuated reference memory, both functions essential for effective complex learning. During the learning process, wild-type mice increased the number of CD4+ T cells in the meninges and production of IL-13, whereas neither Morris water maze–trained IL-4 nor trained IL-13–deficient mice were able to increase CD4+ T cells in the meninges. Mechanistically, we showed that IL-13 is able to stimulate primary astrocytes to produce brain-derived neurotrophic factor, which does foster cognitive functions. Moreover, Morris water maze–trained wild-type mice were able to increase astrocyte-produced glial fibrillary acidic protein in the hippocampus, which was impaired in Morris water maze–trained IL-4– and IL-13–deficient mice. Collectively, this study strongly suggests that the Th2 cytokines, not only IL-4 but also IL-13, are involved in cognitive functions by stimulating astrocytes from the meninges and hippocampus. These results may be important for future development of therapeutic approaches associated with neurologic disorders such as Parkinson disease–associated dementia and HIV-associated dementia among others.

Identifiers:
Authors:
Date:
2018-12-12
Journal:
Mucosal immunology
Content:
Basic leucine zipper transcription factor 2 (Batf2) activation is detrimental in Type 1-controlled infectious diseases, demonstrated during infection with Mycobacterium tuberculosis (Mtb) and Listeria monocytogenes Lm. In Batf2-deficient mice (Batf2-/-), infected with Mtb or Lm, mice survived and displayed reduced tissue pathology compared to infected control mice. Indeed, pulmonary inflammatory macrophage recruitment, pro-inflammatory cytokines and immune effectors were also decreased during tuberculosis. This explains that batf2 mRNA predictive early biomarker found in active TB patients is increased in peripheral blood. Similarly, Lm infection in human macrophages and mouse spleen and liver also increased Batf2 expression. In striking contrast, Type 2-controlled schistosomiasis exacerbates during infected Batf2-/- mice with increased intestinal fibro-granulomatous inflammation, pro-fibrotic immune cells, and elevated cytokine production leading to wasting disease and early death. Together, these data strongly indicate that Batf2 differentially regulates Type 1 and Type 2 immunity in infectious diseases.
Identifiers:
Authors:
Date:
2018-10-31
Journal:
PLoS biology
Content:
Forkhead box P3 (Foxp3+) regulatory T (Treg)-cell function is controlled by environmental cues of which cytokine-mediated signaling is a dominant component. In vivo, interleukin-4 (IL-4)-mediated signaling via IL-4 receptor alpha (IL-4Rα) mediates Treg cell transdifferentiation into ex-Foxp3 T helper 2 (Th2) or T helper 17 (Th17) cells. However, IL-4-mediated signaling also reinforces the Foxp3 Treg compartment in vitro. We generated Foxp3-specific IL-4Rα-deficient mice and demonstrated differential efficiency of IL-4Rα deletion in male (approximately 90%) and female (approximately 40%) animals, because of cyclic recombinase (Cre)-mediated X-linked foxp3 inactivation. Irrespective of the degree of IL-4Rα deletion within the Foxp3+ Treg cell population, mice showed exacerbation of immune effector responses with aggravated tissue pathology in tissue-dwelling helminth infections (Schistosoma mansoni or Nippostrongylus brasiliensis). Mechanistically, IL-4Rα deletion in males and females led to a reduced expression of Foxp3 and subsequently an impaired accumulation of Foxp3+ Treg cells to inflamed tissues. In-depth cellular typing by flow cytometry revealed that the impairment of IL-4Rα-mediated signaling during helminth infections decreased the ability of central Treg cells to convert into effector Treg (eTreg) cells and caused a significant down-regulation of markers associated with Treg cell migration (C-X-C motif chemokine receptor 3 [CXCR3]) and accumulation in inflamed tissues (GATA binding protein 3 [GATA3]) as well as survival (B cell lymphoma 2 [Bcl-2]). These findings unprecedentedly, to our knowledge, uncover a role for IL-4Rα signaling in the positive regulation of Foxp3+ Treg cell function in vivo. Complementing our past knowledge on a widely reported role for IL-4Rα signaling in the negative regulation and transdifferentiation of Foxp3+ Treg cells in vivo, our present findings reveal the host requirement for an intact, but not reduced or potentiated, IL-4Rα-mediated signaling on Foxp3+ Treg cells to optimally control inflammation during helminth infections.
Identifiers:
Authors:
Reto Guler#, Thabo Mpotje#, Mumin Ozturk#, Nono JK#, Suraj P. Parihar#, Julius Ebua Chia, Nada Abdel Aziz, Lerato Hlaka, Santosh Kumar, Sugata Roy, Adam Penn-Nicholson, Willem A. Hanekom, Daniel E. Zak, Thomas J. Scriba, Harukazu Suzuki, Frank Brombacher , Mucosal Immunol. 2018 Dec 12. Doi: 10.1038/s41385-018-0108-2
Date:
2018-12-12
Journal:
Mucosal Immunology
Content:

Basic leucine zipper transcription factor 2 (Batf2) activation is detrimental in Type 1-controlled infectious diseases, demonstrated during infection with Mycobacterium tuberculosis (Mtb) and Listeria monocytogenes Lm. In Batf2-deficient mice (Batf2-/-), infected with Mtb or Lm, mice survived and displayed reduced tissue pathology compared to infected control mice. Indeed, pulmonary inflammatory macrophage recruitment, pro-inflammatory cytokines and immune effectors were also decreased during tuberculosis. This explains that batf2 mRNA predictive early biomarker found in active TB patients is increased in peripheral blood. Similarly, Lm infection in human macrophages and mouse spleen and liver also increased Batf2 expression. In striking contrast, Type 2-controlled schistosomiasis exacerbates during infected Batf2-/- mice with increased intestinal fibro-granulomatous inflammation, pro-fibrotic immune cells, and elevated cytokine production leading to wasting disease and early death. Together, these data strongly indicate that Batf2 differentially regulates Type 1 and Type 2 immunity in infectious diseases.

