The Role of Adaptive Mutations in Mouse Adapted Crimean-Congo Hemorrhagic Fever Virus

Authors' Names

Shanna S. Leventhal, University of Montana, Missoula; NIAID, NIHFollow
David W. Hawman, NIAID, NIHFollow

Presentation Type

Oral Presentation - Campus Access Only

Category

STEM (science, technology, engineering, mathematics)

Abstract/Artist Statement

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is endemic in Europe, Asia, and Africa. The geographic distribution of CCHFV is expanding as Hyalomma ticks, the main carriers of the virus, migrate northward. Infection with CCHFV initially manifests with non-specific symptoms including fever, muscle pains, and nausea that may progress into a hemorrhagic phase characterized by severe bleeding throughout the body. The case fatality rate is reported to range between 9-50%. With increasing numbers of humans at risk, further understanding of how the virus causes disease is essential for developing effective therapeutics. Studies investigating the host and viral determinants of pathogenesis, however, have been constrained due to mouse models requiring mice to be deficient in initial innate immune responses to manifest CCHFV disease symptoms after infection. However, we have recently developed a mouse-adapted CCHFV (MA-CCHFV) which presents with disease similar to human CCHFV cases in fully immunocompetent mice. We hypothesize that adaptive mutations in MA-CCHFV have enabled the virus to overcome mouse innate immunity and cause disease in immunocompetent mice.

CCHFV is an RNA virus with three genomic segments. The S segment encodes the nucleoprotein (NP) and a non-structural protein (NSs) while the M segment encodes a large multi-unit protein which is later cleaved into two structural glycoproteins and three non-structural proteins. The L segment has largely unknown function(s) but does encode a protein required for viral replication. Compared to parental strain CCHFV-Hoti, MA-CCHFV has 6 mutations which result in changes to proteins encoded by the virus. Two mutations occur in the NP, one in the NSs, two in the M segment non-structural proteins GP38 and NSm and two in the viral L protein. These mutations likely indicate key proteins CCHFV uses as virulence factors to cause severe disease. To determine the role of these adaptations, we are examining the responses of human and mouse cell lines to infection with parental and MA-CCHFV strains. In addition, we can express the viral proteins independently of the virus to isolate the specific roles of these proteins and understand how they affect the initial immune responses in mouse cells. Understanding how these mutated proteins uniquely interact with the mouse immune system will help identify the host and viral determinants of CCHFV-induced disease. This will support new avenues of focus in CCHFV research to develop effective therapeutics and vaccines.

This research is funded by the Intramural Research Program, NIAID, NIH.

Mentor Name

Heinrich Feldmann

Personal Statement

The recent SARS-CoV-2 pandemic illustrates the drastic effects an unchecked infectious disease can wreak across the globe. It also elucidates the growing need for preventative measures especially concerning viruses with pandemic potential. In 2017, the World Health Organization created a list of high priority pathogens with the potential to cause such a threat to encourage research on developing therapeutics and vaccines to combat these diseases in endemic countries and in the event of global spread. Crimean Congo Hemorrhagic Fever virus (CCHFV) is listed as one of these pathogens. CCHFV has a high geographic distribution and is found across Southern and Eastern Europe, Africa, the Middle East, and Asia. It is carried and transmitted by Hyalomma genus ticks which, due to climate change, are spreading ever more northward and increasing the risk of CCHFV outbreaks in naive countries. Currently, there are no widely approved, available or efficacious vaccines or therapeutics. One major limitation in developing such interventions is the lack of understanding on how CCHFV causes disease in humans. Commonly, such studies are done in animal models however, human isolates of CCHFV don’t cause disease in mice with fully competent immune systems. Recently, our group developed a mouse-adapted CCHFV (MA-CCHFV) which differs from the human isolate in 6 mutations affecting 4 out of 8 known proteins encoded by the virus which confer it the ability to cause disease in fully immunocompetent mice. MA-CCHFV provides us the novel opportunity to study viral pathogenesis and interactions with the host immune responses. In addition, the mutations may be seen as a significant roadmap pointing to which viral proteins may be responsible for causing disease. Elucidating the role of these proteins and their functions in antagonizing the immune response of the mouse may uncover how CCHFV disease develops and progresses in humans. Therapeutics and vaccines could then be focused on antagonistic proteins or immune pathways utilized by CCHFV to cause disease. Thus, the development and study of this mouse adapted variant is a significant tool of progress in the CCHFV field. Personally, the opportunity to work at the forefront of this discovery is not only exciting but also beneficial to developing my skills as a virologist. The initial startup of this project is straightforward and allows me to develop a strong basis in my laboratory skills and understanding my experiments and goals. However, due to the lack of complete knowledge on how CCHFV proteins function, this project inevitably branches into several new and exciting avenues of research, providing me the opportunity to grow in my abilities to follow data as it is acquired and design and lead new experiments. At the same time, I’m able to broaden by understanding on how my projects, which seem so specific and niche, can impact the global community. Understanding how MA-CCHFV functions in mice will help uncover how CCHFV manifests disease in humans, which will influence the development of new therapeutics and vaccines. It is an ever-increasing excitement to get to work on a project I find interesting and challenging and know will aid development of therapeutics to help those directly affected by or with the potential to be affected by CCHFV. I’m excited to share my research with a non-scientific audience to spread interest, trust and faith in science taking steps to continually protect our greater global community and future.