Date of Award
8-2026
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
School
Biological, Environmental, and Earth Sciences
Committee Chair
Dr. Fengwei Bai
Committee Chair School
Biological, Environmental, and Earth Sciences
Committee Member 2
Dr. Yan-Lin Guo
Committee Member 2 School
Biological, Environmental, and Earth Sciences
Committee Member 3
Dr. Shahid Karim
Committee Member 3 School
Biological, Environmental, and Earth Sciences
Committee Member 4
Dr. Jacques Kessl
Committee Member 4 School
Mathematics and Natural Sciences
Committee Member 5
Dr. Hao Xu
Committee Member 5 School
Biological, Environmental, and Earth Sciences
Abstract
Although chikungunya virus (CHIKV)-caused cardiovascular diseases are frequently reported in clinics, the underlying mechanisms are poorly understood, which is primarily due to a lack of animal models. To develop an animal model for studying CHIKV infection in the heart, I found that CHIKV infection in homozygous interferon α/β receptor-deficient (ifnar1-/-) and interferon α/β/γ receptor-deficient (ifnag-/-) mice resulted in high viral loads in the hearts as early as day (D) 1 post-infection (p.i.) but with 100% mortality within three days p.i.. Interestingly, the heterozygous ifnar1+/-and ifnag+/- mice survived CHIKV infection and had higher viral burdens in the heart tissue than the WT controls. The flow cytometry and immunohistochemistry studies revealed that more leukocytes, particularly neutrophils, infiltrated into the heart of ifnag+/- and ifnar1+/- mice than WT mice. I further evaluated heart pathology to study CHIKV-induced heart damage in ifnag+/- and ifnar1+/-, and WT mice. I also found that CHIKV does not target all parts of the heart equally, with higher viral burden in the left atrium, left ventricle, and aorta compared to the right ventricle and right atrium. These results suggest that ifnag+/- and ifnar1+/- mice may serve as mouse models for studying CHIKV pathogenesis in the heart. Previous studies have reported that the role of interleukin-17A (IL-17A) is associated with promoting CHIKV infection as well as cardiovascular diseases (CVD) in humans and mice. However, the mechanism by which IL-17A mediates CHIKV-induced CVD has not yet been characterized. In this study, I found that Il-17a was highly expressed in infected hearts than in uninfected hearts, and CHIKV RNA was almost undetectable in the hearts of IL-17A-deficient (Il17a-/-) mice inoculated with CHIKV. This study identifies the IL-17A/IL-17RA signaling axis as a primary driver of CHIKV pathogenesis in cardiac tissue. Moving beyond previous clinical observations that merely linked IL-17A to disease severity, my findings, supported by the newly developed mouse models, human primary cells, and therapeutic antibody blockage, demonstrate that IL-17A signaling facilitates CHIKV replication and contributes to inflammatory damage in the heart, suggesting a novel therapeutic strategy for CHIKV-caused myocarditis by targeting IL-17A signaling.
ORCID ID
0009-0002-8980-2183
Copyright
Shazeed-Ul Karim
Recommended Citation
Karim, Shazeed-Ul, "Exploring Heterozygous Interferon-Deficient Mice as a Novel Model for Chikungunya Virus Cardiac Infections and Interleukin-17A Based Therapies" (2026). Dissertations. 2498.
https://aquila.usm.edu/dissertations/2498
Included in
Biology Commons, Cardiovascular Diseases Commons, Cell Biology Commons, Immunology of Infectious Disease Commons, Immunopathology Commons, Therapeutics Commons, Virology Commons, Virus Diseases Commons