Identifiers:
Authors:
Nono JK , author
Pletinckx K , author
Lutz MB , author
Brehm K , author
Date:
2012-01-01
Journal:
PLoS neglected tropical diseases
Content:
Identifiers:
Authors:
Nono JK, Severin Donald Kamdem, Palmer Masumbe Netongo, Smritee Dabee, Michael Schomaker, Alim Oumarou, Frank Brombacher and Roger Moyou-Somo
Date:
2018-10-09
Journal:
Frontiers in Immunology
Content:

Close to 50 years after the discovery and establishment of praziquantel as an anti-parasitic drug to treat human schistosomiasis, the disease persists and is still a public health concern for hundreds of millions of individuals worldwide. Although the wide implementation of mass drug administration campaigns in endemic areas has considerably helped to reduce the prevalence and burden of the disease encouraging a change of narrative from infection control to elimination, the lack of regular monitoring studies in endemic areas has crippled the development of adequately tailored strategies to ensure the site-specific interruption of the disease transmission. Here, we screened 525 schoolchildren including the most affected age groups in two sites in rural Cameroon, a country of close to 20 million inhabitants with 2 million infected individuals and more than 5 million living in rural areas infested with S. mansoni and S. haematobium causing hepatointestinal and urogenital schistosomiasis, respectively. In the studied sites, praziquantel has been administered for the past decade once annually to schoolchildren via a well sustained national control program. We found that just 8 months following the last mass drug treatment, prevalence of infection persisted at alarming levels with older children being more at risk of infection, unveiling the inadequacy of limiting drug treatment to young schoolchildren rather than including the whole community with older individuals. Abnormalities of the urinary bladder were more severe when compared to liver lesions arguing for a more frequent regimen of drug administration on the S. haematobium site in particular. Females presented with a higher risk of infection in the S. mansoni site while contact with the surrounding river waters favored infection at both sites. Overall, a need for further education of the population on the debilitating risk of poor hygienic practices and contact with infested river was identified. Intriguingly, analyses on the S. mansoni site revealed a negative association of schistosomiasis on measles vaccine elicited-responses, further reinstating the morbid nature of schistosomiasis on our communities. Our survey, while appraising the extent of disease distribution and impact in two endemic areas also provides guidelines to ameliorate the fight against schistosomiasis, gearing towards more informed approaches for the elimination and not just the control of the disease.

Identifiers:
Authors:
Hlumani Ndlovu, Nono JK, Natalie Eva Nieuwenhuizen, Frank Brombacher , J Leukoc Biol. 2018 Nov 30. Doi: 10.1002/JLB.MA0318-115R.
Date:
2018-11-30
Journal:
Journal of Leukocyte Biology
Content:

Development of IL-4 receptor alpha (IL-4Rα)-dependent cellular immunity regulates host protection against acute schistosomiasis. In this study, we investigated the importance of IL-4Rα-expressing CD11c+ cells in driving the development of optimal cellular responses to Schistosoma mansoni infection by using CD11ccre IL-4Rα-/lox BALB/c mice, which lacked IL-4Rα expression on dendritic cells and alveolar macrophages. Abrogation of IL-4Rα expression on CD11c+ cells affected activation of CD4+ T cells, resulting in reduced numbers of effector CD4+ T cells and impaired production of Th1 and Th2 cytokines by CD4+ T cells ex vivo. However, secretion of both type 1 and type 2 Ab isotypes was unchanged in infected CD11c-specific IL-4Rα-deficient mice compared to littermate controls. Together, these data demonstrate that IL-4Rα-expressing CD11c+ cells play an important role in maintaining cellular immunity during schistosomiasis in mice.

Identifiers:
Authors:
Nono JK , author
Ndlovu H , author
Aziz NA , author
Mpotje T , author
Hlaka L , author
Brombacher F , author
Date:
2017-08-01
Journal:
PLoS neglected tropical diseases
Content:
Identifiers:
Authors:
Nono JK , author
Ndlovu H , author
Abdel Aziz N , author
Mpotje T , author
Hlaka L , author
Brombacher F , author
Date:
2017-06-01
Journal:
PLoS neglected tropical diseases
Content:
Identifiers:
Authors:
Vendelova E , author
Camargo de Lima J , author
Lorenzatto KR , author
Monteiro KM , author
Mueller T , author
Veepaschit J , author
Grimm C , author
Brehm K , author
Hrčková G , author
Lutz MB , author
Ferreira HB , author
Nono JK , author
Date:
2016-10-01
Journal:
PLoS neglected tropical diseases
Content:
Identifiers:
Authors:
Vendelova E , author
Hrčková G , author
Lutz MB , author
Brehm K , author
Nono JK , author
Date:
2016-07-01
Journal:
Parasite immunology
Content:
Identifiers:
Authors:
Vendelova E., Hrčková G., Lutz MB., Brehm K., Nono JK*
Date:
2016-07-01
Journal:
Parasite Immunology
Content:

