| Targeting YWHAZ and HSPA4 in Powassan-Lyme Co-Infections |
| Paper ID : 1126-IPCA5 (R2) |
| Authors |
|
Fatemeh Shams1, Elina Khanehzar1, Sonia Jafarinia2, Masoud Abedi3, Baran Rahmatian *4, Zahra Khosravi5, Zakkyeh Telmadarraiy6, Amirsajad Jafari7 11. Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran 2. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran 2Faculty of Veterinary Medicine, Islamic Azad University of Karaj Branch, Alborz, Iran 3Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran 4Faculty of Veterinary Medicine, Islamic Azad University of Urmia Branch, West Azerbaijan, Iran 5Faculty of Veterinary Medicine, Islamic Azad University of Babol Branch, Babol, Iran 61. Department of Medical Entomology and Vector Control, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran 2. Rahyan Novin Danesh (RND) University, Sari, Mazandaran, Iran 71. Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
2. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran |
| Abstract |
| The blacklegged tick (Ixodes scapularis) is a major vector of human pathogens, transmitting viruses (e.g., Powassan virus), bacteria (e.g., Borrelia burgdorferi, causing Lyme disease), and parasites. Climate change, habitat shifts, and abundant host populations (e.g., deer, small mammals) have driven the expansion of I. scapularis across North America, increasing the risk of co-infections. These co-infections—marked by overlapping symptoms like fever, fatigue, joint pain, and neurological issues—complicate diagnosis and treatment. The tick’s complex life cycle (egg, larva, nymph, adult) further amplifies transmission opportunities. The growing geographic range of I. scapularis, now widespread in the northeastern, midwestern, and southeastern U.S., underscores the urgent need to unravel shared host-pathogen interaction pathways. Such insights could enable broad-spectrum therapies to combat co-infections like Powassan-Lyme, addressing a critical public health gap exacerbated by diagnostic delays and limited treatment options. We utilized a comprehensive bioinformatics strategy to examine protein-protein interaction (PPI) networks. Initially, human druggable proteins associated with both infections were identified using the Pharos database (https://pharos.nih.gov/). Subsequently, we generated a theoretical PPI network via STRING (https://string-db.org/) and performed topological analysis in Cytoscape to pinpoint critical hub proteins using centrality measures (degree and closeness centrality). Hubs with high connectivity, indicating functional redundancy and tight interactions in key signaling pathways. HSPA4, a high-betweenness bottleneck gene (0.473), likely coordinates critical processes like protein folding and immune response. SFN showed perfect clustering (coefficient = 1.0), forming a tightly interconnected module in p53 signaling, while low-connectivity genes (TLR1, EP300, VARS1) with degree = 1 appeared to play peripheral roles. In the field of in silico drug design aimed at combating tick-borne co-infections, YWHAZ stands out as an exceptionally promising therapeutic target. This is primarily due to its well-defined druggable site, which facilitates the development of effective inhibitors. Additionally, its established role in pathogen interactions underscores its importance in disease progression, making it a compelling focus for intervention. Furthermore, the presence of existing inhibitory scaffolds provides a foundation for drug development, accelerating the process of identifying and refining potential treatments. Collectively, these attributes position YWHAZ as a key molecular target in the fight against tick-borne diseases, offering a strategic avenue for therapeutic advancements. |
| Keywords |
| Bioinformatics, PPI, Drug discovery, Host-pathogen interactions, In silico |
| Status: Abstract Accepted |
