Devignot S, Sapet C, Duong V, Bergon A, Rihet P, Ong S, Lorn PT, Chroeung N, Ngeav S, Tolou HJ, Buchy P, Couissinier-Paris P. (2010). Genome-wide expression profiling deciphers host responses altered during dengue shock syndrome and reveals the role of innate immunity in severe dengue. PLoS One. Jul 20;5(7):e11671.
Comments:
The authors of the Devignot et al. (2010) should be highly commended for producing a awesome study on the gene profiles of dengue shock syndrome (DSS) patients performed at the time of defervescence, during and soon after cardiac decompensation. The strength of the study was that the team performed it on whole blood samples from DF, DHF and DSS patients irrespective of whether the latter patients were undergoing primary or secondary DENV infections, and their incredible ability to interpret and understand the implications of their findings in the unique pathogenesis of DSS. The study corrected the previous belief that the their immune responses of DSS patients were “muted” or “benign” [Long et al. (2010) Infect Dis 199: 537-546], since they were actively suppressed through the very highly significant upregulation of a number of genes (e.g. PTGES and VSIG4 genes) (see Table 2). These authors very conveniently separated the genes involved in T and NK cell related genes (Table 2), anti-inflammatory, tissue remodeling and repair genes (Table 3), and pro-inflammatory genes of the innate immunity (Table 4). In the latter table, the authors showed for the first time the important role of a myriad of significantly upregulated genes of the innate immune response from polymorphonuclear leukocytes, particularly neutrophils (e.g. the DEFA1, DEFA3, DEFA4, CAMP; LTF, S100A8, S100A9; S100A12, MPO, MMP8, ELANE(ELA) genes), as well as monocytes, macrophages in DSS patients, in addition to genes involved in lipid-metabolism. Thus, their results gave an unprecedented understanding of the changes in gene expression and their implications in DSS pathogenesis during the critical stage of disease. As such, these authors have made a remarkable contribution to the field of DENV pathogenesis, and clearly showed the way for further studies aimed at blocking the inappropriate activations of these genes that result in severe and life-threatening disease.

While these authors should have the full credit for making such a remarkable contribution to the field of DENV genome-wide expression profiles, I have been surprised by the claims that were published during the reviewing period of this Devignot et al. manuscript and thereafter, which I will show below:
Loke P, Hammond SN, Leung JM, Kim CC, Batra S, Rocha C, Balmaseda A, Harris E. (2010). Gene expression patterns of dengue virus-infected children from Nicaragua reveal a distinct signature of increased metabolism. PLoS Negl Trop Dis. Jun 15;4(6): e710.
Discussion:
“We noted with interest that Long et al. [9] also observed a significantly higher expression of LTF, DEFA3 and DEFA4 in patient samples with DSS [9]. We found that LTF and DEFA1 were up-regulated in DHF patients but not in DSS patients. Nonetheless, expression of this group of anti-microbial peptides is clearly associated with clinical manifestations more severe than uncomplicated DF.”
Reference:
[9] Long HT, Hibberd ML, Hien TT, Dung NM, Van Ngoc T, et al. (2009) Patterns of gene transcript abundance in the blood of children with severe or uncomplicated dengue highlight differences in disease evolution and host response to dengue virus infection. J Infect Dis 199: 537–546.
Importantly, I could not see the increased expression of LTF, DEF3 and DEF4 in DSS patients in this Loke et al. 2010 paper, and therefore this team were credited with this observation, rather that the Devignot et al. (2010) manuscript that was in review at that time (in review Jan 20 2010, accepted June 22, 2010, published July 20, 2010)!
In addition, later that year (December 2010) the latter team who appreared to be given the credit of the association with neutrophil gene expressions in DSS patients, published the claim to be the first to identify the upregulation of neutrophil-associated genes in DSS patients’ blood samples, despite citing the Devignot et al. (July 2010) paper (see last sentence of the paper):
Hoang LT, Lynn DJ, Henn M, Birren BW, Lennon NJ, Le PT, Duong KT, Nguyen TT, Mai LN, Farrar JJ, Hibberd ML, Simmons CP. (2010). The early whole-blood transcriptional signature of dengue virus and features associated with progression to dengue shock syndrome in Vietnamese children and young adults. J Virol. Dec; 84(24): 12982-12994. Epub 2010 Oct 13.

[N.B. In this paper, there was only a weak upregulation of these genes in the early acute phase serum samples from patients who subsequently developed DSS, making them not useful for DSS prognosis].

Abstract
“Strikingly, the only difference in the transcriptional signatures of early DSS and UC dengue cases was the greater abundance of several neutrophil-associated 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]). 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.”
Discussion
“Neutrophil activation and degranulation were most prominent themes in the DSS-associated differentially expressed gene list. A gene signature consistent with neutrophil activation has also been recently described in whole-blood samples obtained from Cambodian children with DSS (10). We verified that plasma protein concentrations of CTSG, BPI, ELA2, and MPO were also higher in early DSS patients than in control patients, albeit the absolute difference was small and unlikely to be useful for prognosis. Of the differentially expressed genes associated with neutrophil degranulation, ELA2, CTSG, and the defensins (DEF1A and DEF4A) are of particular interest.”
Reference 10
10.Devignot, S., C. Sapet, V. Duong, A. Bergon, P. Rihet, S. Ong, P. T. Lorn, N. Chroeung, S. Ngeav, H. J. Tolou, P. Buchy, and P. Couissinier-Paris. 2010. Genome-wide expression profiling deciphers host responses altered during dengue shock syndrome and reveals the role of innate immunity in severe dengue. PLoS One 5:e11671.