Cestode-mediated diseases hold the interesting feature of persisting metacestode larvae dwelling within the host tissues, in the midst of the immune response. Excretory-secretory (ES) products of the metacestode larval stage modulate the host immune response and modify the outcome of the disease. Therefore, isolation and analysis of axenic metacestode ES products are crucial to study their properties. Here, we report the development of a system for long-term in vitro cultivation of the metacestode of the parasitic cestode Mesocestoides corti (syn. Mesocestoides vogae). Although feeder cells and host serum supported the early growth of the parasite, long-term survival was not dependent on host serum or host-derived factors enabling the collection of parasite released products in serum-free medium. Functionally, these axenic ES products recapitulated M. corti tetrathyridia's ability to inhibit LPS-driven IL-12p70 secretion by dendritic cells. Thus, our new axenic culture system will simplify the identification and characterization of M. corti-derived immunomodulatory factors that will indirectly enable the identification and characterization of corresponding factors in the metacestode larvae of medically relevant cestodes such as Echinococcus multilocularis that are not yet amenable to serum-free cultivation.

Identifiers:
Authors:
Nono JK, Hlumani Ndlovu, Nada Abdel Aziz, Thabo Mpotje, Lerato Hlaka, Frank Brombacher
Date:
2017-08-21
Journal:
Plos NTDs
Content:

Interleukin-4 receptor (IL-4Rα) is critical for the initiation of type-2 immune responses and implicated in the pathogenesis of experimental schistosomiasis. IL-4Rα mediated type-2 responses are critical for the control of pathology during acute schistosomiasis. However, type-2 responses tightly associate with fibrogranulomatous inflammation that drives host pathology during chronic schistosomiasis. To address such controversy on the role of IL-4Rα, we generated a novel inducible IL-4Rα-deficient mouse model that allows for temporal knockdown of il-4rα gene after oral administration of Tamoxifen. Interrupting IL-4Rα mediated signaling during the acute phase impaired the development of protective type-2 immune responses, leading to rapid weight loss and premature death, confirming a protective role of IL-4Rα during acute schistosomiasis. Conversely, IL-4Rα removal at the chronic phase of schistosomiasis ameliorated the pathological fibro-granulomatous pathology and reversed liver scarification without affecting the host fitness. This amelioration of the morbidity was accompanied by a reduced Th2 response and increased frequencies of FoxP3+ Tregs and CD1dhiCD5+ Bregs. Collectively, these data demonstrate that IL-4Rα mediated signaling has two opposing functions during experimental schistosomiasis depending on the stage of advancement of the disease and indicate that interrupting IL-4Rα mediated signaling is a viable therapeutic strategy to ameliorate liver fibroproliferative pathology in diseases like chronic schistosomiasis.

Identifiers:
Authors:
Severin Donald Kamdem, Roger Moyou-Somo , Brombacher F, Nono JK*. , Front. Immunol. | doi: 10.3389/fimmu.2018.02781
Date:
2018-11-12
Journal:
Frontiers in Immunology
Content:

Liver fibrosis is a wound-healing process purposely aimed at restoring organ integrity after severe injury caused by autoimmune reactions, mechanical stress or infections. The uncontrolled solicitation of this process is pathogenic and a pathognomonic feature of diseases like hepatosplenic schistosomiasis where exacerbated liver fibrosis is centrally positioned among the drivers of the disease morbidity and mortality. Intriguingly, however, liver fibrosis occurs and progresses dissimilarly in schistosomiasis-diseased individuals with the same egg burden and biosocial features including age, duration of residence in the endemic site and gender. This suggests that parasite-independent and currently poorly defined host intrinsic factors might play a defining role in the regulation of liver fibrosis, the hallmark of morbidity, during schistosomiasis. In this review, we therefore provide a comprehensive overview of all known host candidate regulators of liver fibrosis reported in the context of human schistosomiasis.

Identifiers:
Authors:
Hlumani Ndlovu, Nono JK, Abdel Aziz N, Natalie Eva Nieuwenhuizen, Frank Brombacher , Front Immunol. 2018 Dec 18;9:2928. Doi: 10.3389/fimmu.2018.02928.
Date:
2018-12-18
Journal:
Frontiers in Immunology
Content:

