Identifying Immunological Signatures in Blood Predictive of Host Response to Plasmodium Falciparum Vaccines and Infections Using Computational Methods

dc.contributor.advisorTran, Tuan M.
dc.contributor.authorSenkpeil, Leetah Celine
dc.contributor.otherSullivan, William J., Jr.
dc.contributor.otherYu, Andy Q.
dc.contributor.otherZhang, Jie
dc.date.accessioned2023-05-24T19:59:57Z
dc.date.available2023-05-24T19:59:57Z
dc.date.issued2023-05
dc.degree.date2023en_US
dc.degree.discipline
dc.degree.grantorIndiana Universityen_US
dc.degree.levelPh.D.en_US
dc.descriptionIndiana University-Purdue University Indianapolis (IUPUI)en_US
dc.description.abstractMalaria infects more than 240 million people every year, causing more than 640,000 deaths in 2021 alone. The complex interactions between the Plasmodium parasites that cause malaria and host immune system have made it difficult to identify specific mechanisms of vaccine-induced and naturally acquired immunity. After more than half a century of research into potential immunization methods, reliable immune correlates of malaria protection still have yet to be identified, and questions underlying the reduced protective efficacy of malaria vaccines in field studies of endemic populations relative to non-endemic populations still remain. In this thesis, I use computational methods to identify biological determinants of whole-parasite vaccine-induced immunity and immune correlates of protection from clinical malaria. Our systems analysis of a PfSPZ Vaccine clinical trial revealed that innate signatures were predictive of increased antibody response but also a decrease in the cytotoxic response required for sterilizing immunity. Conversely, these myeloid signatures predicted protection against parasitemia for subjects receiving a saline placebo, suggesting a role for myeloid-lineage cells in clearing pre-erythrocytic parasite stages. Based on these findings, I created a structural equation model to examine the interactions between cellular, humoral, and transcriptomic responses and the effects these have on protection outcome. This revealed a direct positive effect of CD11+ monocyte-derived cells on parasitemia outcome post-vaccination that was mediated by the presence of P. falciparum-specific antibodies at pre-vaccination baseline. Additionally, this model illustrates an indirect role of CD14+ monocyte activation in restricting immune priming by the PfSPZ Vaccine. Together, this data supports our hypothesis that innate immune activation and antigen presentation are uncoupled from cytotoxic cell-dependent immunity from the PfSPZ Vaccine and that this effect may be antibody-dependent.en_US
dc.identifier.urihttps://hdl.handle.net/1805/33296
dc.identifier.urihttp://dx.doi.org/10.7912/C2/3151
dc.language.isoen_USen_US
dc.subjectComputational biologyen_US
dc.subjectMalariaen_US
dc.subjectSystems vaccinologyen_US
dc.titleIdentifying Immunological Signatures in Blood Predictive of Host Response to Plasmodium Falciparum Vaccines and Infections Using Computational Methodsen_US
dc.typeThesis
Files
Original bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
Senkpeil_iupui_0104D_10678.pdf
Size:
3.93 MB
Format:
Adobe Portable Document Format
Description:
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.99 KB
Format:
Item-specific license agreed upon to submission
Description: