Uncovering the Cytoskeletal Battlefield

Download or read book Uncovering the Cytoskeletal Battlefield written by Donté Alexander Stevens and published by . This book was released on 2023 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Successful viral infection, replication, and dissemination depend on the ability of a virus to subvert host cell processes. The molecular interplay between viruses and their hosts is an ancient and ongoing evolutionary "arms race," with each side constantly evolving new strategies to outwit the other. The existing literature regarding the impact of viral conflicts on mammalian evolution has predominantly concentrated on proteins that are directly involved in immune responses. Thus, in known cases of host-virus interactions, we see evolutionary signatures of conflict in host genes that encode viral antagonists. However, the principles of natural selection postulate that this paradigm is not exclusive to immune genes. Instead, we can infer that any protein interacting with viruses is subject to the selective pressures driving genetic adaptation. As such, we reasoned that genes involved in the active transport of macromolecules within the cell are one potential source of conflict. Due to the large size of eukaryotic cells, along with the high density of macromolecules, diffusion is limited. Cells transport intracellular cargo using dynein and kinesin motors, which move on microtubules in opposite directions to overcome this diffusion-limited environment. Viruses co-opt this cellular machinery for cellular entry, the transportation of viral components to replication sites, remodeling of cellular compartments, and viral egress. Conversely, the host adaptive and innate immune responses require movement of signaling components, transport of endocytic and exocytic vesicles, organelle recycling, and cellular remodeling, all of which require the microtubule-based trafficking machinery. Motivated by the competing interest of microtubule-based transport in aiding and inhibiting viral replication, we set out to identify conflicts over the intracellular trafficking machinery between viruses and their host cells. In this dissertation, I present collaborative work that identifies several intracellular trafficking genes exhibiting evolutionary signatures of conflict. Of these candidate genes, I characterize a novel role in the innate antiviral immune response for ninein-like (NINL), a dynein activating adaptor. Overall, this work provides a glimpse into the impact that viruses may have on the evolution of the intracellular transport machinery and demonstrates how leveraging evolutionary signatures of conflict can uncover novel host-pathogen interactions that could become therapeutic targets.