Heng Sothy

Bhabha Hospital

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Veasna Duong

Institut Pasteur du Cambodge

Philippe Dussart

Institut Pasteur du Cambodge

Denis Laurent

Bhabha Hospital

Tineke Cantaert

Institut Pasteur du Cambodge

Philippe Buchy

Institut Pasteur du Laos

Vinit Upasani

University of Groningen

Ky Santy

Bhabha Hospital

Izabela A. Rodenhuis‐Zybert

University Medical Center Groningen

Arnaud Tarantola

Santé Publique France

Beat Richner

Bhabha Hospital

Cooperative Institutions

Inserm

Institut Pasteur du Cambodge

Université Paris Cité

Institut Pasteur

Rockefeller University

Centre National de la Recherche Scientifique

Institut des Maladies Génétiques Imagine

Assistance Publique – Hôpitaux de Paris

Mahosot Hospital

Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit

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

Nature Communications (2020)

José A. Aguilar-Briseño Vinit Upasani Bram M. ter Ellen Jill Moser Mindaugas Paužuolis

Abstract Vascular permeability and plasma leakage are immune-pathologies of severe dengue virus (DENV) infection, but the mechanisms underlying the exacerbated inflammation during DENV pathogenesis are unclear. Here, we demonstrate that TLR2, together with its co-receptors CD14 and TLR6, is an innate sensor of DENV particles inducing inflammatory cytokine expression and impairing vascular integrity in vitro. Blocking TLR2 prior to DENV infection in vitro abrogates NF-κB activation while CD14 and TLR6 block has a moderate effect. Moreover, TLR2 block prior to DENV infection of peripheral blood mononuclear cells prevents activation of human vascular endothelium, suggesting a potential role of the TLR2-responses in vascular integrity. TLR2 expression on CD14 + + classical monocytes isolated in an acute phase from DENV-infected pediatric patients correlates with severe disease development. Altogether, these data identify a role for TLR2 in DENV infection and provide insights into the complex interaction between the virus and innate receptors that may underlie disease pathogenesis.

Pathogenesis

10.1038/s41467-020-16849-7

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Citations (46)

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

International Journal of Infectious Diseases (2017)

Yoann Crabol Polidy Pean Channa Mey Veasna Duong Beat Richner

Enterovirus 71

Throat

10.1016/j.ijid.2017.04.005

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Citations (15)

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

Frontiers in Immunology (2020)

Vinit Upasani Carolina Scagnolari Federica Frasca Nikaïa Smith Vincent Bondet

The clinical presentation of dengue virus (DENV) infection is variable. Severe complications mainly result from exacerbated immune responses. Type I interferons (IFN-I) are important in antiviral responses and form a crucial link between innate and adaptive immunity. Their contribution to host defense during DENV infection remains under-studied, as direct quantification of IFN-I is challenging. We combined ultra-sensitive single-molecule array (Simoa) digital ELISA with IFN-I gene expression to elucidate the role of IFN-I in a well-characterized cohort of hospitalized Cambodian children undergoing acute DENV infection. Higher concentrations of type I IFN proteins were observed in blood of DENV patients, compared to healthy donors, and correlated with viral load. Stratifying patients for disease severity, we found a decreased expression of IFN-I in patients with a more severe clinical outcome, such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). This was seen in parallel to a correlation between low IFNα protein concentrations and decreased platelet counts. Type I IFNs concentrations were correlated to frequencies of plasmacytoid DCs, not DENV-infected myloid DCs and correlated inversely with neutralizing anti-DENV antibody titers. Hence, type I IFN produced in the acute phase of infection is associated with less severe outcome of dengue disease.

10.3389/fimmu.2020.605087

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Aetiology of acute meningoencephalitis in Cambodian children, 2010–2013

Emerging Microbes & Infections (2017)

Paul F. Horwood Veasna Duong Denis Laurent Channa Mey Heng Sothy

Acute meningoencephalitis (AME) is associated with considerable morbidity and mortality in children in developing countries. Clinical specimens were collected from children presenting with AME at two Cambodian paediatric hospitals to determine the major aetiologies associated with AME in the country. Cerebrospinal fluid (CSF) and blood samples were screened by molecular and cell culture methods for a range of pathogens previously associated with AME in the region. CSF and serum (acute and convalescent) were screened for antibodies to arboviruses such as Japanese encephalitis virus (JEV), dengue virus (DENV), and chikungunya virus (CHIKV). From July 2010 through December 2013, 1160 children (one month to 15 years of age) presenting with AME to two major paediatric hospitals were enroled into the study. Pathogens associated with AME were identified using molecular diagnostics, cell culture and serology. According to a diagnostic algorithm, a confirmed or highly probable aetiologic agent was detected in 35.0% (n=406) of AME cases, with a further 9.2% (total: 44.2%, n=513) aetiologies defined as suspected. JEV (24.4%, n=283) was the most commonly identified pathogen followed by Orientia tsutsugamushi (4.7%, n=55), DENV (4.6%, n=53), enteroviruses (3.5%, n=41), CHIKV (2.0%, n=23) and Streptococcus pneumoniae (1.6%, n=19). The majority of aetiologies identified for paediatric AME in Cambodia were vaccine preventable and/or treatable with appropriate antimicrobials.Emerging Microbes & Infections (2017) 6, e35; doi:10.1038/emi.2017.15; published online 24 May 2017

