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RESEARCH

Immunology

The Immunology Unit researches the human host immune response to infectious diseases of high prevalence in Cambodia. Our mission is to provide insight into both the innate and adaptive immune response to various viral infections for novel vaccine and therapeutics design. We aim to improve vaccination strategies for vaccine-preventable diseases and identify novel biomarkers of severity or treatment response.

RESEARCH

Immunology

The Immunology Unit researches the human host immune response to infectious diseases of high prevalence in Cambodia. Our mission is to provide insight into both the innate and adaptive immune response to various viral infections for novel vaccine and therapeutics design. We aim to improve vaccination strategies for vaccine-preventable diseases and identify novel biomarkers of severity or treatment response.

Main Projects

Understanding protective immune mechanisms in asymptomatic dengue-infected individuals

Dengue is caused by dengue virus (DENV), a virus which can be transmitted by Aedes mosquitos. Vaccine development for the prevention of dengue infection is challenging because there are 4 different serotypes of dengue and an individual can be infected consecutively with different serotypes. Clinical outcome after infection range from asymptomatic infection to life threatening dengue shock syndrome. The immunopathology of the disease remains largely unknown and there are no biomarkers that can either predict severe outcome after infection or immunoprotection after natural infection or vaccination. We employ single cell technologies and cell based assays to unravel both the innate and adaptive immune response after secondary dengue infection in a unique cohort of acute, asymptomatic dengue infected individuals and hospitalized cases. The proposed work will provide ground-breaking insights into host protective mechanisms during dengue virus infection. The results will establish a foundation for the development of new vaccination strategies and will identify novel correlates of protection to be used in vaccine efficacy studies.

Immunopathology of chronic chikungunya infection

Chikungunya virus (CHIKV) is a reemerging human arbovirus that has seen a rapid global spread in the two past decades. Infection typically involves two phases, with an acute phase where patients develop fever and arthralgia. In 20-40% of the cases, arthralgia is persistent and evolves in a chronic disease. The drivers of chronicity are unknown. In addition, a new CHIKV genotype has been circulating in Cambodia in 2020 with unknown clinical outcome. Therefore, we aim to evaluate clinical outcome in children, adults and pregnant woman infected with the new CHIKV strain. We will perform a detailed immunoprofiling of CHIKV infection in the acute phase of disease, including scRNAseq, multi-parameter flow cytometry, antibody effector functions and type I IFN assessment. This will help us to understand the immunological responses during the acute phase of disease that could lead to chronic pathology after CHIKV infection and to identify a possible novel biomarker for future case management.

Investigation of skin immunity to Aedes mosquito saliva

Both chikungunya and dengue virus are transmitted by Aedes mosquitos. In addition to factors to facilitate a bloodmeal, mosquito saliva also contains proteins that modulate both innate and adaptive immune responses. Little is known about skin immunity to mosquito saliva, particularly in endemic volunteers. Hence, characterization of the immune responses to vector saliva and arboviral pathogens will be important in order to identify critical aspects of the innate and adaptive immune responses after an infected vector bite. In this proposal, we will focus on the interplay between dengue and chikungunya virus, arboviruses highly endemic in Cambodia, its vectors Aedes Aegypti and Aedes Albopictus, and the human skin immune environment. This work can lead to the development of alternative vaccine strategies based on the interaction between host, virus and vector.

Immune responses in HIV/TB infected patients

Tuberculosis (TB) is one of the most common opportunistic infections among HIV-infected patients especially in resource-limited countries such as Cambodia. The diagnosis of pulmonary TB currently relies on sputum smears microscopy, which has poor sensitivity. Additional tools are urgently needed not only to help diagnose TB but also to assess the response to TB treatment. In a previous study, we found that IL-1Ra plasma concentrations dropped dramatically after two months of TB treatment. The objective of this proof-of-concept study is to demonstrate that IL-1Ra concentrations significantly decrease earlier within two weeks following TB treatment initiation in adults with documented TB. Two other biomarkers IP-10 and sCD163 will also be evaluated in this study. We demonstrated in previous study that the degranulation capacity of NK cell plays a role in the pathogenesis of immune reconstitution inflammatory syndrome (IRIS) in tuberculosis and HIV co-infection. The prevention of IRIS is the main challenge of early antiretroviral therapy. However, up to today no laboratory test can be used to diagnose and/or predict the occurrence of IRIS. This study aims to validate blood based microRNA detection by flow cytometry as laboratory tool for prediction and/or prognosis of the clinical outcome of tuberculosis in HIV infected patients and to elucidate the fundamental mechanism of IRIS. 

