Medical Biology - Theses

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Subject: Dengue × Subject: Immunology ×

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    Identification of molecular pathways associated with susceptibility and immunity to severe dengue and malaria
    Studniberg, Stephanie Irene ( 2023-12)
    In this era of increasing globalisation, urbanisation, and worsening climate change, the geographical range of transmission-competent mosquito vectors is shifting. Mosquito-borne diseases such as malaria and dengue are gradually emerging in previously unaffected areas, and re-emerging in areas where they had once previously subsided. With alarming increases in dengue case incidence, and for the first time, a chapter addressing the influence of climate change on malaria transmission in the World Malaria Report, it is clear that these two important vector-borne diseases are of utmost global relevance. As per the World Health Organization (WHO) guidelines, individuals presenting with warning signs signifying progression to severe dengue are required to remain under hospital observation. However, these warning signs appear late in the disease course and are non-specific. Consequentially, hospitals become overwhelmed with patients admitted for in-patient observation, many of whom do not progress to severe dengue. Biomarkers to detect progression to severe dengue upon hospital presentation are much needed to improve patient triage and resource allocation. In malaria, despite the great achievement of the recommendation by the WHO for the use of the RTS,S and R21/Matrix-M vaccines in children living in endemic areas, reductions in malaria case incidence remain at a prolonged stall. It is clear that efficacious vaccines approved for children to adults are required to reduce the global malaria burden. Further elucidation of the molecular mechanisms underlying the immune response to dengue and malaria is imperative if these outcomes are to be achieved. To address these outstanding concerns, an integrative systems immunology approach was utilised to identify molecular pathways associated with susceptibility and immunity to severe dengue and malaria. The studies within this thesis have integrated data from single-cell mass cytometry, serology, and transcriptional profiling of peripheral blood mononuclear cells from individuals progressing to either dengue fever (DF) or dengue haemorrhagic fever (DHF), as well as individuals living in a malaria-endemic regions of Indonesia with either symptomatic or asymptomatic Plasmodium falciparum and Plasmodium vivax malaria. Integrative data analysis identified frequencies and transcriptional profiles of effector CD4+ and CD8+ T cells as important components of dengue immunity in individuals progressing to DF. Furthermore, high frequencies of defined populations of CD4+ non-classical monocytes were associated with increased odds of developing DHF. Our approach discovered a strong transcriptional phenotype of immunosuppression underlying asymptomatic P. falciparum malaria, suggesting that the carriage of these infections could preclude complete parasite clearance. Lastly, unlike symptomatic P. falciparum malaria that induced a highly inflammatory response, clinical P. vivax infection featured the upregulation of anti-inflammatory pathways and checkpoint receptors, providing a feedback loop to ameliorate symptomatic infection. Furthermore, gene set enrichment analysis revealed profound dysfunction of the blood monocyte compartment in both symptomatic and asymptomatic P. vivax malaria. Together, the findings in this thesis have critical implications for the deployment and efficacy of malaria vaccines, and for the development of diagnostic tools to predict disease outcomes for dengue patients at point-of-care.
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    Manipulation of host signalling for the characterisation and control of dengue fever
    Forsyth, Wasan Otis ( 2020)
    Dengue fever is a mosquito-transmitted disease of the tropics and sub-tropics that is caused by dengue virus (DENV). There are an estimated 60-100 million clinical cases of dengue fever per year, resulting in at least 10,000 deaths. Most clinical cases of dengue are characterised by flu-like symptoms. However, for unknown reasons, a small proportion (1-2%) of clinical cases progress to a life-threatening form of disease referred to as “severe dengue”. Severe dengue is characterised by cytokine storms, heightened endothelial permeability and associated sequelae such as shock and haemorrhage. During the onset of severe dengue, viraemia and viral antigenaemia are sharply declining or absent. Therefore, it is logical to deduce that dysregulated host signalling is the underlying cause of the cytokine storm phenotype and symptoms of severe dengue. However, although many host factors have been characterised in the context of DENV infection, the root cause of this signalling dysregulation is still poorly understood. Furthermore, there are currently no drug treatments available for the treatment of severe dengue, and although there is a licensed dengue vaccine, it confers only moderate protection, and administration of this vaccine to dengue naive individuals is contraindicated by the World Health Organisation. In the first part of this thesis, I characterised how genetic disruption of key host signalling pathways altered the response of macrophages and mice to DENV infection. I found that infection of cells and mice that had a co-deletion of genes encoding cellular inhibitor of apoptosis proteins (cIAPs) resulted in decreased production of virus, and an exaggerated production of inflammatory cytokines. In the second part of this thesis, I determined whether clinical stage cancer therapeutics could be repurposed as treatments for severe dengue. To investigate this, I established an in vivo mouse model of severe dengue and treated these mice with anti-inflammatory compounds. However, these drug treatments did not reduce clinical manifestations of infection or improve the survival of the infected mice. These studies suggest that cIAPs facilitate the efficient replication of DENV. In addition, I hope that the negative results from my therapeutic experiments can inform future experimental plans, and contribute to reducing the worldwide burden of severe dengue.