Faculty & Research

Molecular Biology Faculty

Alexander Ploss

Assistant Professor of molecular biology

Alexander Ploss

Phone (609) 258-7128
locationLewis Thomas Lab, 110
Phone Lab (609) 258-2914
Faculty Assistant
Mary Gidaro
Phone (609) 258-8956

Research Focus

Infectious diseases account for at least 15 million deaths each year - almost a quarter of all human deaths worldwide. Against a constant background of established infections, epidemics of new and old infectious diseases periodically emerge, greatly magnifying the global burden of infections. Many pathogens causing disease in humans exhibit nearly unique human tropism, posing additional challenges for studying host-pathogen interaction and for efficiently testing anti-microbial intervention strategies. Humanized mice, i.e. mice expressing human genes or containing human tissues, have emerged as powerful systems to model human infections in vivo. We have and continue to construct humanized hosts genetically or via xenotransplantation to analyze previously intractable human (hepatotropic) pathogens. These systems offer unprecedented opportunities to effectively study host-pathogen interactions in vivo and to preclinically evaluate drug and vaccine candidates.

The research of my lab focuses on immune responses and pathogenesis to human pathogens infecting the liver, including hepatitis B (HBV) and C viruses (HCV), yellow fever and Dengue viruses and plasmodial parasites. My group combines tissue engineering, molecular virology/pathogenesis, and animal construction, to create and apply innovative technologies for the study and intervention of human hepatotropic infections.

Determinants of interspecies tropism of human hepatotropic pathogens

Many of these pathogens display unique human tropism, and the development of novel intervention strategies has been hampered by the lack of robust, cost effective and predictive models that accurately reproduce the hallmarks of human infections. While rodents and non-human primates have been employed in biomedical research and drug/vaccine development, they often do not yield reliable pre-clinical results that translate into effective human treatments. Two important factors contribute to this failure: on the microbial side, surrogate pathogens often differ significantly from highly restricted human counterparts; on the host side, the immune correlates of protection in non-human mammalian species often diverge from human responses.

My group uses several independent but possibly complementary approaches to overcome current species barriers and generate a small animal model for microbial pathogenesis: 1. Adaptation of microbial genomes to infect hepatocytes of non-human origin (mice and/or smaller non-human primates). 2. Humanization of the mouse liver and immune system by transplanting human hematopoietic stem cells and hepatocytes into a single murine recipient, thus allowing studies of pathology, immune correlates, and mechanisms of pathogen persistence. 3. Genetic host adaptation to create inbred murine models for viral pathogens. The latter approach encompasses systematic screens to identify and overcome additional species restrictions. We apply genome-engineering techniques to render the murine host environment more conducive to infections with the respective human pathogens.

Pathogenesis of viral hepatitis

Five distinct viruses, hepatitis A, B, C, delta and E viruses, are known to cause hepatitis in humans. HAV and HEV infections cause by-and-large acute, spontaneously resolving infections. In contrast, in excess of 500 million people are persistently infected with HBV/HDV and HCV. Chronic carriers are at risk of developing severe liver disease, including fibrosis, cirrhosis and hepatocellular carcinoma. An effective vaccine has been developed to prevent HBV infection, however, established infections are currently incurable and require life-long suppression with antiviral drugs. HBV pathogenesis is frequently exacerbated by co-infection with HDV. HDV is generally considered to be a subviral satellite because it can propagate only in the presence of the HBV. HBV persist in host cells as covalently closed circular DNA (cccDNA). Mechanisms of HBV persistence are incompletely understood.

Likewise, HCV has a high propensity of establishing chronic infections in human. A protective vaccine for HCV has not yet been developed. Current treatment - although projected to be improving considerably in the future - is only partially effective and plagued with side-effects but can result in complete elimination of the virus. We aim to shed light on the mechanisms governing HCV persistence.

Molecular characterization of plasmodial dormancy

Malaria accounts for more than 2% of all human deaths world-wide. A call was made for the global elimination of malaria, involving the eradication of all human malaria parasite species. Malaria is an arthropod borne infection caused in humans by five different species of Plasmodium, of which primarily P. vivax (Pv) – responsible for 70-80 million infections annually - has a high propensity for developing dormant stages - hypnozoites. In any attempt to eradicate malaria it will be necessary to know how, when and where to attack hypnozoites.

