Natasha Kafai
Program: Immunology
Current advisor: Michael S. Diamond, MD, PhD
Undergraduate university: University of California-Berkeley
Research summary
Alphaviruses are enveloped positive-stranded RNA viruses of the Togaviridae family whose natural endemic cycles require mosquito vectors and nonhuman mammal or bird species. Alphaviruses are primarily transmitted to humans via mosquitoes and can cause a range of clinical signs and symptoms in humans including headache, arthralgia, and encephalitis. Venezuelan equine encephalitis virus (VEEV) constitutes one such encephalitic alphavirus and is responsible for periodic epidemics in equine and human populations across the Americas. Its potential for use as an aerosolized bioterrorism weapon and the demonstrated risk it poses in research settings highlight the need for a more effective vaccine and available countermeasures.
Although candidate VEEV vaccines have been developed using live-attenuated, replication defective, and DNA plasmid technologies, little has been done to characterize the epitope specificity and mechanisms of the protective humoral immune response to VEEV. Using a panel of murine and human VEEV-specific monoclonal antibodies (mAb), I am working to define mAb epitope specificity and correlates of VEEV protection and further, determine targeted epitopes and the role of Fc-mediated effector function in alphavirus cross-protective antibodies.
Our laboratory recently identified low-density lipoprotein receptor class A domain containing 3 (Ldlrad3) as a host receptor required for VEEV entry, infection, and pathogenesis. Gene editing of Ldlrad3 results in markedly reduced VEEV infection in neuronal cell lines. I have found that wild-type mice treated with an engineered decoy receptor Ldlrad3-Fc fusion protein survive lethal VEEV challenge, and newly generated Ldlrad3-/- mice are resistant to lethal infection. I am further exploring the biology of Ldlrad3 in vivo in the context of VEEV pathogenesis and have identified neurons as a target of LDLRAD3-mediated infection.
Overall, my research projects seek to contribute to the development of novel protective strategies specific to VEEV via the study of humoral-mediated responses to infection and novel host receptor biology.
Graduate publications
Ma H, Adams LJ, Raju S, Sariol A, Kafai NM, Janova H, Klimstra WB, Fremont DH, Diamond MS. 2024 The low-density lipoprotein receptor promotes infection of multiple encephalitic alphaviruses. Nat Commun, 15(1):246.
Zimmerman O, Holmes AC, Kafai NM, Adams LJ, Diamond MS. 2023 Entry receptors – the gateway to alphavirus infection. J Clin Invest, 133(2):e165307.
Kafai NM, Janova H, Cain MD, Alippe Y, Muraro S, Sariol A, Elam-Noll M, Klein RS, Diamond MS. 2023 Entry receptor LDLRAD3 is required for Venezuelan equine encephalitis virus peripheral infection and neurotropism leading to pathogenesis in mice. Cell Rep, 2(8):112946.
Kafai NM, Williamson LE, Binshtein E, Sukupolvi-Petty S, Gardner CL, Liu J, Mackin S, Kim AS, Kose N, Carnahan RH, Jung A, Droit L, Reed DS, Handley SA, Klimstra WB, Crowe JE, Diamond MS. 2022 Neutralizing antibodies protect mice against Venezuelan equine encephalitis virus aerosol challenge. J Exp Med, 219(4):e20212532.
Hunt AC, Case JB, Park YJ, Cao L, Wu K, Walls AC, Liu Z, Bowen JE, Yeh HW, Saini S, Helms L, Zhao YT, Hsiang TY, Starr TN, Goreshnik I, Kozodoy L, Carter L, Ravichandran R, Green LB, Matochko WL, Thomson CA, Vögeli B, Krüger A, VanBlargan LA, Chen RE, Ying B, Bailey AL, Kafai NM, Boyken SE, Ljubetic A, Edman N, Ueda G, Chow CM, Johnson M, Addetia A, Navarro MJ, Panpradist N, Gale M Jr, Freedman BS, Bloom JD, Ruohola-Baker H, Whelan SPJ, Stewart L, Diamond MS, Veesler D, Jewett MC, Baker D. 2022 Multivalent designed proteins neutralize SARS-CoV-2 variants of concern and confer protection against infection in mice. Sci Transl Med, 14(646):eabn1252.