10.1038/emi.2017.15

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Characterization of Soluble TLR2 and CD14 Levels During Acute Dengue Virus Infection

SSRN Electronic Journal (2022)

Vinit Upasani Bram M. ter Ellen Sotheary Sann Sokchea Lay Heng Sothy

Dengue virus infection results in a broad spectrum of diseases ranging from mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Hitherto, there is no consensus biomarker for the prediction of severe dengue disease in patients. Yet, early identification of patients who progress to severe dengue is pivotal for better clinical management. We have recently reported that an increased frequency of classical (CD14 ++ CD16 - ) monocytes with sustained high TLR2 expression in acutely infected dengue patients correlates with severe dengue development. Here, we hypothesized that the relatively lower TLR2 and CD14 expression in mild dengue patients is due to the shedding of their soluble forms (sTLR2 and sCD14) and that these could be used as indicators of disease progression. Therefore, we evaluated the release of sTLR2 and sCD14 by peripheral blood mononuclear cells (PBMCs) in response to in vitro dengue virus (DENV) infection and assessed their levels in acute-phase plasma of 109 dengue patients. We show that while both sTLR2 and sCD14 are released by PBMCs in response to dengue virus (DENV) infection in vitro, their co-circulation in an acute phase of the disease is not always apparent. In fact, sTLR2 was found only in 20% of patients irrespective of disease status. In contrast, sCD14 levels were detected in all patients and were significantly elevated in DF patients when compared to DHF patients and age-matched healthy donors. Altogether, our results suggest that sCD14 may help in identifying patients at risk of severe dengue at hospital admittance.Funding Information: This study has been funded by a Research Grant 2019 from the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) to IRZ. TC was funded by the Institute Pasteur International Network and is an HHMI-Wellcome Trust International Research Scholar (208710/Z/17/Z). VU was funded by the Institute Pasteur International Network Calmette and Yersin Ph.D. scholarship and UMCG. Conflict of Interests: The authors have declared that no competing interests exist.Ethical Approval: The clinical study was approved by the National Ethics Committee of Health Research of Cambodia. Written informed consent was obtained from the guardians of participants prior to their inclusion in the study.

10.2139/ssrn.4245553

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

Frontiers in Immunology (2019)

Vinit Upasani Hoa Thi My Vo Sivlin Ung Heng Sothy Denis Laurent

Dengue is a mosquito-borne viral disease caused by dengue virus (DENV). The disease is endemic to more than 100 countries with 390 million dengue infections per year. Humoral immune responses during primary and secondary DENV infections are well investigated. However, the impact of DENV infection on B cell subsets and their antibody-independent functions are not well documented. Through this study, we aimed to define the distribution of B cell subsets in the acute phase of DENV infection and characterise the effect of DENV infection on B cell functions such as differentiation into memory and plasma cells and cytokine production. In our cohort of Cambodian children, we observed decreased percentages of CD24hiCD38hi B cells and CD27- naïve B cells within the CD19 population and increased percentages of CD27+CD38hiCD138+ plasma cells as early as 4 days post appearance of fever in patients with severe dengue compared to patients with mild disease. Lower percentages of CD19+CD24hiCD38hi B cells in DENV-infected patients were associated with decreased concentrations of soluble CD40L in patient plasma and decreased platelet counts in these patients. In addition, CD19+CD24hiCD38hi and CD19+CD27- B cells from DENV-infected patients did not produce IL-10 or TNF-α upon stimulation in vitro suggesting their contribution to an altered immune response during DENV infection. In addition, CD19+CD27- naïve B cells isolated from dengue patients were refractory to TLR/anti-IgM stimulation in vitro, which correlated to the increased expression of inhibitory Fcγ receptors (FcγR) CD32 and LILRB1 on CD19+CD27- naïve B cells from DENV-infected patients. Collectively, our results indicate that a defective B cell response in dengue patients may contribute to the pathogenesis of dengue during the early phase of infection.

