Prof Cameron P Simmons

Research Area: Global Health
Scientific Themes: Tropical Medicine & Global Health
Keywords: Dengue virus, Immune response, Anti-virals, Pathogenesis and Genetic susceptibility
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Dengue is the most important arboviral disease of humans and an enormous and growing public health problem. There are no licensed vaccines or anti-virals, no good animal models of disease and no validated methods of identifying patients who might develop complications from their illness. Our research programme is designed to better understand the pathogenesis of dengue and develop better methods of identifying patients at risk of severe disease.
Our studies in dengue patients are conducted in collaboration with clinical partners in hospitals throughout VietNam and particularly the Mekong Delta region. Through genomic studies of the virus and host, combined with investigations of the host immune response, we are gaining a better understanding of the factors associated with severe dengue. From this base we also evaluate new diagnostic tests and anti-viral drugs in randomised, controlled trials. Our research incorporates skills in epidemiology, genomics, bioinformatics, clinical trials, immunology and virology.

Name Department Institution Country
Matt Henn Broad Institute USA
Martin Hibberd Genome Institute of Singapore Singapore
Paul Young University of Queensland Australia
Steve Whitehead Laboratory of Infectious Diseases, NIH USA
Alex Matter Novartis Institute for Tropical Diseases Singapore

Hoang LT, Lynn DJ, Henn M, Birren BW, Lennon NJ, Le PT, Duong KT, Nguyen TT et al. 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, 84 (24), pp. 12982-12994. Read abstract | Read more

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 interferon-inducible 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 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]). 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. Hide abstract

Chau TN, Quyen NT, Thuy TT, Tuan NM, Hoang DM, Dung NT, Lien LEB, Quy NT et al. 2008. Dengue in Vietnamese infants--results of infection-enhancement assays correlate with age-related disease epidemiology, and cellular immune responses correlate with disease severity. J Infect Dis, 198 (4), pp. 516-524. Read abstract | Read more

The pathogenesis of severe dengue is not well understood. Maternally derived subneutralizing levels of dengue virus-reactive IgG are postulated to be a critical risk factor for severe dengue during infancy. In this study, we found that, in healthy Vietnamese infants, there was a strong temporal association between the Fc-dependent, dengue virus infection-enhancing activity of neat plasma and the age-related epidemiology of severe dengue. We then postulated that disease severity in infants with primary infections would be associated with a robust immune response, possibly as a consequence of higher viral burdens in vivo. Accordingly, in infants hospitalized with acute dengue, the activation phenotype of peripheral-blood NK cells and CD8+ and CD4+ T cells correlated with overall disease severity, but HLA-A*1101-restricted NS3(133-142)-specific CD8+ T cells were not measurable until early convalescence. Plasma levels of cytokines/chemokines were generally higher in infants with dengue shock syndrome. Collectively, these data support a model of dengue pathogenesis in infants whereby antibody-dependent enhancement of infection explains the age-related case epidemiology and could account for antigen-driven immune activation and its association with disease severity. These results also highlight potential risks in the use of live attenuated dengue vaccines in infants in countries where dengue is endemic. Hide abstract

Simmons CP, Chau TN, Thuy TT, Tuan NM, Hoang DM, Thien NT, Lien LEB, Quy NT et al. 2007. Maternal antibody and viral factors in the pathogenesis of dengue virus in infants. J Infect Dis, 196 (3), pp. 416-424. Read abstract | Read more

The pathogenesis of dengue in infants is poorly understood. We postulated that dengue severity in infants would be positively associated with markers of viral burden and that maternally derived, neutralizing anti-dengue antibody would have decayed before the age at which infants with dengue presented to the hospital. In 75 Vietnamese infants with primary dengue, we found significant heterogeneity in viremia and NS1 antigenemia at hospital presentation, and these factors were independent of disease grade or continuous measures of disease severity. Neutralizing antibody titers, predicted in each infant at the time of their illness, suggested that the majority of infants (65%) experienced dengue hemorrhagic fever when the maternally derived neutralizing antibody titer had declined to <1 : 20. Collectively, these data have important implications for dengue vaccine research because they suggest that viral burden may not solely explain severe dengue in infants and that neutralizing antibody is a reasonable but not absolute marker of protective immunity in infants. Hide abstract