 

 

Analysis of adaptive immune responses to SARS-CoV-2

The duration of immunity of SARS-CoV-2 will dictate the course of the COVID-19 pandemic and the post-pandemic dynamics. Hence, understanding factors influencing the kinetics and the quality of the memory immune response in different populations is crucial. Therefore, we are following a cohort of Cambodian laboratory-confirmed COVID-19 patients over time to evaluate the emergence and persistence of the memory immune response. T cell response to various SARS-CoV-2 proteins are evaluated, and Spike-specific memory B cells are quantified and their BCR is sequenced. We are evaluating the humoral immune response in depth, by analyzing cross-reacitivty between SARS-CoV-2 and other coronaviruses and by evaluating antibody-effector functions trough cell based assays. 

 

 

Consortia and Platforms:

Pasteur International Center for Research on Emerging Infectious Diseases (PICREID): 

We participate in the NIH-funded CREID network with studies focused on understanding the host adaptive immune response to emerging infectious diseases in South-East Asia with a particular focus on arboviruses. With a cluster investigation approach, we are identifying a set of Cambodian childeren that are undergoing acute arbovirus infection but are completely healthy before and during a 10-day follow up period. In addition, we are collecting well characterized patient samples from major pediatric hospitals in Kampong Thom Province. This longitudinal patient cohort provides us with a unique opportunity to study the immune responses initiated after arbovirus infection that provide protection from disease, but clear the virus.

 

Single Cell analysis Platform:

The laboratory is equipped with a new installed Biosafety level 2+ laboratory dedicated to work with human infectious samples. A BD FACSAriaTM Fusion cell sorter (4 laser, 18 color) has been installed in 2020. Moreover, the lab is equipped with a 10x Chromium Controller to perform scRNAseq experiments, and we have the capacity to produce monoclonal antibodies derived from plasmablasts/memory B cells of virus-infected patients. 

Recent Publications

Editorial: Balanced and Unbalanced Immune Response to Dengue Virus in Disease Protection and Pathogenesis

Tineke Cantaert, Nolwenn Jouvenet, Sean A. Diehl.

Frontiers in Immunology. DOI: 10.3389/fimmu.2022.835731

 

Robust and Functional Immune Memory Up to 9 Months After SARS-CoV-2 Infection: A Southeast Asian Longitudinal Cohort

Hoa Thi My Vo, Alvino Maestri, Heidi Auerswald, Sopheak Sorn, Sokchea Lay, Heng Seng, Sotheary Sann, Nisa Ya, Polidy Pean, Philippe Dussart, Olivier Schwartz, Sovann Ly, Timothée Bruel, Sowath Ly, Veasna Duong, Erik A. Karlsson, Tineke Cantaert.

Frontiers in Immunology. DOI: 10.3389/fimmu.2022.817905

Previous Publications

Antibody fucosylation predicts disease severity in secondary dengue infection

Stylianos Bournazos, Hoa Thi My VoVeasna DuongHeidi AuerswaldSowath Ly, Anavaj Sakuntabhai, Philippe DussartTineke Cantaert**, Jeffrey V. Ravetch**

Science. American Association for the Advancement of Science; 2021;372(6546):11025. DOI: 10.1126/science.abc7303

 

Antibody-independent functions of B cells during viral infections

Vinit Upasani, Izabela Rodenhuis-Zybert, Tineke Cantaert.

PLoS Pathog. 2021;17(7):e1009708. DOI: 10.1371/journal.ppat.1009708

 

Differential levels of IFNα subtypes in autoimmunity and viral infection

Vincent Bondet, Mathieu P. Rodero, Céline Posseme, Pierre Bost, Jérémie Decalf, Liis Haljasmägi, Nassima Bekaddour, Gillian I. Rice, Vinit Upasani, Jean-Philippe Herbeuval, John A. Reynolds, Tracy A. Briggs, Ian N. Bruce, Claudia Mauri, David Isenberg, Madhvi Menon, David Hunt, Benno Schwikowski, Xavier Mariette, Stanislas Pol, Flore Rozenberg, Tineke Cantaert, J. Eric Gottenberg, Kai Kisand, Darragh Duffy.

Cytokine. 2021;144:155533. DOI: 10.1016/j.cyto.2021.155533

 

Direct Infection of B Cells by Dengue Virus Modulates B Cell Responses in a Cambodian Pediatric Cohort

Vinit UpasaniHoa Thi My VoHeidi Auerswald, Denis Laurent, Sothy Heng, Veasna Duong, Izabela A. Rodenhuis-Zybert, Philippe DussartTineke Cantaert.

Front Immunol. 2021;11. DOI: 10.3389/fimmu.2020.594813

 

Aedes Mosquito Salivary Components and Their Effect on the Immune Response to Arboviruses.

David Guerrero, Tineke Cantaert, Dorothée Missé.

