Understanding Exosomal Extracellular Vesicles and Morphine in the Neuropathology of Human Immunodeficiency Virus and Differential Zika Virus Strain-associated Pathology

Authors

Allen Caobi, Florida International UniversityFollow

Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Biomedical Sciences

First Advisor's Name

Andrea D. Raymond

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Alejandro Barbieri

Second Advisor's Committee Title

Committee Member

Third Advisor's Name

Nazira El-Hage

Third Advisor's Committee Title

Committee Member

Fourth Advisor's Name

Fatah Kashanchi

Fourth Advisor's Committee Title

Committee Member

Fifth Advisor's Name

Ajeet Kaushik

Fifth Advisor's Committee Title

Committee Member

Keywords

Exosomes, HIV, ZIKV, miRNA

Date of Defense

4-1-2022

Abstract

Exosomal Extracellular Vesicles (xEVs), integral to intercellular communication and regulation of immune responses, have functional effects based on their contents, which they transport to neighboring cells. However, in the context of infection, EV cargo can be modulated, by either infected or uninfected cells. We hypothesize that CNS-associated neuropathology, is partially, due to the cargo transported by the exosomes. We theorize that the cargo released from infected cell-derived xEVs may either facilitate or inhibit viral neuropathogenicity. Here we investigated xEVs in the case of two neurotropic viruses, Zika virus (ZIKV) and Human Immunodeficiency Virus (HIV). The hallmark characteristic of ZIKV-infection is fetal microcephaly, with unclear mechanisms. Findings from this study demonstrate that ZIKV pathogenic strain, FLR, induces differential gene expression and miRNA expression, relative to the non- 5 pathogenic Ugandan ZIKV strain, MR766, modulating inflammation and immune function. To understand the mechanisms of microcephaly we looked at exosomes that have crossed or are released from infected placental cells. ZIKV-FLR infection of Human Villous Trophoblasts (HVTs), a placental cell, was infected using a Transwell placental barrier (PB) model to mimic exosome transfer across the PB, in addition to evaluating PB integrity and permeability. HVTs resulted in the release of EVs containing an enhanced concentration of hsa-mir-612, hsa-mir-873-5p, and hsa-mir-1305. hsa-mir-612 targets genes which disrupt signaling cascades and promote apoptosis. The ZIKV-Envelope protein (EP) was found to promote apoptosis. Overall findings suggest that NGF-differentiated neurons were more susceptible to ZIKV infection. 25-30% of people living with HIV (PLWH) develop neurocognitive impairment (NCI) despite successful viral suppression by Anti-Retroviral Therapy (ART). Opiate abuse is known to exacerbate HIV transmission and neuropathology. NCI disrupts the quality of life of PLWHs by disrupting executive functions, motor skills, and memory. The battery of psychological examinations to ascertain NCI status is often a cumbersome and arduous task. Neuroinflammation is implicated in NCI and given the role of xEVs in regulating inflammatory responses; we postulate that xEVs may contribute to NCI pathology, with EV-derived miRNA profiles functioning as a barcode identifying NCI status. The data shows that there is some differential expression of protein, dependent on NCI status (ANI/MND).

Identifier

FIDC010698

Previously Published In

1. Allen Caobi, Rachel Fields, Mario Gomez , Jana Miles , Mickensone Andre, Adriana Yndart , Francisco Lima-Hernandez , Madhavan Nair , and Andrea D. Raymond. Exosomal extracellular vesicles containing Nef are indicative of HIV-associated Neurocognitive Impairment status. Cells. Submitted, 2022.
2. Caobi, A., Andre, M., Miles, J., Tomitaka, A., Nikkhah-Moshaie, R., Hernandez, A., Nair, M., & Raymond, A. D. (2020). Magnetic Nanoparticle and Exosomal Therapeutic (M-NEXT) Effects on HIV-Associated Neurotoxicity. Critical reviews in biomedical engineering, 48(3), 189–198. https://doi.org/10.1615/CritRevBiomedEng.2020034629.
3. Caobi, A., Nair, M., & Raymond, A. D. (2020). Extracellular Vesicles in the Pathogenesis of Viral Infections in Humans. Viruses, 12(10), 1200. https://doi.org/10.3390/v12101200

Recommended Citation

Caobi, Allen, "Understanding Exosomal Extracellular Vesicles and Morphine in the Neuropathology of Human Immunodeficiency Virus and Differential Zika Virus Strain-associated Pathology" (2022). FIU Electronic Theses and Dissertations. 4961.
https://digitalcommons.fiu.edu/etd/4961