Macrophage Activation Syndrome-Associated Markers in Severe Dengue

Ab-Rahman, Hasliana Azrah; Rahim, Hafiz; AbuBakar, Sazaly; Wong, Pooi-Fong

doi:10.7150/ijms.13680

Cited by 33 publications

(33 citation statements)

References 54 publications

(49 reference statements)

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“…3 E ). It has been previously reported that MX2 is one of only four IFN-induced genes induced in an IRF3 and IRF7 independent manner in DENV-infected mice (38) and that CD163 in macrophages and CD14 + CD16 + monocytes contributes to the pathogenesis of SD (39, 40). Given the small number of subjects analyzed in this study and the female predominance, the predictive power of these candidate biomarkers warrants further validation in larger cohorts with a balanced number of females and males.…”

Section: Discussionmentioning

confidence: 99%

Virus-inclusive single-cell RNA sequencing reveals the molecular signature of progression to severe dengue

Zanini

Robinson

Croote

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

142

177

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SignificanceA fraction of the 400 million people infected with dengue annually progresses to severe dengue (SD). Yet, there are currently no biomarkers to predict disease progression. We profiled the landscape of host transcripts and viral RNA in thousands of single blood cells from dengue patients prior to progressing to SD. We discovered cell type-specific immune activation and candidate predictive biomarkers. We also determined preferential virus association with specific cell populations, particularly naive B cells and monocytes. We explored immune activation of bystander cells, clonality and somatic evolution of adaptive immune repertoires, as well as viral genomics. This multifaceted approach could advance understanding of pathogenesis of any viral infection, map an atlas of infected cells, and promote the development of prognostics.

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Section: Discussionmentioning

confidence: 99%

Virus-inclusive single-cell RNA sequencing reveals the molecular signature of progression to severe dengue

Zanini

Robinson

Croote

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

142

177

View full text Add to dashboard Cite

show abstract

“…3E). It has been previously reported that MX2 is one of only four interferon-induced genes induced in an IRF3 and IRF7 independent manner in DENV infected mice [38] , and that CD163 in macrophages and CD14+ CD16+ monocytes contributes to the pathogenesis of SD [39,40] . Given the small number of subjects analyzed in this study, the predictive power of these candidate biomarkers warrants further validation in larger cohorts.…”

Section: Discussionmentioning

confidence: 97%

Virus-inclusive single cell RNA sequencing reveals molecular signature predictive of progression to severe dengue infection

Zanini

Croote

et al. 2018

Preprint

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Dengue virus (DENV) infection can result in severe complications. Yet, the understanding of the molecular correlates of severity is limited, partly due to difficulties in defining the peripheral blood mononuclear cells (PBMCs) that are associated with DENV in vivo. Additionally, t here are currently no biomarkers predictive of progression to severe dengue (SD) . Bulk transcriptomics data are difficult to interpret because blood consists of multiple cell types that may react differently to infection. Here we applied virus-inclusive single cell RNA-seq approach (viscRNA-Seq) to profile transcriptomes of thousands of single PBMCs derived early in the course of disease from six dengue patients and four healthy controls, and to characterize distinct DENV-associated leukocytes. Multiple genes, particularly interferon response genes, were upregulated in a cell-specific manner prior to progression to SD. Expression of MX2 in naive B cells and CD163 in CD14 + CD16 + monocytes was predictive of SD. The majority of DENV-associated cells in the blood of two patients who progressed to SD were naive IgM B cells expressing the CD69 and CXCR4 receptors and antiviral genes, followed by monocytes.Bystander uninfected B cells also demonstrated immune activation, and plasmablasts from two patients exhibited antibody lineages with convergently hypermutated heavy chain sequences. Lastly, assembly of the DENV genome revealed diversity at unexpected genomic sites. This study presents a multi-faceted molecular elucidation of natural dengue infection in humans and proposes biomarkers for prediction of SD, with implications for profiling any tissue and viral infection, and for the development of a dengue prognostic assay. SignificanceA fraction of the 400 million people infected with dengue annually progresses to severe dengue (SD). Yet, there are currently no biomarkers to effectively predict disease progression. We profiled the landscape of host transcripts and viral RNA in thousands of single blood cells from dengue patients prior to progressing to SD. We discovered cell-type specific immune activation and candidate predictive biomarkers. We also revealed preferential virus association with specific cell populations, particularly naive B cells and monocytes. We then explored immune activation of bystander cells, clonality and somatic evolution of adaptive immune repertoires, and viral genomics. This multi-faceted approach could advance understanding of pathogenesis of any viral infection, map an atlas of infected cells and promote the development of prognostics.

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“…To the best of our knowledge, only one instance of diagnosis of dengue in an individual with SLE has been reported; this person was treated as an outpatient , suggesting that she had only mild symptoms. Most reported individuals with both dengue and autoimmune disease apparently developed the autoimmune diseases after having a DENV infection .…”

Section: Discussionmentioning

confidence: 99%

Sera of patients with systemic lupus erythematosus cross‐neutralizes dengue viruses

Zainal

Tan

Johari

et al. 2018

Microbiology and Immunology

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Dengue is the most prevalent mosquito‐borne disease in Southeast Asia, where the incidence of systemic lupus erythematosus (SLE) is approximately 30 to 53 per 100,000. Severe dengue, however, is rarely reported among individuals with SLE. Here, whether sera of patients with SLE cross‐neutralize dengue virus (DENV) was investigated. Serum samples were obtained from individuals with SLE who were dengue IgG and IgM serology negative. Neutralization assays were performed against the three major DENV serotypes. Of the dengue serology negative sera of individuals with SLE, 60%, 61% and 52% of the sera at 1/320 dilution showed more than 50% inhibition against dengue type‐1 virus (DENV‐1), DENV‐2 and DENV‐3, respectively. The neutralizing capacity of the sera was significantly greater against DENV‐1 (P < 0.001) and DENV‐3 (P < 0.01) than against DENV‐2 (P < 0.05). Neutralization against the DENV correlated with dengue‐specific IgG serum titers below the cut‐off point for dengue positivity. Depletion of total IgG from the sera of patients with SLE resulted in significant decreases of up to 80% in DENV inhibition, suggesting that IgG plays an important role. However, some of the SLE sera was still able to neutralize DENV, even with IgG titers <0.1 OD absorbance. Our findings suggest that sera of patients with SLE contain IgG, and possibly other type of antibodies, that can cross‐neutralize DENV, which may explain the rarity of severe dengue in individuals with SLE. Further studies, are needed to further substantiate this finding and to elucidate the specific neutralizing epitopes recognized by the sera of individuals with SLE.

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Macrophage Activation Syndrome-Associated Markers in Severe Dengue

Cited by 33 publications

References 54 publications

Virus-inclusive single-cell RNA sequencing reveals the molecular signature of progression to severe dengue

Virus-inclusive single-cell RNA sequencing reveals the molecular signature of progression to severe dengue

Virus-inclusive single cell RNA sequencing reveals molecular signature predictive of progression to severe dengue infection

Sera of patients with systemic lupus erythematosus cross‐neutralizes dengue viruses

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