The Early Whole-Blood Transcriptional Signature of Dengue Virus and Features Associated with Progression to Dengue Shock Syndrome in Vietnamese Children and Young Adults

Abstract

Dengue is a pantropic public health problem. In children, dengue shock syndrome (DSS) is the most common life-threatening complication. The ability to predict which patients may develop DSS may improve triage and treatment. To this end, we conducted a nested case-control comparison of the early host transcriptional features in 24 DSS patients and 56 sex-, age-, and virus serotype-matched uncomplicated (UC) dengue patients. In the first instance, we defined the "early dengue" profile. The transcriptional signature in acute rather than convalescent samples (<72 h post-illness onset) was defined by an overabundance of interferoninducible transcripts (31% of the 551 overabundant transcripts) and canonical gene ontology terms that included the following: response to virus, immune response, innate immune response, and inflammatory response. Pathway and network analyses identified STAT1, STAT2, STAT3, IRF7, IRF9, IRF1, CEBPB, and SP1 as key transcriptional factors mediating the early response. Strikingly, the only difference in the transcriptional signatures of early DSS and UC dengue cases was the greater abundance of several neutrophilassociated transcripts in patients who progressed to DSS, a finding supported by higher plasma concentrations of several canonical proteins associated with neutrophil degranulation (bactericidal/permeability-increasing protein [BPI], elastase 2 [ELA2], and defensin 1 alpha [DEF1A]). Elevated levels of neutrophil-associated transcripts were independent of the neutrophil count and also of the genotype of the infecting virus, as genome-length sequences of dengue virus serotype 1 (DENV-1) (n ‫؍‬ 15) and DENV-2 (n ‫؍‬ 3) sampled from DSS patients were phylogenetically indistinguishable from those sampled from uncomplicated dengue patients (32 DENV-1 and 9 DENV-2 sequences). Collectively, these data suggest a hitherto unrecognized association between neutrophil activation, pathogenesis, and the development of DSS and point to future strategies for guiding prognosis.

The pathogenesis of dengue

“…80 The significance of these observations with the independent observation that early NS1 concentrations in blood are positively associated with disease severity are not yet clear, but are consistent with a role for NS1 and complement in pathogenesis . 81,82 Finally, it is plausible that the low levels of complement observed in severe dengue are merely a marker of a severe systemic disease rather than an indicator of their role in capillary permeability.…”

“…Each of the DEN virus serotypes is capable of causing severe dengue and early viral burdens in the course of illness are associated with severe disease. 74,82,115 Oscillations in the prevalence of each serotype are common in endemic settings. Typically, one serotype is dominant for a period of 2-4 years, after which it declines in prevalence as a different serotype(s) emerges to replace it.…”

Dengue Fever in Pakistan, Episodes of Epidemic to Endemic: Treatment Challenges, Prevention and Current Facts

“…Studies also suggest use of RNA interference against viruses of family Flaviviridae, to suppress viral genome. It not only works against dengue virus but also has activity against Poliovirus, Influenza A virus, Human Immunodeficiency virus (HIV) type-1, Hepatitis C virus (HCV), Hepatitis B virus (HBV) [36].…”

The Cells of Innate Systems in Tick-Borne Encephalitis

“…Elevated levels of neutrophil-associated transcripts were independent of the neutrophil count and also of the genotype of the infecting virus, as genome-length sequences of dengue virus serotype 1 and serotype 2 sampled from DSS patients were phylogenetically indistinguishable from those sampled from uncomplicated dengue patients. Collectively, these data suggest a hitherto unrecognized association between neutrophil activation, pathogenesis, and the development of DSS and point to future strategies for guiding prognosis of diseases (Hoang et al, 2010). We study the morphofunctional characteristic of neutrophils in TBEV infections.…”