Kafai NM, Diamond MS, Fox JM. 2022 Distinct Cellular Tropism and Immune Responses to Alphavirus Infection. Annu Rev Immunol, 40():615-649.
Ying B, Whitener B, VanBlargan LA, Hassan AO, Shrihari S, Liang CY, Karl CE, Mackin S, Chen RE, Kafai NM, Wilks SH, Smith DJ, Carreño JM, Singh G, Krammer F, Carfi A, Elbashir SM, Edwards DK, Thackray LB, Diamond MS. 2022 Protective activity of mRNA vaccines against ancestral and variant SARS-CoV-2 strains. Sci Transl Med, 14(630):eabm3302.
Basore K, Ma H, Kafai NM, Mackin S, Kim AS, Nelson CA, Diamond MS, Fremont DH.. 2021 Structure of Venezuelan equine encephalitis virus in complex with the LDLRAD3 receptor. Nature, 598(7882):672-76.
Dejnirattisai W, Zhou D, Ginn HM, Duyvesteyn HME, Supasa P, Case JB, Zhao Y, Walter TS, Mentzer AJ, Liu C, Wang B, Paesen GC, Slon-Campos J, López-Camacho C, Kafai NM, Bailey AL, Chen RE, Ying B, Thompson C, Bolton J, Fyfe A, Gupta S, Tan TK, Gilbert-Jaramillo J, James W, Knight M, Carroll MW, Skelly D, Dold C, Peng Y, Levin R, Dong T, Pollard AJ, Knight JC, Klenerman P, Temperton N, Hall DR, Williams MA, Paterson NG, Bertram FKR, Siebert CA, Clare DK, Howe A, Radecke J, Song Y, Townsend AR, Huang KA, Fry EE, Mongkolsapaya J, Diamond MS, Ren J, Stuart DI, Screaton GR. 2021 The antigenic anatomy of SARS-CoV-2 receptor binding domain. Cell, 184(8):2183-2200.e22.
VanBlargan LA, Errico JM, Kafai NM, Burgomaster KE, Jethva PN, Broeckel RM, Meade-White K, Nelson CA, Himansu S, Wang D, Handley SA, Gross ML, Best SM, Pierson TC, Fremont DH, Diamond M. 2021 Broadly neutralizing monoclonal antibodies protect against multiple tick-borne flaviviruses. J Exp Med, 218(5):e20210174.
Kim AS, Kafai NM, Winkler ES, Gilliland TC Jr, Cottle EL, Earnest JT, Jethva PN, Kaplonek P, Shah AP, Fong RH, Davidson E, Malonis RJ, Quiroz JA, Williamson LE, Vang L, Mack M, Crowe JE Jr, Doranz BJ, Lai JR, Alter G, Gross ML, Klimstra WB, Fremont DH, Diamond MS. 2021 Pan-protective anti-alphavirus human antibodies target a conserved E1 protein epitope. Cell, 184(17):4414-4429.e19.
Case JB, Chen RE, Cao L, Ying B, Winkler ES, Johnson M, Goreshnik I, Pham MN, Shrihari S, Kafai NM, Bailey AL, Xie X, Shi PY, Ravichandran R, Carter L, Stewart L, Baker D, Diamond MS. 2021 Ultrapotent miniproteins targeting the SARS-CoV-2 receptor-binding domain protect against infection and disease. Cell Host Microbe, 29(7):1151-1161.e5.
Winkler ES, Bailey AL, Kafai NM, Nair S, McCune BT, Yu J, Fox JM, Chen RE, Earnest JT, Keeler SP, Ritter JH, Kang LI, Dort S, Robichaud A, Head R, Holtzman MJ, Diamond MS. 2020 SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Nat Immunol, 21(11):1327-1335.