Lühn K, Simmons CP, Moran E, Dung NT, Chau TN, Quyen NT, Thao LETT, Van Ngoc T et al. 2007. Increased frequencies of CD4+ CD25(high) regulatory T cells in acute dengue infection. J Exp Med, 204 (5), pp. 979-985. Read abstract | Read more

Dengue virus infection is an increasingly important tropical disease, causing 100 million cases each year. Symptoms range from mild febrile illness to severe hemorrhagic fever. The pathogenesis is incompletely understood, but immunopathology is thought to play a part, with antibody-dependent enhancement and massive immune activation of T cells and monocytes/macrophages leading to a disproportionate production of proinflammatory cytokines. We sought to investigate whether a defective population of regulatory T cells (T reg cells) could be contributing to immunopathology in severe dengue disease. CD4(+)CD25(high)FoxP3(+) T reg cells of patients with acute dengue infection of different severities showed a conventional phenotype. Unexpectedly, their capacity to suppress T cell proliferation and to secrete interleukin-10 was not altered. Moreover, T reg cells suppressed the production of vasoactive cytokines after dengue-specific stimulation. Furthermore, T reg cell frequencies and also T reg cell/effector T cell ratios were increased in patients with acute infection. A strong indication that a relative rise of T reg cell/effector T cell ratios is beneficial for disease outcome comes from patients with mild disease in which this ratio is significantly increased (P < 0.0001) in contrast to severe cases (P = 0.2145). We conclude that although T reg cells expand and function normally in acute dengue infection, their relative frequencies are insufficient to control the immunopathology of severe disease. Hide abstract

Simmons CP, Popper S, Dolocek C, Chau TN, Griffiths M, Dung NT, Long TH, Hoang DM et al. 2007. Patterns of host genome-wide gene transcript abundance in the peripheral blood of patients with acute dengue hemorrhagic fever. J Infect Dis, 195 (8), pp. 1097-1107. Read abstract | Read more

Responses by peripheral blood leukocytes may contribute to the pathogenesis of dengue hemorrhagic fever (DHF). We used DNA microarrays to reveal transcriptional patterns in the blood of 14 adults with DHF. Acute DHF was defined by an abundance of transcripts from cell cycle- and endoplasmic reticulum (ER)-related genes, suggesting a proliferative response accompanied by ER stress. Transcript-abundance levels for immunoresponse-associated genes, including cell surface markers, immunoglobulin, and innate response elements, were also elevated. Twenty-four genes were identified for which transcript abundance distinguished patients with dengue shock syndrome (DSS) from those without DSS. All the gene transcripts associated with DSS, many of which are induced by type I interferons, were less abundant in patients with DSS than in those without DSS. To our knowledge, these data provide the first snapshot of gene-expression patterns in peripheral blood during acute dengue and suggest that DSS is associated with attenuation of selected aspects of the innate host response. Hide abstract

Thwaites GE, Macmullen-Price J, Tran TH, Pham PM, Nguyen TD, Simmons CP, White NJ, Tran TH, Summers D, Farrar JJ. 2007. Serial MRI to determine the effect of dexamethasone on the cerebral pathology of tuberculous meningitis: an observational study. Lancet Neurol, 6 (3), pp. 230-236. Read abstract | Read more

Adjunctive dexamethasone increases survival from tuberculous meningitis, but the underlying mechanism is unclear. We aimed to determine the effect of dexamethasone on cerebral MRI changes and their association with intracerebral inflammatory responses and clinical outcome in adults treated for tuberculous meningitis. Hide abstract

Simmons CP, Bernasconi NL, Suguitan AL, Mills K, Ward JM, Chau NV, Hien TT, Sallusto F et al. 2007. Prophylactic and therapeutic efficacy of human monoclonal antibodies against H5N1 influenza. PLoS Med, 4 (5), pp. e178. Read abstract | Read more

New prophylactic and therapeutic strategies to combat human infections with highly pathogenic avian influenza (HPAI) H5N1 viruses are needed. We generated neutralizing anti-H5N1 human monoclonal antibodies (mAbs) and tested their efficacy for prophylaxis and therapy in a murine model of infection. Hide abstract

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