10.3389/fimmu.2019.02500

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Citations (15)

Isolation and full-genome sequences of Japanese encephalitis virus genotype I strains from Cambodian human patients, mosquitoes and pigs

Journal of General Virology (2017)

Veasna Duong Rithy Choeung Christopher Gorman Denis Laurent Yoann Crabol

Japanese encephalitis remains the most important cause of viral encephalitis in humans in several southeast Asian countries, including Cambodia, causing at least 65 000 cases of encephalitis per year. This vector-borne viral zoonosis - caused by Japanese encephalitis virus (JEV) - is considered to be a rural disease and is transmitted by mosquitoes, with birds and pigs being the natural reservoirs, while humans are accidental hosts. In this study we report the first two JEV isolations in Cambodia from human encephalitis cases from two studies on the aetiology of central nervous system disease, conducted at the two major paediatric hospitals in the country. We also report JEV isolation from Culextritaeniorhynchus mosquitoes and from pig samples collected in two farms, located in peri-urban and rural areas. Out of 11 reverse-transcription polymerase chain reaction-positive original samples, we generated full-genome sequences from 5 JEV isolates. Five additional partial sequences of the JEV NS3 gene from viruses detected in five pigs and one complete coding sequence of the envelope gene of a strain identified in a pig were generated. Phylogenetic analyses revealed that JEV detected in Cambodia belonged to genotype I and clustered in two clades: genotype I-a, mainly comprising strains from Thailand, and genotype I-b, comprising strains from Vietnam that dispersed northwards to China. Finally, in this study, we provide proof that the sequenced JEV strains circulate between pigs, Culex tritaeniorhynchus and humans in the Phnom Penh vicinity.

Isolation

Virus isolation

10.1099/jgv.0.000892

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Citations (19)

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

Frontiers in Immunology (2021)

Vinit Upasani Hoa Thi My Vo Heidi Auerswald Denis Laurent Heng Sothy

Dengue is an acute viral disease caused by dengue virus (DENV), which is transmitted by Aedes mosquitoes. Symptoms of DENV infection range from inapparent to severe and can be life-threatening. DENV replicates in primary immune cells such as dendritic cells and macrophages, which contribute to the dissemination of the virus. Susceptibility of other immune cells such as B cells to direct infection by DENV and their subsequent response to infection is not well defined. In a cohort of 60 Cambodian children, we showed that B cells are susceptible to DENV infection. Moreover, we show that B cells can support viral replication of laboratory adapted and patient-derived DENV strains. B cells were permissive to DENV infection albeit low titers of infectious virions were released in cell supernatants CD300a, a phosphatidylserine receptor, was identified as a potential attachment factor or receptor for entry of DENV into B cells. In spite of expressing Fc γ -receptors, antibody-mediated enhancement of DENV infection was not observed in B cells in an in vitro model. Direct infection by DENV induced proliferation of B cells in dengue patients in vivo and plasmablast/plasma cell formation in vitro . To summarize, our results show that B cells are susceptible to direct infection by DENV via CD300a and the subsequent B cell responses could contribute to dengue pathogenesis.

Antibody-dependent enhancement

10.3389/fimmu.2020.594813

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Citations (25)

A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity

The Journal of Experimental Medicine (2024)

Fahd Al Qureshah Jérémie Le Pen Nicole A. de Weerd Marcela Moncada‐Vélez Marie Materna

Autosomal recessive deficiency of the IFNAR1 or IFNAR2 chain of the human type I IFN receptor abolishes cellular responses to IFN-α, -β, and -ω, underlies severe viral diseases, and is globally very rare, except for IFNAR1 and IFNAR2 deficiency in Western Polynesia and the Arctic, respectively. We report 11 human IFNAR1 alleles, the products of which impair but do not abolish responses to IFN-α and -ω without affecting responses to IFN-β. Ten of these alleles are rare in all populations studied, but the remaining allele (P335del) is common in Southern China (minor allele frequency ≈2%). Cells heterozygous for these variants display a dominant phenotype in vitro with impaired responses to IFN-α and -ω, but not -β, and viral susceptibility. Negative dominance, rather than haploinsufficiency, accounts for this dominance. Patients heterozygous for these variants are prone to viral diseases, attesting to both the dominance of these variants clinically and the importance of IFN-α and -ω for protective immunity against some viruses.

Dominance (genetics)

Haploinsufficiency

Heterozygote advantage

10.1084/jem.20241413

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Childhood encephalitis in the Greater Mekong region (the SouthEast Asia Encephalitis Project): a multicentre prospective study

The Lancet Global Health (2022)

Jean‐David Pommier Chris Gorman Yoann Crabol Kevin Bleakley Heng Sothy

Encephalitis is a worldwide public health issue, with a substantially high burden among children in southeast Asia. We aimed to determine the causes of encephalitis in children admitted to hospitals across the Greater Mekong region by implementing a comprehensive state-of-the-art diagnostic procedure harmonised across all centres, and identifying clinical characteristics related to patients' conditions.

Acute disseminated encephalomyelitis

Viral encephalitis

10.1016/s2214-109x(22)00174-7

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Citations (25)