Front Cell Infect Microbiol. 2020;10:407. DOI: 10.3389/fcimb.2020.00407

 

Autoantibody Profiling in Plasma of Dengue Virus-Infected Individuals

Vo Hoa Thi My, Duong Veasna, Ly Sowath,Li, Quan-Zhen, Dussart Philippe, Cantaert Tineke.

Pathogens. 2020;9(12). DOI: 10.3390/pathogens9121060

 

Comparison of dengue case classification schemes and evaluation of biological changes in different dengue clinical patterns in a longitudinal follow-up of hospitalized children in Cambodia

Dussart Philippe*, Duong Veasna*, Bleakley Kevin, Fortas Camille, Lorn Try Patrich, Kim Kim Srorn, Choeung Rithy, In Saraden, Andries Anne-Claire, Cantaert Tineke, Flamand Marie, Buchy Philippe, Sakuntabhai Anavaj.

PLoS Negl Trop Dis. 2020;14(9):e0008603. DOI: 10.1371/journal.pntd.0008603

 

Decreased Type I Interferon Production by Plasmacytoid Dendritic Cells Contributes to Severe Dengue

Upasani Vinit, Scagnolari Carolina; Frasca Federica,  Smith Nikaïa,  Bondet Vincent,  Vanderlinden Axelle,  Lay Sokchea,  Auerswald Heidi,  Heng Sothy,  Laurent Denis,  Ly Sowath,  Duong Veasna,  Antonelli Guido,  Dussart Philippe,  Duffy Darragh,  Cantaert Tineke.

Front Immunol. 2020;11:605087. DOI: 10.3389/fimmu.2020.605087

 

TLR2 on blood monocytes senses dengue virus infection and its expression correlates with disease pathogenesis

Aguilar-Briseño José A., Upasani Vinit, Ellen Bram M. ter, Moser Jill, Pauzuolis Mindaugas, Ruiz-Silva Mariana, Heng Sothy, Laurent Denis, Choeung Rithy, Dussart Philippe, Cantaert Tineke, Smit Jolanda M., Rodenhuis-Zybert Izabela A.

Nature Communications. Nature Publishing Group; 2020;11(1):1‑14. DOI: 10.1038/s41467-020-16849-7

 

 

A 1-week intradermal dose-sparing regimen for rabies post-exposure prophylaxis (RESIST-2): an observational cohort study

Tineke Cantaert, Laurence Borand, Lauriane Kergoat, Chanthy Leng, Sivlin Ung, Sotheary In, Yiksing Peng, Chandara Phoeun, Chanthy Hing, Chun Navy Taing, Manil Saman, Sivuth Ong, Channa Mey, Rithy Choeung, Sowath Ly, Philippe Dussart, Hervé Bourhy, Arnaud Tarantola.

Lancet Infect Dis. 2019;19(12):1355‑62. DOI: 10.1016/S1473-3099(19)30311-1

 

A Modified mRNA Vaccine Targeting Immunodominant NS Epitopes Protects Against Dengue Virus Infection in HLA Class I Transgenic Mice

Claude Roth, Tineke Cantaert, Chloé Colas, Matthieu Prot, Isabelle Casadémont, Laurine Levillayer, Jessie Thalmensi, Pierre Langlade-Demoyen, Christiane Gerke, Kapil Bahl, Giuseppe Ciaramella, Etienne Simon-Loriere, Anavaj Sakuntabhai.

Frontiers in Immunology. 2019. DOI: 10.3389/fimmu.2019.01424

 

A Treatment-Decision Score for HIV-Infected Children With Suspected Tuberculosis

Olivier Marcy, Laurence Borand, Vibol Ung, Philippe Msellati, Mathurin Tejiokem, Khanh Truong Huu, Viet Do Chau, Duong Ngoc Tran, Francis Ateba-Ndongo, Suzie Tetang-Ndiang, Boubacar Nacro, Bintou Sanogo, Leakhena Neou, Sophie Goyet, Bunnet Dim, Polidy Pean, Catherine Quillet, Isabelle Fournier, Laureline Berteloot, Guislaine Carcelain, Sylvain Godreuil, Stéphane Blanche, Christophe Delacourt, ANRS 12229 PAANTHER 01 STUDY GROUP.

Pediatrics. 2019;144(3):e20182065. DOI: 10.1542/peds.2018-2065

 

High Activation of γδ T Cells and the γδ2pos T-Cell Subset Is Associated With the Onset of Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome, ANRS 12153 CAPRI NK

Polidy Pean, Janin Nouhin, Meng Ratana, Yoann Madec, Laurence Borand, Olivier Marcy, Didier Laureillard, Marcelo Fernandez, Françoise Barré-Sinoussi, Laurence Weiss, Daniel Scott-Algara.

