Alex Wessel

Program: Immunology

Current advisor: Michael S. Diamond, MD, PhD

Undergraduate university: University of Wisconsin – Madison

Research summary
My research in the Diamond lab focused on flaviviruses, which are arthropod-transmitted RNA viruses including yellow fever, dengue, Zika (ZIKV), and West Nile (WNV) viruses. Flaviviruses cause a spectrum of potentially life-threatening diseases including hepatitis, vascular shock, congenital abnormalities, and encephalitis. However, the viral factors mediating these specific clinical disorders are not completely understood. Furthermore, many flaviviruses, such as ZIKV and WNV, lack approved vaccines and therapeutics despite considerable global health impacts. Flavivirus non-structural protein 1 (NS1) serves as an essential scaffolding molecule during virus replication, but also is expressed on the cell surface and secreted as a soluble glycoprotein that circulates in the blood of infected individuals. Although extracellular forms of NS1 are implicated in immune modulation and endothelial dysfunction at blood-tissue barriers, it has been challenging to isolate and study the effects of NS1 on pathogenesis without disrupting its key role in virus replication. For part of my work in the Diamond lab, we identified WNV NS1 variants that do not affect virus replication and evaluated their effects on pathogenesis in mice. Our characterization of a particular WNV NS1 variant suggests that secreted NS1 in circulation facilitates WNV dissemination to the brain and affects disease outcome. Our findings help to understand the role of secreted NS1 during flavivirus infection and support antiviral strategies that target circulating forms of NS1. Vaccines and therapeutic antibodies against flaviviruses usually promote neutralization by targeting the envelope protein of the virion. However, this approach is hindered by the concern for antibody-dependent enhancement (ADE) of infection, a phenomenon that leads to paradoxical worsening of disease. As an alternative strategy, antibodies targeting flavivirus NS1, which is absent from the virion, can protect against disease while avoiding ADE. Most of my work in the Diamond lab centered on evaluating the structure-function relationships and protective activity of flavivirus NS1-specific monoclonal antibodies (mAbs). We identified groups of anti-NS1 mAbs that protect mice against ZIKV and WNV challenge and mapped their structural epitopes using mutagenesis, hydrogen-deuterium exchange, and cryo-electron microscopy. Our studies suggest that antibodies targeting specific domains in NS1 could serve as the basis for the design of rational, structure-guided vaccines and antiviral countermeasures.

Graduate publications
Georgiev GI, Malonis RJ, Wirchnianski AS, Wessel AW, Jung HS, Cahill SM, Nyakatura EK, Vergnolle O, Dowd KA, Cowburn D, Pierson TC, Diamond MS, Lai JR. 2022 Resurfaced ZIKV EDIII nanoparticle immunogens elicit neutralizing and protective responses in vivo. Cell Chem Biol, 29(5):811-823.e7.

Wessel AW, Dowd KA, Biering SB, Zhang P, Edeling MA, Nelson CA, Funk KE, DeMaso CR, Klein RS, Smith JL, Cao TM, Kuhn RJ, Fremont DH, Harris E, Pierson TC, Diamond MS. 2021 Levels of Circulating NS1 Impact West Nile Virus Spread to the Brain. J Virol, 95(20):e0084421.

Wessel AW, Doyle MP, Engdahl TB, Rodriguez J, Crowe JE Jr, Diamond MS. 2021 Human Monoclonal Antibodies against NS1 Protein Protect against Lethal West Nile Virus Infection. mBio, (Epub ahead of print):e0244021.

Shema Mugisha C, Vuong HR, Puray-Chavez M, Bailey AL, Fox JM, Chen RE, Wessel AW, Scott JM, Harastani HH, Boon ACM, Shin H, Kutluay SB. 2020 A Simplified Quantitative Real-Time PCR Assay for Monitoring SARS-CoV-2 Growth in Cell Culture. mSphere, 5(5):e00658-20.

Hassan AO, Kafai NM, Dmitriev IP, Fox JM, Smith BK, Harvey IB, Chen RE, Winkler ES, Wessel AW, Case JB, Kashentseva E, McCune BT, Bailey AL, Zhao H, VanBlargan LA, Dai YN, Ma M, Adams LJ, Shrihari S, Danis JE, Gralinski LE, Hou YJ, Schäfer A, Kim AS, Keeler SP, Weiskopf D, Baric RS, Holtzman MJ, Fremont DH, Curiel DT, Diamond MS. 2020 A Single-Dose Intranasal ChAd Vaccine Protects Upper and Lower Respiratory Tracts against SARS-CoV-2. Cell, 183(1):169-184.e13.

hu Z, Mesci P, Bernatchez JA, Gimple RC, Wang X, Schafer ST, Wettersten HI, Beck S, Clark AE, Wu Q, Prager BC, Kim LJY, Dhanwani R, Sharma S, Garancher A, Weis SM, Mack SC, Negraes PD, Trujillo CA, Penalva LO, Feng J, Lan Z, Zhang R, Wessel AW, Dhawan S, Diamond MS, Chen CC, Wechsler-Reya RJ, Gage FH, Hu H, Siqueira-Neto JL, Muotri AR, Cheresh DA, Rich JN. 2020 Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin αvβ5 Axis. Cell Stem Cell, 26(2):187-204.

Wessel AW, Kose N, Bombardi RG, Roy V, Chantima W, Mongkolsapaya J, Edeling MA, Nelson CA, Bosch I, Alter G, Screaton GR, Fremont DH, Crowe JE Jr, Diamond MS. 2020 Antibodies targeting epitopes on the cell-surface form of NS1 protect against Zika virus infection during pregnancy. Nat Commun, 11(1):5278.

Goo L, Debbink K, Kose N, Sapparapu G, Doyle MP, Wessel AW, Richner JM, Burgomaster KE, Larman BC, Dowd KA, Diamond MS, Crowe JE Jr, Pierson TC. 2019 A protective human monoclonal antibody targeting the West Nile virus E protein preferentially recognizes mature virions. Nat Microbiol, 4(1):71-77.