Vanderbilt University School of Medicine

Smith, Scott Alan , MD, PhD
Assistant Professor of Medicine

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Phone Number: 343-4028


Smith, Scott's picture

Office Address   Mailing Address

1161 21st Avenue South A2210 Medical Center North

Research Description
Symptomatic dengue virus infection ranges in disease severity from an influenza-like illness to life-threatening shock. One model of the mechanism underlying severe disease proposes that weakly cross-reactive antibodies induced during a primary infection facilitate virus entry into Fc receptor-bearing cells during a subsequent secondary infection, increasing viral replication and release of cytokines and vasoactive mediators, culminating in shock. This unique process, known as antibody-dependent enhancement of infection, has significantly hindered vaccine development. There is a concern that potent neutralizing antibodies must be generated to all four dengue virus serotypes, as a vaccine that induce weakly cross-reactive non-neutralizing antibodies may increase the likelihood of developing severe disease. Much of our understanding of this process has come from studies using mouse mAbs, however antibody responses in mice typically exhibit less complexity than those in humans. A better understanding of the humoral immune response to natural dengue virus infection in humans is sorely needed. Using a high-efficiency human hybridoma technology developed in our laboratory, it is now possible to generate human hybridomas reliably using B cells from the peripheral blood of individuals who have recovered from an infection. Employing this technology, we have generated over 250 hybridomas secreting human mAbs to dengue virus from subjects who had recovered from primary or secondary infection. The vast majority of these antibodies are broadly serotype cross-reactive, directed against either E or prM protein, and capable of antibody-mediated enhancement of infection in vitro; very few exhibited serotype-specific binding or potent neutralizing activity. By employing a flow cytometric neutralization screening approach, we were able to enrich in the numbers of potently neutralizing mAbs that can be identified. This tactic resulted in the identification of several major phenotypic groups of human mAbs, each exhibiting unique neutralization and functional properties. Interestingly, mAbs that display serotype specific, virion-only binding, and exhibit potent serotype specific neutralizing activity with little enhancing properties also are produced naturally by humans in response to infection. Understanding the epitopes and activity of these naturally-occurring human antibodies is critical for vaccine development. Ideally, the reactivity of epitopes bound by enhancing antibodies should be reduced or eliminated in candidate antigens during the rational development of a dengue vaccine, so as to discourage such dominant recognition of these antigenic features by the humoral immune response. The long-term goal is to use such molecular information in the rational design of dengue vaccines that enhance the induction of protective neutralizing antibodies and reduce the risk of development of severe disease.

Fibriansah, G, Tan, JL, Smith, SA, de Alwis, AR, Ng, TS, Kostyuchenko, VA, Ibarra, KD, Wang, J, Harris, E, de Silva, A, Crowe, JE, Lok, SM. A potent anti-dengue human antibody preferentially recognizes the conformation of E protein monomers assembled on the virus surface. EMBO Mol Med, , , 2014.

Messer, WB, de Alwis, R, Yount, BL, Royal, SR, Huynh, JP, Smith, SA, Crowe, JE, Doranz, BJ, Kahle, KM, Pfaff, JM, White, LJ, Sariol, CA, de Silva, AM, Baric, RS. Dengue virus envelope protein domain I/II hinge determines long-lived serotype-specific dengue immunity. Proc Natl Acad Sci U S A, 111(5), 1939-44, 2014.

Smith, SA, de Alwis, AR, Kose, N, Harris, E, Ibarra, KD, Kahle, KM, Pfaff, JM, Xiang, X, Doranz, BJ, de Silva, AM, Austin, SK, Sukupolvi-Petty, S, Diamond, MS, Crowe, JE. The potent and broadly neutralizing human dengue virus-specific monoclonal antibody 1C19 reveals a unique cross-reactive epitope on the bc loop of domain II of the envelope protein. MBio, 4(6), e00873-13, 2013.

Smith, SA, de Alwis, R, Kose, N, Durbin, AP, Whitehead, SS, de Silva, AM, Crowe, JE. Human monoclonal antibodies derived from memory B cells following live attenuated dengue virus vaccination or natural infection exhibit similar characteristics. J Infect Dis, 207(12), 1898-908, 2013.

Smith, SA, Zhou, Y, Olivarez, NP, Broadwater, AH, de Silva, AM, Crowe, JE. Persistence of circulating memory B cell clones with potential for dengue virus disease enhancement for decades following infection. J Virol, 86(5), 2665-75, 2012.

de Alwis, R, Smith, SA, Olivarez, NP, Messer, WB, Huynh, JP, Wahala, WM, White, LJ, Diamond, MS, Baric, RS, Crowe, JE, de Silva, AM. Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions. Proc Natl Acad Sci U S A, , , 2012.

Krause, JC, Tsibane, T, Tumpey, TM, Huffman, CJ, Briney, BS, Smith, SA, Basler, CF, Crowe, JE. Epitope-specific human influenza antibody repertoires diversify by B cell intraclonal sequence divergence and interclonal convergence. J Immunol, 187(7), 3704-11, 2011.

Ganesh, VK, Muthuvel, SK, Smith, SA, Kotwal, GJ, Murthy, KH. Structural basis for antagonism by suramin of heparin binding to vaccinia complement protein. Biochemistry, 44(32), 10757-65, 2005.