Schistosomiasis (bilharzia) is a parasitic helminth disease that can cause severe inflammatory pathology leading to organ damage in humans. Failure of the host to regulate egg-driven granulomatous inflammation causes host morbidity during chronic infection with Schistosoma mansoni. Although the importance of B cells in regulating pathology during chronic infection has been well defined, the specific contribution of IL-4Rα-expressing B cells is still unknown. To address this, we examined B cell-specific IL-4Rα-deficient (mb1creIL-4Rα-/lox) mice in three experimental models of schistosomiasis: high-dose (100 cercariae), low dose (30 cercariae), and a synchronous egg challenge. In the high dose model, we found that mice deficient in IL-4Rα-expressing B cells were more susceptible to acute schistosomiasis than B cell-deficient (μMT) mice, succumbing to infection at the acute stage whereas μMT mice survived until the chronic stage. An S. mansoni egg challenge model demonstrated that deleting IL-4Rα expression specifically on B cells resulted in increased lung granulomatous pathology, suggesting a role for this B cell subset in controlling granulomatous pathology. In agreement with this, a low dose model of schistosomiasis-which mimics the course of clinical chronic disease-demonstrated that depleting IL-4Rα-expressing B cells in mb1creIL-4Rα-/lox mice considerably impaired the host ability to down-modulate granulomatous inflammation in the liver and gut during chronic schistosomiasis. Taken together, our findings indicate that within the B cell compartment, IL-4Rα-expressing B cells in particular down-modulate the deleterious egg-driven tissue granulomatous inflammation to enable host survival during schistosomiasis in mice.

Identifiers:
Authors:
Nono JK., Lutz MB, Brehm K.
Date:
2014-01-02
Journal:
Plos NTDs
Content:

BACKGROUND:

Alveolar echinococcosis (AE), caused by the metacestode of the tapeworm Echinococcus multilocularis, is a lethal zoonosis associated with host immunomodulation. T helper cells are instrumental to control the disease in the host. Whereas Th1 cells can restrict parasite proliferation, Th2 immune responses are associated with parasite proliferation. Although the early phase of host colonization by E. multilocularis is dominated by a potentially parasitocidal Th1 immune response, the molecular basis of this response is unknown.

PRINCIPAL FINDINGS:

We describe EmTIP, an E. multilocularis homologue of the human T-cell immunomodulatory protein, TIP. By immunohistochemistry we show EmTIP localization to the intercellular space within parasite larvae. Immunoprecipitation and Western blot experiments revealed the presence of EmTIP in the excretory/secretory (E/S) products of parasite primary cell cultures, representing the early developing metacestode, but not in those of mature metacestode vesicles. Using an in vitro T-cell stimulation assay, we found that primary cell E/S products promoted interferon (IFN)-γ release by murine CD4+ T-cells, whereas metacestode E/S products did not. IFN-γ release by T-cells exposed to parasite products was abrogated by an anti-EmTIP antibody. When recombinantly expressed, EmTIP promoted IFN-γ release by CD4+ T-cells in vitro. After incubation with anti-EmTIP antibody, primary cells showed an impaired ability to proliferate and to form metacestode vesicles in vitro.

CONCLUSIONS:

We provide for the first time a possible explanation for the early Th1 response observed during E. multilocularis infections. Our data indicate that parasite primary cells release a T-cell immunomodulatory protein, EmTIP, capable of promoting IFN-γ release by CD4+ T-cells, which is probably driving or supporting the onset of the early Th1 response during AE. The impairment of primary cell proliferation and the inhibition of metacestode vesicle formation by anti-EmTIP antibodies suggest that this factor fulfills an important role in early E. multilocularis development within the intermediate host.

Identifiers:
Authors:
Hurdayal R , author
Ndlovu HH , author
Revaz-Breton M , author
Parihar SP , author
Nono JK , author
Govender M , author
Brombacher F , author
Date:
2017-10-01
Journal:
Proceedings of the National Academy of Sciences of the United States of America
Content:
Identifiers:
Authors:
Frank Brombacher
Date:
2021-08-10
Journal:
Trends in Parasitology
Content:

Schistosomiasis is a debilitating helminthiasis which commonly establishes as a chronic infection in people from endemic areas. As a potent modulator of the host immune response, the Schistosoma parasite and its associated products can directly interfere with its host’s ability to mount adequate immune responses to unrelated antigens. As a result, increased attention is gathering on studies assessing the influence of helminths, particularly the causal agent of schistosomiasis, on host responsiveness to vaccines. However, to date, no consensus has been drawn regarding the influence of schistosomiasis on host vaccine responses. Here, we review available evidence on the influence of transgenerational and direct Schistosoma parasite exposure on host immune responses to unrelated vaccines. In addition, we evaluate the potential of praziquantel (PZQ) treatment in restoring schistosomiasis-impacted vaccine responses.

Identifiers:
DOI:HTTPS://DOI.ORG/10.1016/J.PT.2021.07.009: not informed
Authors:
Date:
2018-11-30
Journal:
Journal of leukocyte biology
Content:
Development of IL-4 receptor alpha (IL-4Rα)-dependent cellular immunity regulates host protection against acute schistosomiasis. In this study, we investigated the importance of IL-4Rα-expressing CD11c+ cells in driving the development of optimal cellular responses to Schistosoma mansoni infection by using CD11ccre IL-4Rα-/lox BALB/c mice, which lacked IL-4Rα expression on dendritic cells and alveolar macrophages. Abrogation of IL-4Rα expression on CD11c+ cells affected activation of CD4+ T cells, resulting in reduced numbers of effector CD4+ T cells and impaired production of Th1 and Th2 cytokines by CD4+ T cells ex vivo. However, secretion of both type 1 and type 2 Ab isotypes was unchanged in infected CD11c-specific IL-4Rα-deficient mice compared to littermate controls. Together, these data demonstrate that IL-4Rα-expressing CD11c+ cells play an important role in maintaining cellular immunity during schistosomiasis in mice.
Identifiers:
Authors:
Nada Abdel Aziz; Justin Nono Komguep; Thabo Rantanta Mpotje; Frank Brombacher , PLoS Biol. 2018 Oct 31;16(10):e2005850. doi: 10.1371/journal.pbio.2005850
Date:
2018-10-31
Journal:
Plos Biology
Content:

