Dissertation
The role of macrophages in ebola virus infection
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2021
DOI: 10.17077/etd.006228
Abstract
Ebola virus (EBOV) is a member of the Filoviridae, a family of highly pathogenic viruses that cause sporadic outbreaks of severe hemorrhagic fever with mortality rates averaging 50%. While there are no approved vaccines or therapeutics currently available, there are several promising candidates in clinical trials. While better treatments and preventative measures seem to be on the horizon, geopolitical instability in regions most heavily affected by EBOV makes it difficult to deploy the resources necessary for quarantine, diagnosis, and treatment. Coupled with an unknown animal reservoir and poorly characterized mechanisms of spread, future outbreaks are likely to occur. As such, we have taken a concerted effort to increase our understanding of the biology of EBOV in critical cell types with the goal of using that knowledge to develop future therapeutic approaches and thus increase the tools at our disposal.
EBOV is thought to infect tissue macrophages (Mϕs) early during infection. Infection of Mϕs is highly productive, leading to increased viral load, and facilitating systemic dissemination. Infection of Mϕs stimulates the production of proinflammatory and immunomodulatory cytokines and chemokines, leading to the production of a cytokine storm, while simultaneously increasing tissue factor production and thus facilitating disseminated intravascular coagulation, a hallmark of hemorrhagic fever. Given the many roles that Mϕs play during EBOV infection, we have focused here on several aspect of macrophage biology in response to EBOV infection to better understand the factors that govern their susceptibility to infection.
Mϕs are known to adopt a wide variety of phenotypes based on the chemical signals present in their environment. Broadly, these signals can induce either pro-inflammatory (M1) or anti-inflammatory (M2) effector phenotypes. We previously identified the M1 stimulus interferon gamma (IFN-γ) as a potent inhibitor or EBOV replication and found a strong protective effect both in vitro as well as in a mouse model. Here we show that the M2 stimuli IL-4/IL-13 serve to enhance EBOV infection of Mϕs by up regulating critical receptors that allow for enhanced binding and entry of virions. Furthermore, we find that this enhanced entry results in higher levels of mortality in a mouse model. This, in conjunction with our work with M1 Mϕs and the work of others, provides a framework for pursuing the various host factors that govern outcomes in human patients.
Given the role of Mϕ polarization on outcomes in EBOV infection, we also sought to identify cell intrinsic mechanisms that could alter the phenotype of Mϕs in response to EBOV infection. Intrinsically we focused on the innate signaling molecule CD40 and its ligand CD154. We found that CD40 on macrophages was critical for the initiation of an early protective inflammatory response, with CD40 deficient mice succumbing to EBOV infection more rapidly than their CD40 sufficient counterparts. Mechanistically we found that CD40 signaling on Mϕs directly stimulated IL-12 production, which acted in a paracrine fashion to stimulate IFN-γ production by lymphocytes. These studies build on our work with Mϕ polarization and also provide a new paradigm for CD40 signaling, which was previously thought of as a component of adaptive, but not innate, immunity.
The logical conclusion of these studies was to identify extrinsic factors that might skew Mϕ populations within the host and influence the response to EBOV. For this we turned to co-infection as a likely means by which this might occur. To this end, it was recently observed in epidemiological studies that patients co-infected with both Plasmodium and EBOV were less likely to succumb to EBOV. We postulated this was due to a robust pro-inflammatory response to Plamsodium and investigated this with a mouse model of co-infection. We found that Plasmodium infection dramatically reduced mortality due to EBOV in an IFN-γ dependent manner, and that this protective effect was long lasting. Furthermore, we found that sub-clinical infections that occurred in Plasmodium infected rodents elicited a detectable antibody response, which was sufficient to protect mice from a subsequent EBOV challenge. These observations complement those made in human populations during the 2013 outbreak and have the potential to shape the way future outbreaks are managed.In total, our studies build upon the existing literature by emphasizing the critical role of macrophages during EBOV infection and provide a new model for understanding the critical factors that govern outcomes in EBOV infection.
Details
- Title: Subtitle
- The role of macrophages in ebola virus infection
- Creators
- Kai Jordan Rogers
- Contributors
- Wendy J Maury (Advisor)Richard J Roller (Committee Member)Aloysius J Klingelhutz (Committee Member)Jon C Houtman (Committee Member)John D Colgan (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Microbiology
- Date degree season
- Spring 2021
- DOI
- 10.17077/etd.006228
- Publisher
- University of Iowa
- Number of pages
- xix, 186 pages
- Copyright
- Copyright 2019 Kai Jordan Rogers
- Language
- English
- Description illustrations
- illustrations (some color)
- Description bibliographic
- Includes bibliographical references (pages 170-186)
- Public Abstract (ETD)
Ebola virus causes a highly lethal disease in humans. Outbreaks of Ebola occur sporadically in Africa, the largest of which lasted from 2013-2016 and resulted in over 11,000 deaths. With no vaccine and few treatment options, it is important to gain a better understanding of the cells that Ebola infects to guide future drug development. One such cell is the macrophage, a key component of the early immune response, and an important cell during Ebola infection. My work has focused on understanding several aspects of macrophage biology in order to better understand the role of these cells in infection. First, I found that different types of macrophage are more or less susceptible to Ebola virus infection. I also demonstrated that signals macrophages receive from other immune cells could dramatically reduce their susceptibility to Ebola. Finally, I showed that other infectious diseases, specifically malaria, could cause changes in the host immune response that protect from Ebola virus infection. In total, my work has shown that macrophages are a critical cell population to consider for future drug development, and I have identified a number of ways to target macrophages to benefit the patient.
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984188270102771
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