Ghebremariam, YT, Smith, SA, Anderson, JB, Kahn, D, Kotwal, GJ. Intervention strategies and agents mediating the prevention of xenorejection. Ann N Y Acad Sci, 1056, 123-43, 2005.

Jha, P, Smith, SA, Justus, DE, Kotwal, GJ. Vaccinia virus complement control protein ameliorates collagen-induced arthritic mice. Ann N Y Acad Sci, 1056, 55-68, 2005.

Billings, B, Smith, SA, Zhang, Z, Lahiri, DK, Kotwal, GJ. Lack of N1L gene expression results in a significant decrease of vaccinia virus replication in mouse brain. Ann N Y Acad Sci, 1030, 297-302, 2004.

Ganesh, VK, Smith, SA, Kotwal, GJ, Murthy, KH. Structure of vaccinia complement protein in complex with heparin and potential implications for complement regulation. Proc Natl Acad Sci U S A, 101(24), 8924-9, 2004. PMCID:428448

Reynolds, DN, Smith, SA, Zhang, YP, Mengsheng, Q, Lahiri, DK, Morassutti, DJ, Shields, CB, Kotwal, GJ. Vaccinia virus complement control protein reduces inflammation and improves spinal cord integrity following spinal cord injury. Ann N Y Acad Sci, 1035, 165-78, 2004.

Anderson, JB, Smith, SA, van Wijk, R, Chien, S, Kotwal, GJ. Vaccinia virus complement control protein inhibits hyperacute xenorejection in a guinea pig-to-rat heterotopic cervical cardiac xenograft model by blocking both xenoantibody binding and complement pathway activation. Transpl Immunol, 11(2), 129-35, 2003. PMCID:428448

Jha, P, Smith, SA, Justus, DE, Kotwal, GJ. Prolonged retention of vaccinia virus complement control protein following IP injection: implications in blocking xenorejection. Transplant Proc, 35(8), 3160-2, 2003. PMCID:428448

Kahn, D, Smith, SA, Kotwal, GJ. Dose-dependent inhibition of complement in baboons by vaccinia virus complement control protein: implications in xenotransplantation. Transplant Proc, 35(4), 1606-8, 2003. PMCID:428448

Reynolds, DN, Smith, SA, Zhang, YP, Lahiri, DK, Morassutti, DJ, Shields, CB, Kotwal, GJ. Vaccinia virus complement control protein modulates inflammation following spinal cord injury. Ann N Y Acad Sci, 1010, 534-9, 2003. PMCID:428448

Smith, SA, Sreenivasan, R, Krishnasamy, G, Judge, KW, Murthy, KH, Arjunwadkar, SJ, Pugh, DR, Kotwal, GJ. Mapping of regions within the vaccinia virus complement control protein involved in dose-dependent binding to key complement components and heparin using surface plasmon resonance. Biochim Biophys Acta, 1650(1-2), 30-9, 2003. PMCID:428448

Anderson, JB, Smith, SA, Kotwal, GJ. Vaccinia virus complement control protein inhibits hyperacute xenorejection. Transplant Proc, 34(4), 1083-5, 2002. PMCID:428448

Anderson, JB, Smith, SA, van Wijk, R, Chien, S, Kotwal, GJ. Vaccinia virus complement control protein ameliorates hyperacute xenorejection by inhibiting xenoantibody binding. Transplant Proc, 34(8), 3277-81, 2002. PMCID:428448

Hicks, RR, Keeling, KL, Yang, MY, Smith, SA, Simons, AM, Kotwal, GJ. Vaccinia virus complement control protein enhances functional recovery after traumatic brain injury. J Neurotrauma, 19(6), 705-14, 2002. PMCID:428448

Smith, SA, Kotwal, GJ. Immune response to poxvirus infections in various animals. Crit Rev Microbiol, 28(3), 149-85, 2002. PMCID:428448

Smith, SA, Krishnasamy, G, Murthy, KH, Cooper, A, Bromek, K, Barlow, PN, Kotwal, GJ. Vaccinia virus complement control protein is monomeric, and retains structural and functional integrity after exposure to adverse conditions. Biochim Biophys Acta, 1598(1-2), 55-64, 2002. PMCID:428448

Murthy, KH, Smith, SA, Ganesh, VK, Judge, KW, Mullin, N, Barlow, PN, Ogata, CM, Kotwal, GJ. Crystal structure of a complement control protein that regulates both pathways of complement activation and binds heparan sulfate proteoglycans. Cell, 104(2), 301-11, 2001. PMCID:428448

Smith, SA, Kotwal, GJ. Virokines: novel immunomodulatory agents. Expert Opin Biol Ther, 1(3), 343-57, 2001. PMCID:428448

Smith, SA, Mullin, NP, Parkinson, J, Shchelkunov, SN, Totmenin, AV, Loparev, VN, Srisatjaluk, R, Reynolds, DN, Keeling, KL, Justus, DE, Barlow, PN, Kotwal, GJ. Conserved surface-exposed K/R-X-K/R motifs and net positive charge on poxvirus complement control proteins serve as putative heparin binding sites and contribute to inhibition of molecular interactions with human endothelial cells: a novel mechanism for evasion of host defense. J Virol, 74(12), 5659-66, 2000. PMCID:112054

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