Forkhead box P3 (Foxp3+) regulatory T (Treg)-cell function is controlled by environmental cues of which cytokine-mediated signaling is a dominant component. In vivo, interleukin-4 (IL-4)-mediated signaling via IL-4 receptor alpha (IL-4Rα) mediates Treg cell transdifferentiation into ex-Foxp3 T helper 2 (Th2) or T helper 17 (Th17) cells. However, IL-4-mediated signaling also reinforces the Foxp3 Treg compartment in vitro. We generated Foxp3-specific IL-4Rα-deficient mice and demonstrated differential efficiency of IL-4Rα deletion in male (approximately 90%) and female (approximately 40%) animals, because of cyclic recombinase (Cre)-mediated X-linked foxp3 inactivation. Irrespective of the degree of IL-4Rα deletion within the Foxp3+ Treg cell population, mice showed exacerbation of immune effector responses with aggravated tissue pathology in tissue-dwelling helminth infections (Schistosoma mansoni or Nippostrongylus brasiliensis). Mechanistically, IL-4Rα deletion in males and females led to a reduced expression of Foxp3 and subsequently an impaired accumulation of Foxp3+ Treg cells to inflamed tissues. In-depth cellular typing by flow cytometry revealed that the impairment of IL-4Rα-mediated signaling during helminth infections decreased the ability of central Treg cells to convert into effector Treg (eTreg) cells and caused a significant down-regulation of markers associated with Treg cell migration (C-X-C motif chemokine receptor 3 [CXCR3]) and accumulation in inflamed tissues (GATA binding protein 3 [GATA3]) as well as survival (B cell lymphoma 2 [Bcl-2]). These findings unprecedentedly, to our knowledge, uncover a role for IL-4Rα signaling in the positive regulation of Foxp3+ Treg cell function in vivo. Complementing our past knowledge on a widely reported role for IL-4Rα signaling in the negative regulation and transdifferentiation of Foxp3+ Treg cells in vivo, our present findings reveal the host requirement for an intact, but not reduced or potentiated, IL-4Rα-mediated signaling on Foxp3+Treg cells to optimally control inflammation during helminth infections.

Identifiers:
Authors:
Date:
2018-12-18
Journal:
Frontiers in immunology
Content:
Schistosomiasis (bilharzia) is a parasitic helminth disease that can cause severe inflammatory pathology leading to organ damage in humans. Failure of the host to regulate egg-driven granulomatous inflammation causes host morbidity during chronic infection with Schistosoma mansoni. Although the importance of B cells in regulating pathology during chronic infection has been well defined, the specific contribution of IL-4Rα-expressing B cells is still unknown. To address this, we examined B cell-specific IL-4Rα-deficient (mb1creIL-4Rα-/lox) mice in three experimental models of schistosomiasis: high-dose (100 cercariae), low dose (30 cercariae), and a synchronous egg challenge. In the high dose model, we found that mice deficient in IL-4Rα-expressing B cells were more susceptible to acute schistosomiasis than B cell-deficient (μMT) mice, succumbing to infection at the acute stage whereas μMT mice survived until the chronic stage. An S. mansoni egg challenge model demonstrated that deleting IL-4Rα expression specifically on B cells resulted in increased lung granulomatous pathology, suggesting a role for this B cell subset in controlling granulomatous pathology. In agreement with this, a low dose model of schistosomiasis-which mimics the course of clinical chronic disease-demonstrated that depleting IL-4Rα-expressing B cells in mb1creIL-4Rα-/lox mice considerably impaired the host ability to down-modulate granulomatous inflammation in the liver and gut during chronic schistosomiasis. Taken together, our findings indicate that within the B cell compartment, IL-4Rα-expressing B cells in particular down-modulate the deleterious egg-driven tissue granulomatous inflammation to enable host survival during schistosomiasis in mice.
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Authors:
Date:
2018-10-09
Journal:
Frontiers in immunology
Content:
Background and Methods: Schistosomiasis is debilitating and reported to impair immune responsiveness of infected hosts. In Cameroon, mass drug administration (MDA) is used in schoolchildren to reduce transmission of S. haematobium and S. mansoni. The effects of MDA and the impact of schistosomiasis on the titers of antibodies in vaccinated children have been poorly studied. We therefore assessed the prevalence of schistosomiasis in schoolchildren, eight months after MDA, in two locations: Barombi Koto (BK), endemic for S. haematobium (N = 169) and Yoro (Y), endemic for S. mansoni (N = 356). Age, gender, residence time and frequency of contact with river water were assessed as risk factors for infection and morbidity in both localities. In 70 schoolchildren from BK and 83 from Y, ultrasound was used to assess morbidity according to the WHO guidelines. Evaluation of measles antibodies was performed in previously vaccinated schoolchildren (14 with S. haematobium and 12 egg-negative controls from BK and 47 with S. mansoni and12 egg-negative controls from Y). Principal Findings and conclusions: The prevalence of S. haematobium was 25. 4% in BK (43/169) and 34.8% for S. mansoni in Y (124/356), indicating the persistent transmission of schistosomiasis despite MDA. Older age (AOR 1.31; 95%CI 1.12-1.54) and higher frequencies of exposure to river water (AOR 1.99; 95%CI 1.03-3.86) were identified as risks for infection in BK whereas only older age (OR 1.15; 95%CI 1.04-1.27) was a risk for infection in Y. Bladder pathology (score 2 to 5) was observed in 29.2% (7/24) of egg-positive children in BK and liver pathology (pattern C) in 31.1% (19/61) of egg-positive children in Y. There was a positive correlation between S. haematobium egg burden and bladder pathology (AOR 1.01; 95% CI 0.99-1.02) and positive correlation between S. mansoni-driven liver pathology and female gender (AOR 3.01; 95% CI 0.88-10.26). Anti-measles antibodies in vaccinated children were significantly lower in S. mansoni-infected when compared to egg-negative controls (p = 0.001), which was not observed in the S. haematobium-infected group from BK. Our results demonstrate a questionable efficacy of MDA alone in halting schistosomiasis transmission and confirm a possible immunomodulatory effect of S. mansoni on response to vaccines.
Identifiers:
Authors:
Kamdem SD, Kuemkon EM, Meyo Kamguia L, Tchanana GK, Konhawa F, Nche F, Oumarou A, Hamza M, Ghislain Essomba R, Kengne M, Netongo PM, Ondigui BE, Okomo Assoumou MC, Brombacher F, Nono JK , Scientific Reports volume 10, Article number: 2773 (2020)
Date:
2020-02-17
Journal:
Scientific Reports
Content:

