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

Nikolayeva, Iryna; Bost, Pierre; Casadémont, Isabelle; Duong, Veasna; Koeth, Fanny; Prot, Matthieu; Czerwińska, Urszula; Ly, Sowath; Bleakley, Kevin; Cantaert, Tineke; Dussart, Philippe; Buchy, Philippe; Simon‐Lorière, Etienne; Sakuntabhai, Anavaj; Schwikowski, Benno

doi:10.1093/infdis/jiy086

Cited by 29 publications

(50 citation statements)

References 28 publications

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“…However, deciphering the complex regulatory processes of pathophysiological pathways in human brain remains a challenge due to the inaccessibility of antemortem tissue. Fortunately, the studies on peripheral blood can provide important mechanistic knowledge that may have therapeutic implications [ 13 – 15 ] as shown previously into various infectious and neurological diseases [ 16 – 19 ]. Hence, we speculated that multiple dysregulated pathways may favor CM and that we are able to identify most of them in peripheral blood.…”

Section: Discussionmentioning

confidence: 99%

Understanding Human Cerebral Malaria through a Blood Transcriptomic Signature: Evidences for Erythrocyte Alteration, Immune/Inflammatory Dysregulation, and Brain Dysfunction

Cabantous

Poudiougou

Bergon

et al. 2020

Mediators of Inflammation

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Background. Cerebral malaria (CM), a reversible encephalopathy affecting young children, is a medical emergency requiring rapid clinical assessment and treatment. However, understanding of the genes/proteins and the biological pathways involved in the disease outcome is still limited. Methods. We have performed a whole transcriptomic analysis of blood samples from Malian children with CM or uncomplicated malaria (UM). Hierarchical clustering and pathway, network, and upstream regulator analyses were performed to explore differentially expressed genes (DEGs). We validated gene expression for 8 genes using real-time quantitative PCR (RT-qPCR). Plasma levels were measured for IP-10/CXCL10 and IL-18. Results. A blood RNA signature including 538 DEGs (∣FC∣≥2.0, adjusted P value ≤ 0.01) allowed to discriminate between CM and UM. Ingenuity Pathway Analysis (IPA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed novel genes and biological pathways related to immune/inflammatory responses, erythrocyte alteration, and neurodegenerative disorders. Gene expressions of CXCL10, IL12RB2, IL18BP, IL2RA, AXIN2, and NET were significantly lower in CM whereas ARG1 and SLC6A9 were higher in CM compared to UM. Plasma protein levels of IP-10/CXCL10 were significantly lower in CM than in UM while levels of IL-18 were higher. Interestingly, among children with CM, those who died from a complication of malaria tended to have higher concentrations of IP-10/CXCL10 and IFN-γ than those who recovered. Conclusions. This study identified some new factors and mechanisms that play crucial roles in CM and characterized their respective biological pathways as well as some upstream regulators.

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Section: Discussionmentioning

confidence: 99%

Understanding Human Cerebral Malaria through a Blood Transcriptomic Signature: Evidences for Erythrocyte Alteration, Immune/Inflammatory Dysregulation, and Brain Dysfunction

Cabantous

Poudiougou

Bergon

et al. 2020

Mediators of Inflammation

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“…Severe dengue patients have been shown to exhibit reduced LRP1 expression levels [69]. Based on this result, a proposal was put forth to include LRP1, together with another 17 genes, into a molecular signature for the prognosis of dengue disease [69].…”

Section: Discussionmentioning

confidence: 99%

The low-density lipoprotein receptor-related protein-1 is essential for Dengue virus infection

Huerta

Martín

Sarría

et al. 2020

Preprint

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19Dengue virus (DENV) causes the most prevalent and rapidly spreading arboviral 20 disease of humans. It enters human cells by receptor-mediated endocytosis. Numerous 21 cell surface proteins have been proposed as DENV entry factors. Among these, the 99 Regulation of lipid metabolism influences significantly the efficiency of DENV infection 100 and replication in vitro e in vivo [25-28]. Sequence stretches on DENV E and capsid 101 proteins resemble receptor binding motifs of ApoE [29]. ApoE is present in many 102 lipoproteins and interacts with several receptors of the low-density lipoprotein receptor 103 (LDLR) family [30]. Bovine lactoferrin, partially inhibits DENV and Japanese encephalitis 104 infection presumably competing for binding to the LDLR [31,32]. Collectively, these 105 results have suggested that LDLR may be involved on DENV entry to target cells. Yet, 106 conclusive evidences of the participation of LDLR on DENV attachment and/or entry 107 have not been obtained. 108 The LDLR family comprises at least 13 separate cell receptors that mediate lipoprotein 109 internalization, although some also play a role in the regulation of cellular physiology 110 and intracellular signaling [33]. In the context of the early events of the DENV infectious 111 cycle we decided to focus our interest on a different member of the family, the LRP1 112 receptor. This protein plays a role not only in lipoprotein endocytosis but also in the 7 113 internalization of protease:serpin complexes and, particularly of activated alpha-2-114 macroglobulin (α2M*):protease complexes [34]. We have found that proteins 115 participating in these processes are significantly enriched within the plasma DENV 116 interactome [35,36]. Also we have shown that α2M*, a ligand of LRP1, directly binds 117 DENV virions and favors DENV infection [37]. 118

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“…Nhi et al identified plasma proteins exhibiting different relative concentrations in patients diagnosed for a severe dengue [20]. Nikolayeva et al worked on a small number of gene expression markers to detect severe cases of dengue fever from blood samples from young patients with secondary infection [21]. Once the biological prognostic markers for severe dengue fever are identified, their validation will require large and independent cohorts of dengue patients who differ in ages and immune status.…”

Section: Asymptomatic and Symptomatic Cases Of Denguementioning

confidence: 99%

Dengue: a growing threat requiring vaccine development for disease prevention

Bos

Gadéa

Desprès

2018

Pathogens and Global Health

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Dengue disease is the most prevalent mosquito-borne viral infection in humans. At least one half of the global population is estimated at risk of infection and an estimated 390 million people are infected each year. Over the past few years, dengue burden continued to increase, mainly impacting developing countries. Alarming changes in dengue epidemiology were observed highlighting a spread from tropical to subtropical regions as well as urban to rural areas. An increase in the co-infections with the four serotypes has also been noticed, involving a shift in the targeted population from pediatric to adult. Facing these global changes, authorities will have to reinforce preventive actions and adapt healthcare management. New prophylactic strategies are urgently needed to prevent severe forms of dengue disease. The lack of specific antiviral therapies available turns vaccine development into a socio-economic challenge. In this review, we propose an update on the dengue global trends and different vaccine strategies in development. A particular attention will be paid to up-to-date information on dengue transmission and the protective efficacy of newly commercialized tetravalent dengue vaccine Dengvaxia®, as well as the most advanced candidate vaccines in clinical development.

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

Cited by 29 publications

References 28 publications

Understanding Human Cerebral Malaria through a Blood Transcriptomic Signature: Evidences for Erythrocyte Alteration, Immune/Inflammatory Dysregulation, and Brain Dysfunction

Understanding Human Cerebral Malaria through a Blood Transcriptomic Signature: Evidences for Erythrocyte Alteration, Immune/Inflammatory Dysregulation, and Brain Dysfunction

The low-density lipoprotein receptor-related protein-1 is essential for Dengue virus infection

Dengue: a growing threat requiring vaccine development for disease prevention

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