Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


NMG_dissertation_FINAL.pdf (5.78 MB)

ETD Abstract Container

Abstract Header

Characterizing and Manipulating Biological Interactions of Viruses

Gulati, Neetu Mehek
http://rave.ohiolink.edu/etdc/view?acc_num=case1505991239211632

Abstract Details

2018, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
Viruses are both pathogenic and can be repurposed for novel roles in nanotechnology. Tobacco mosaic virus (TMV) plant viral nanoparticles are promising drug delivery agents. In this work TMV nanoparticles are stealth-coated with serum albumin (SA), the most abundant protein in human plasma. SA-camouflaged nanoparticles successfully evade immune recognition in vitro. Cryo-electron tomography of SA-conjugated TMV reveals that SA provides steric hindrance for TMV-specific antibodies and that SA adopts random orientations relative to the viral rod. Random orientations could be advantageous for preventing an immune response based on pathogen-associated molecular patterns (PAMPs). Studies on SA-TMV constructs with different SA coverage levels and linker lengths indicate that constructs with high SA coverage with short linkers are best for immune evasion. In vivo antibody production experiments reveal that administration of SA-TMV constructs results in the production of TMV-specific antibodies but not SA-specific antibodies. Nevertheless, intact SA-shielded nanoparticles are protected from recognition by these antibodies. Confocal microscopy results suggest that after SA-TMV is taken up by macrophages, the TMV and stealth-coating components are processed through different pathways: TMV is degraded in the lysosome while SA is recycled to the cell surface. These results highlight the potential for tuning the immune evasion properties of a viral-based nanoparticle. Numerous viruses can infect humans and cause disease and there are only a handful of anti-viral drugs currently available. Human papillomavirus (HPV) 16, together with HPV18, are the two most oncogenic HPV types and are thought to cause 70% of cervical cancer cases worldwide. HPV16 can be neutralized by human alpha-defensin 5 (HD5), an innate immune peptide. Cryo-electron microscopy structural studies reveal that HD5 stabilizes the HPV16 capsid and strengthens the interaction between the capsid and viral genome, thus presumably blocking separation of the capsid and the genome necessary for productive infection. Characterizing the neutralization mechanism of HD5 is significant for developing HD5-based HPV16 treatments, as no therapies currently exist for the treatment of HPV infections. Overall this body of work reveals the importance of characterizing and manipulating the intricate interactions between viruses and biological factors encountered in their natural hosts and in nanotechnology applications.
Phoebe Stewart (Advisor)
Nicole Steinmetz (Advisor)
Vera Moiseenkova-Bell (Committee Chair)
Jun Qin (Committee Member)
Vivien Yee (Committee Member)
Derek Taylor (Committee Member)
234 p.
Biomedical Engineering; Biomedical Research; Biophysics; Nanotechnology; Pharmacology; Virology

Recommended Citations

Citations

  • Gulati, N. M. (2018). Characterizing and Manipulating Biological Interactions of Viruses [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1505991239211632

    APA Style (7th edition)

  • Gulati, Neetu. Characterizing and Manipulating Biological Interactions of Viruses. 2018. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1505991239211632.

    MLA Style (8th edition)

  • Gulati, Neetu. "Characterizing and Manipulating Biological Interactions of Viruses." Doctoral dissertation, Case Western Reserve University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1505991239211632

    Chicago Manual of Style (17th edition)

case1505991239211632
272
© 2017, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.