The grading system for ultrasonographic assessment of Schistosoma mansoni morbidity is crucial for evaluation of control programs. This requires prior definition of normal liver organometric ranges in the population from the endemic area. A cross-sectional study was conducted in a S. mansoni endemic area in rural Cameroon. 1002 Participants were screened and 234 of them, free from all common liver-affecting diseases in the area (schistosomiasis, malaria, hepatitis B and C) and with no ultrasonographic signs of liver disease were selected and their liver parameters measured by ultrasonography. All statistics were considered significant for p-values < 0.05. Normal dimensions of livers lobe sizes, portal vein wall thickness and portal vein diameters are reported. The liver organometric data are presented for the entire study population as a whole and separately for males and females as prediction plots, with observed values and fitted regression line with 95% confidence. Reference ranges for liver parameters (size, portal vein thickness and diameter) adjusted for body height established in the current study are novel for Cameroon. The prediction plots generated should improve the accuracy of the assessment of liver morbidity by ultrasonography in the region.

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Authors:
Nono JK., Pletinckx K, Lutz MB, Brehm K.
Date:
2012-02-21
Journal:
Plos NTDs
Content:

BACKGROUND:

Alveolar echinococcosis, caused by Echinococcus multilocularis larvae, is a chronic disease associated with considerable modulation of the host immune response. Dendritic cells (DC) are key effectors in shaping the immune response and among the first cells encountered by the parasite during an infection. Although it is assumed that E.multilocularis, by excretory/secretory (E/S)-products, specifically affects DC to deviate immune responses, little information is available on the molecular nature of respective E/S-products and their mode of action.

METHODOLOGY/PRINCIPAL FINDINGS:

We established cultivation systems for exposing DC to live material from early (oncosphere), chronic (metacestode) and late (protoscolex) infectious stages. When co-incubated with Echinococcus primary cells, representing the invading oncosphere, or metacestode vesicles, a significant proportion of DC underwent apoptosis and the surviving DC failed to mature. In contrast, DC exposed to protoscoleces upregulated maturation markers and did not undergo apoptosis. After pre-incubation with primary cells and metacestode vesicles, DC showed a strongly impaired ability to be activated by the TLR ligand LPS, which was not observed in DC pre-treated with protoscolex E/S-products. While none of the larvae induced the secretion of pro-inflammatory IL-12p70, the production of immunosuppressive IL-10 was elevated in response to primary cell E/S-products. Finally, upon incubation with DC and naïve T-cells, E/S-products from metacestode vesicles led to a significant expansion of Foxp3+ T cells in vitro.

CONCLUSIONS:

This is the first report on the induction of apoptosis in DC by cestode E/S-products. Our data indicate that the early infective stage of E. multilocularis is a strong inducer of tolerance in DC, which is most probably important for generating an immunosuppressive environment at an infection phase in which the parasite is highly vulnerable to host attacks. The induction of CD4+CD25+Foxp3+ T cells through metacestode E/S-products suggests that these cells fulfill an important role for parasite persistence during chronic echinococcosis.