Zost SJ, Gilchuk P, Case JB, Binshtein E, Chen RE, Nkolola JP, Schäfer A, Reidy JX, Trivette A, Nargi RS, Sutton RE, Suryadevara N, Martinez DR, Williamson LE, Chen EC, Jones T, Day S, Myers L, Hassan AO, Kafai NM, Winkler ES, Fox JM, Shrihari S, Mueller BK, Meiler J, Chandrashekar A, Mercado NB, Steinhardt JJ, Ren K, Loo YM, Kallewaard NL, McCune BT, Keeler SP, Holtzman MJ, Barouch DH, Gralinski LE, Baric RS, Thackray LB, Diamond MS, Carnahan RH, Crowe JE Jr. 2020 Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature, 584(7821):443-449.
Hassan AO, Case JB, Winkler ES, Thackray LB, Kafai NM, Bailey AL, McCune BT, Fox JM, Chen RE, Alsoussi WB, Turner JS, Schmitz AJ, Lei T, Shrihari S, Keeler SP, Fremont DH, Greco S, McCray PB Jr, Perlman S, Holtzman MJ, Ellebedy AH, Diamond MS. 2020 A SARS-CoV-2 Infection Model in Mice Demonstrates Protection by Neutralizing Antibodies. Cell, 182(3):744-453.e4.
Ma H, Kim AS, Kafai NM, Earnest JT, Shah AP, Case JB, Basore K, Gilliland TC, Sun C, Nelson CA, Thackray LB, Klimstra WB, Fremont DH, Diamond MS. 2020 LDLRAD3 is a receptor for Venezuelan equine encephalitis virus. Nature, 588(7837):308-14.
Case JB, Rothlauf PW, Chen RE, Kafai NM, Fox JM, Smith BK, Shrihari S, McCune BT, Harvey IB, Keeler SP, Bloyet LM, Zhao H, Ma M, Adams LJ, Winkler ES, Holtzman MJ, Fremont DH, Whelan SPJ, Diamond MS. 2020 Replication-Competent Vesicular Stomatitis Virus Vaccine Vector Protects against SARS-CoV-2-Mediated Pathogenesis in Mice. Cell Host Microbe, 28(3):465-474.e4.
Alsoussi WB, Turner JS, Case JB, Zhao H, Schmitz AJ, Zhou JQ, Chen RE, Lei T, Rizk AA, McIntire KM, Winkler ES, Fox JM, Kafai NM, Thackray LB, Hassan AO, Amanat F, Krammer F, Watson CT, Kleinstein SH, Fremont DH, Diamond MS, Ellebedy AH. 2020 A Potently Neutralizing Antibody Protects Mice against SARS-CoV-2 Infection. J Immunol, 205(4):915-22.
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.
Guggisberg AM, Frasse PM, Jezewski AJ, Kafai NM, Gandhi AY, Erlinger SJ, Odom John AR. 2018 Suppression of Drug Resistance Reveals a Genetic Mechanism of Metabolic Plasticity in Malaria Parasites. mBio, 9(6):e01193-18.
Kafai NM, Odom John AR. 2018 Malaria in Children. Infect Dis Clin North Am, 32(1):189-200.
Lamason RL, Kafai NM, Welch MD. 2018 A streamlined method for transposon mutagenesis of Rickettsia parkeri yields numerous mutations that impact infection. PLoS ONE, 13(5):.
Scott A, Kafai NM, Shivakumar N, et al. (2018) A Pilot Program Integrating Undergraduate Students in the Washington University Saturday Neighborhood Clinic. Society of Student Run Free Clinics Conference, Omaha, NE, Abstract.
Kafai N, et al.. (2017) Bacterial genes required for Rickettsia parkeri infection. ASCI/AAP/APSA Annual Joint Meeting, Chicago, IL, Abstract.