Front Immunol. 2019;10:2018. DOI: 10.3389/fimmu.2019.02018

 

Impaired Antibody-Independent Immune Response of B Cells in Patients With Acute Dengue Infection

Vinit Upasani, Hoa Thi My Vo, Sivlin Ung, Sothy Heng, Denis Laurent, Rithy Choeung, Veasna Duong, Sopheak Sorn, Sowath Ly, Izabela A. Rodenhuis-Zybert, Philippe Dussart, Tineke Cantaert.

Front Immunol. 2019;10:2500. DOI: 10.3389/fimmu.2019.02500

 

Time to Micromanage the Pathogen-Host-Vector Interface: Considerations for Vaccine Development

Jessica E. Manning, Tineke Cantaert.

Vaccines. 2019;7(1):10. DOI: 10.3390/vaccines7010010

 

A Blood RNA Signature Detecting Severe Disease in Young Dengue Patients at Hospital Arrival

Iryna Nikolayeva, Pierre Bost, Isabelle Casademont, Veasna Duong, Fanny Koeth, Matthieu Prot, Urszula Czerwinska, Sowath Ly, Kevin Bleakley, Tineke Cantaert, Philippe Dussart, Philippe Buchy, Etienne Simon-Lorière, Anavaj Sakuntabhai, Benno Schwikowski.

The Journal of Infectious Diseases. 2018;217(11):1690‑8. DOI: 10.1093/infdis/jiy086

 

Host genetic control of mosquito-borne Flavivirus infections

Caroline Manet, Claude Roth, Ahmed Tawfik, Tineke Cantaert, Anavaj Sakuntabhai, Xavier Montagutelli.

Mamm Genome. 2018;29(7‑8):384‑407. DOI: 10.1007/s00335-018-9775-2

A prospective, comparative study of severe neurological and uncomplicated hand, foot and mouth forms of paediatric enterovirus 71 infections

Yoann CrabolPolidy PeanChanna MeyVeasna Duong, Beat Richner, Denis Laurent, Ky Santy, Heng Sothy, Philippe DussartArnaud TarantolaPhilippe Buchy**, Paul F. Horwood**.

Int J Infect Dis. 2017;59:69‑76. DOI: 10.1016/j.ijid.2017.04.005

 

Increased adaptive immune responses and proper feedback regulation protect against clinical dengue

Etienne Simon-Lorière, Veasna Duong, Ahmed Tawfik, Sivlin UngSowath Ly, Isabelle Casadémont, Matthieu Prot, Noémie Courtejoie, Kevin Bleakley, Philippe Buchy, Arnaud TarantolaPhilippe DussartTineke Cantaert, Anavaj Sakuntabhai.

Sci Transl Med. 2017;9(405). DOI: 10.1126/scitranslmed.aal5088

 

Interleukin-1 receptor antagonist, a biomarker of response to anti-TB treatment in HIV/TB co-infected patients

Janin Nouhin, Polidy Pean, Yoann Madec, Mathieu F. Chevalier, Celine Didier, Laurence Borand, François-Xavier Blanc, Daniel Scott-Algara, Didier Laureillard, Laurence Weiss.

J Infect. 2017;74(5):456‑65. DOI: 10.1016/j.jinf.2017.01.016

 

Necrotic Tuberculin Skin (Mantoux) Test Reaction: A Case Report and an Estimation of FrequencyBunnet D, Kerleguer A, Kim P, Pean P, Phuong V, Heng N, Peng Y, Borand L, Tarantola A.  Chest 2015, 148(1):e1-4.

 

TB-IRIS, T-Cell Activation, and Remodeling of the T-Cell Compartment in Highly Immunosuppressed Hiv-Infected Patients with TB. Haridas, V., P. Pean, L. D. Jasenosky, Y. Madec, D. Laureillard, T. Sok, S. Sath, L. Borand, O. Marcy, S. Chan, E. Tsitsikov, J. F. Delfraissy, F. X. Blanc, A. E. Goldfeld and Capri- T. Study Team AIDS. 2015 Jan 28;29(3):263-73. doi: 10.1097/QAD.0000000000000546.

 

Natural killer cell degranulation capacity predicts early onset of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients with tuberculosis. Pean P, Nerrienet E, Madec Y, Borand L, Laureillard D, Fernandez M, Marcy O, Sarin C, Phon K, Taylor S, Pancino G, Barré-Sinoussi F, Scott-Algara D; Cambodian Early versus Late Introduction of Antiretroviral Drugs (CAMELIA) study team. Blood. 2012 Apr 5;119(14):3315-20.

 

Virologic and immunologic outcomes in HIV-infected Cambodian children after 18 months of highly active antiretroviral therapy (HAART) 2010. Sophan S, Meng CY, Pean P, Harwell J, Hutton E, Trzmielina S, Somasundaran M, Luzuriaga K, Pugatch D.  Southeast Asian J Trop Med Public Health. 2010 Jan;41(1):126-37.