Identifiers:
Authors:
Justin Komguep Nono, Hlumani Ndlovu, Nada Abdel Aziz, Thabo Mpotje, Lerato Hlaka, Frank Brombacher
Date:
2017-06-26
Journal:
Plos NTDs
Content:

There is currently no vaccine against parasitic nematodes and the knowledge on the mechanisms by which protective immunity against this class of parasites is achieved is continuously expanding. Nematode parasites trigger a host protective type 2 immune response via interleukin-4 receptor alpha (IL-4Rα). Despite this central role, it is not known whether IL-4Rα has a role in maintaining host type 2 immune responses following polarization. To determine the role of IL-4Rα after polarization, we used a recently established strain of rosaCreERT2-/+IL-4Rα-/Lox mice where il4rα gene deletion can be temporally controlled. We show that sustained expression of IL-4Rα is required for the maintenance of type 2 immune responses and protective immunity following interruption after polarization with Nippostrongylus brasiliensis primary infection. Moreover, we show by temporal deletion of IL-4Rα prior to secondary infection with Nbrasiliensis that signaling via this receptor drives more efficient recall of type 2 immune responses and clearance of the parasites. Together, this study demonstrates that sustained IL-4Rα mediated signaling is required for the maintenance of anti-nematode type 2 immune responses, describing a novel function for IL-4Rα that is distinct from its role in immune polarization.

Identifiers:
Authors:
Brombacher TM , author
Nono JK , author
De Gouveia KS , author
Makena N , author
Darby M , author
Womersley J , author
Tamgue O , author
Brombacher F , author
Date:
2017-04-01
Journal:
Journal of immunology (Baltimore, Md. : 1950)
Content:
Identifiers:
Authors:
Kamdem SD, Konhawa F, Kuemkon EM, Meyo Kamguia L, Tchanana GK, Nche F, Oumarou A, Hamza M, Ouratou Y, Tcheutchoua MN, Ghislain Essomba R, Ngogang MP, Kengne M, Netongo PM, Ondigui BE, Okomo Assoumou MC, Brombacher F, Nono JK , Front Immunol. 2019 Dec 3;10:2827. doi: 10.3389/fimmu.2019.02827
Date:
2019-12-03
Journal:
Frontiers in Immunology
Content:

Background: This study aimed to investigate the association of plasma levels of IL-33, a mucosal alarmin known to elicit type-2 immunity, with infection and liver fibrosis profiles of school children from an endemic area for Schistosoma mansoni, malaria and hepatitis (B & C) in rural Cameroon. Methods: A cross-sectional study enrolling schoolchildren from 5 public schools was conducted. Single schistosomiasis, malaria and hepatitis infections or co-infections were assessed by kato katz, microscopy, and rapid diagnostic tests, respectively. Hepatic fibrosis was assessed by ultrasound according to WHO Niamey guidelines and plasma levels of Interleukin 33 were determined by ELISA. All statistics were performed using R studio software. Principal findings: We found a prevalence of 13.5% (37/275), 18.2% (50/275), and 8% (22/275), respectively for schistosomiasis, malaria and hepatitis (B or C) single infections. Only 7.6% (21/275) of co-infections were reported. Although Plasma IL-33 showed a minimal negative risk for schistosomiasis infection (AOR 0.99; 95% CI 0.97-1.01), S. mansoni infected participants had lower levels of plasma IL-33 (p = 0.003) which decreased significantly as eggs burdens increased (p = 0.01) with a negative Pearson coefficient of r = -0.22. Hepatic fibrosis occurred in 47.3% (130/275) of our study population independently from plasma levels of IL-33 (AOR 1.00; 95% CI 0.99-1.01). Conclusion/Significance: Our data failed to show an association between plasma IL-33 levels and liver disease but convincingly report on a negative association between plasma IL-33 levels and schistosomiasis infection and egg burden in school children from a polyparasitic schistosomiasis endemic area.

Identifiers:
Authors:
Hurdayal R, Ndlovu HH, Revaz-Breton M, Parihar SP, Nono JK, Govender M, and Frank Brombacher
Date:
2017-09-15
Journal:
PNAS
Content:

Interleukin-4 (IL-4)-induced T helper (Th) 2 cells promote susceptibility to the protozoan parasite Leishmania major, while conferring immunity to the intestinal trematode Schistosoma mansoni Here, we report that abrogation of IL-4 receptor alpha (IL-4Rα) signaling on B cells in BALB/c mice (mb1creIL-4Rα-/lox) transformed nonhealer BALB/c to a healer phenotype with an early type 1 and dramatically reduced type 2immune response and an absence of ulceration and necrosis during cutaneous leishmaniasis. From adoptive reconstitution and mixed bone-marrow chimera studies in B cell-deficient (µMT) mice, we reveal a central role for B cell-derived IL-4 and IL-4Rα in the optimal induction of the susceptible type 2 phenotype to L. major infection. We further demonstrate that the absence of IL-4Rα signaling on B cells exacerbated S. mansoni-induced mortality and pathology in BALB/c mice, due to a diminished type 2 immune response. In both disease models, IL-4Rα-responsive B cells displayed increased IL-4 production as early as day 1 after infection. Together, these results demonstrate that IL-4-producing and IL-4Rα-responsive B cells are critical in regulating and assisting early T helper dichotomy toward Th2 responses, which are detrimental in cutaneous leishmaniasis but beneficial in acute schistosomiasis.

