Abstract
Human challenge models, in which volunteers are experimentally infected with a pathogen of interest, provide the opportunity to directly identify both natural and vaccine-induced correlates of protection. In this review, we highlight how the application of transcriptomics to human challenge studies allows for the identification of novel correlates and gives insight into the immunological pathways required to develop functional immunity. In malaria challenge trials for example, innate immune pathways appear to play a previously underappreciated role in conferring protective immunity. Transcriptomic analyses of samples obtained in human challenge studies can also deepen our understanding of the immune responses preceding symptom onset, allowing characterization of innate immunity and early gene signatures, which may influence disease outcome. Influenza challenge studies demonstrate that these gene signatures have diagnostic potential in the context of pandemics, in which presymptomatic diagnosis of at-risk individuals could allow early initiation of antiviral treatment and help limit transmission. Furthermore, gene expression analysis facilitates the identification of host factors contributing to disease susceptibility, such as C4BPA expression in enterotoxigenic Escherichia coli infection. Overall, these studies highlight the exceptional value of transcriptional data generated in human challenge trials and illustrate the broad impact molecular data analysis may have on global health through rational vaccine design and biomarker discovery.
Highlights
Human challenge studies, the deliberate infection of volunteers with a pathogen of interest, have been used to interrogate disease pathogenesis and vaccine efficacy since the smallpox challenge of James Phipps by Edward Jenner in 1796 [1]
Whereas microarrays measure the hybridization of fluorescently labeled transcripts to nucleotide probes on a bead chip, RNAseq involves sequencing of each transcript followed by alignment to a reference genome
We summarize the application of transcriptomics to human challenge models, providing examples of work exploring (i) host factors affecting susceptibility to disease, (ii) host–pathogen interactions, (iii) factors associated with symptom severity, (iv) modulation of immune responses by vaccination, and (v) early exposure signatures with diagnostic potential
Summary
The deliberate infection of volunteers with a pathogen of interest, have been used to interrogate disease pathogenesis and vaccine efficacy since the smallpox challenge of James Phipps by Edward Jenner in 1796 [1]. We summarize the application of transcriptomics to human challenge models, providing examples of work exploring (i) host factors affecting susceptibility to disease, (ii) host–pathogen interactions, (iii) factors associated with symptom severity, (iv) modulation of immune responses by vaccination, and (v) early exposure signatures with diagnostic potential. Apoptosis is one of the few pathways overrepresented in natural P. falciparum infection compared with experimental infection, possibly as a result of greater parasite load in those naturally infected [23] Another fundamental process often observed in the host transcriptional response to infection is a signature representing the cell cycle, seen to be significantly upregulated following challenge of naïve participants with S.
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