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Date:
2019-04-24
Journal:
Content:
ABSTRACTBackgroundAlveolar echinococcosis (AE), caused by the metacestode larval stage of the fox-tapeworm Echinococcus multilocularis, is a chronic zoonosis associated with significant modulation of the host immune response. A role of regulatory T-cells (Treg) in generating an immunosuppressive environment around the metacestode during chronic disease has been reported, but the molecular mechanisms of Treg induction by E. multilocularis remain elusive so far.Methodology/Principal findingsWe herein demonstrate that excretory/secretory (E/S) products of the E. multilocularis metacestode promote the formation of Foxp3+ Treg from CD4+ T-cells in vitro in a TGF-β-dependent manner. We also show that host T-cells secrete elevated levels of the immunosuppressive cytokine IL-10 in response to metacestode E/S products. Within the E/S fraction of the metacestode we identified an E. multilocularis activin A homolog (EmACT) that displays significant similarities to mammalian Transforming Growth Factor-β (TGF-β)/activin subfamily members. EmACT obtained from heterologous expression promoted host TGF-β-driven CD4+ Foxp3+ Treg conversion in vitro. Furthermore, like in the case of metacestode E/S products, EmACT-treated CD4+ T-cells secreted higher levels of IL-10. These observations suggest a contribution of EmACT in the in vitro expansion of Foxp3+ Treg by the E. multilocularis metacestode. Using infection experiments we show that intraperitoneally injected metacestode tissue expands host Foxp3+ Treg, confirming the expansion of this cell type in vivo during parasite establishment.Conclusions/SignificanceIn conclusion, we herein show that E. multilocularis larvae secrete a factor with clear structural and functional homologies to mammalian activin A. Like its mammalian homolog, this protein induces the secretion of IL-10 by T-cells and contributes to the expansion of TGF-β-driven Foxp3+ Treg, a cell type that has been reported crucial for generating a tolerogenic environment to support parasite establishment and proliferation.AUTHOR SUMMARYThe metacestode larval stage of the tapeworm E. multilocularis grows infiltratively, like a malignant tumor, within the organs of its human host, thus causing the lethal disease alveolar echinococcosis (AE). Immunosuppression plays an important role in both survival and proliferation of the metacestode, which mainly depends on factors that are released by the parasite. These parasite-derived molecules are potential targets for developing new anti-echinococcosis drugs and/or improving the effectiveness of current therapies. Additionally, an optimized use of such factors could help minimize pathologies resulting from over-reactive immune responses, like allergies and autoimmune diseases. The authors herein demonstrate that the E. multilocularis metacestode releases a protein, EmACT, with significant homology to activin A, a cytokine that might support host TGF-β in its ability to induce the generation of immunosuppressive regulatory T-cells (Treg) in mammals. Like its mammalian counterpart, EmACT was associated with the expansion of TGF-β-induced Treg and stimulated the release of elevated amounts of immunosuppressive IL-10 by CD4+ T-cells. The authors also demonstrate that Treg are locally expanded by the metacestode during an infection of mice. These data confirm an important role of Treg for parasite establishment and growth during AE and suggest a potential role of EmACT in the expansion of these immunosuppressive cells around the parasite.
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Authors:
Date:
2018-11-28
Journal:
Frontiers in immunology
Content:
Liver fibrosis is a wound-healing process purposely aimed at restoring organ integrity after severe injury caused by autoimmune reactions, mechanical stress or infections. The uncontrolled solicitation of this process is pathogenic and a pathognomonic feature of diseases like hepatosplenic schistosomiasis where exacerbated liver fibrosis is centrally positioned among the drivers of the disease morbidity and mortality. Intriguingly, however, liver fibrosis occurs and progresses dissimilarly in schistosomiasis-diseased individuals with the same egg burden and biosocial features including age, duration of residence in the endemic site and gender. This suggests that parasite-independent and currently poorly defined host intrinsic factors might play a defining role in the regulation of liver fibrosis, the hallmark of morbidity, during schistosomiasis. In this review, we therefore provide a comprehensive overview of all known host candidate regulators of liver fibrosis reported in the context of human schistosomiasis.
Identifiers:
Authors:
Emilia Vendelova, Jeferson Camargo de Lima , Karina Rodrigues Lorenzatto, Karina Mariante Monteiro , Thomas Mueller, Jyotishman Veepaschit, Clemens Grimm, Klaus Brehm, Gabriela Hrčková, Manfred B. Lutz, Henrique B. Ferreira*, Nono JK
Date:
2016-10-13
Journal:
Plos NTDs
Content:

Accumulating evidences have assigned a central role to parasite-derived proteins in immunomodulation. Here, we report on the proteomicidentification and characterization of immunomodulatory excretory-secretory (ES) products from the metacestode larva (tetrathyridium) of the tapeworm Mesocestoides corti (syn. M. vogae). We demonstrate that ES products but not larval homogenates inhibit the stimuli-driven release of the pro-inflammatory, Th1-inducing cytokine IL-12p70 by murine bone marrow-derived dendritic cells (BMDCs). Within the ES fraction, we biochemically narrowed down the immunosuppressive activity to glycoproteins since active components were lipid-free, but sensitive to heat- and carbohydrate-treatment. Finally, using bioassay-guided chromatographic analyses assisted by comparative proteomics of active and inactive fractions of the ES products, we defined a comprehensive list of candidate proteins released by M. corti tetrathyridia as potential suppressors of DC functions. Our study provides a comprehensive library of somatic and ES products and highlight some candidate parasite factors that might drive the subversion of DC functions to facilitate the persistence of M. corti tetrathyridia in their hosts.

Identifiers:
Authors:
Nono JK , author
Lutz MB , author
Brehm K , author
Date:
2014-01-01
Journal:
PLoS neglected tropical diseases
Content:
Identifiers:

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