Due to the lack of experimental systems hypnozoites are almost completely undefined and mechanisms of their formation and/or reactivation are unknown. The primate parasite P. cynomolgi (Pcy) offers a model for dormancy and relapse but large-scale experiments in non-human primates, e.g. to identify new drugs, are restricted for ethical and financial reasons. To bridge this gap we have generated human and simian liver chimeric mice, which are powerful tools to Pv and Pcy in their native environment. We will profile Pv and Pcy liver stages and their host cells using transcriptomic and/or proteomic approaches. Molecular signatures of malarial dormancy will be critical for identifying putative therapeutic intervention points.

Generation of humanized for the study of human infectious disease

"Humanized" mice are versatile tools in the investigation of human disease. These are amenable small animal models transplanted with human cells or tissues (and/or equipped with human transgenes) that may be ideally suited for direct investigation of human infectious agents. Successful engraftment depends on avoiding rejection and maximizing tissue function, ensured by correct localization and appropriate tissue support by host factors. Despite the challenges, humanized mouse technology has made rapid progress over the last few years and it is now possible to achieve high levels of human chimerism in various host organs/tissues, particularly the immune system and liver. Such humanized mice provide a new opportunity to perform pre-clinical studies of intractable human pathogens. Despite their promise as challenge models, immune responses to infection remain suboptimal in humanized mice. In order to improve immune function, we employ a combination strategies including enhancing the ablation of endogenous mouse subsets to create "space" for human cells, providing exogenous cytokines to overcome impaired biological cross-reactivity between mouse and human, counteracting active graft destruction, and expressing human MHC molecules to ensure proper T cell education and homeostasis.

Selected Publications

Douam F, Ding Q, Ploss A. Recent advances in understanding hepatitis C. F1000Res. 2016 Feb 3;5. eCollection 2016. PMCID: PMC4755394.

Douam F, Gaska JM, Winer BY, Ding Q, von Schaewen M, Ploss A. (2015) Genetic Dissection of the Host Tropism of Human-Tropic Pathogens. Annu Rev Genet.  49:21-45. Pubmed

Scull MA, Shi C, de Jong YP, ... Rice CM, Ploss A. (2015) Hepatitis C virus infects rhesus macaque hepatocytes and simianized mice. Hepatology. 62(1): 57-67. Pubmed

Winer BY, Ploss A. (2015) Breaking the species barrier for hepatitis delta virus.  Hepatology.  63(1):334-6. Pubmed

Perin PM, Haid S, ... Meuleman P, Ploss A, Pietschmann T. (2015) Flunarizine prevents hepatitis C virus membrane fusion in a genotype-dependent manner by targeting the potential fusion peptide within E1. Hepatology. 63(1):49-62. Pubmed

Ploss A, Walker CM. (2015) Editorial overview: Progress and challenges in modeling human viral diseases in vivo. Curr Opin Virol. 13:v-vii. Pubmed

Winer BY, Ploss A. (2015) Determinants of hepatitis B and delta virus host tropism. Curr Opin Virol. 13:109-16. Pubmed

Douam F, Ploss A. (2015) Proteomic approaches to analyzing hepatitis C virus biology. Proteomics.15(12):2051-65. Pubmed

Stoddard MB, Li H, Wang S,...Ploss A,...Shaw GM6. (2015) Identification, molecular cloning, and analysis of full-length hepatitis C virus transmitted/founder genotypes 1, 3, and 4. MBio. 6. pii: e02518-14. Pubmed

Siu E, Ploss A. (2015) Modeling malaria in humanized mice: opportunities and challenges. Ann N Y Acad Sci. 134:29-36. Pubmed

Gaska JM, Ploss A. (2015) Study of viral pathogenesis in humanized mice. Curr Opin Virol. 11C:14-20. Pubmed

Ding Q, von Schaewen M, Ploss A. (2014) The impact of Hepatitis C virus entry on viral tropism. Cell Host Microbe. 16:562-568. Pubmed

Lacek K, Urbanowicz RA, Troise F,... Ploss A, Pessi A. (2014) Dramatic potentiation of the antiviral activity of HIV antibodies by cholesterol conjugation. J Biol Chem. 289:35015-28. Pubmed

de Jong YP, Dorner M, Mommersteeg MC,...Ploss A. (2014) Broadly neutralizing antibodies abrogate established hepatitis C virus infection. Sci Transl Med. 6: 254ra129. Pubmed

von Schaewen M, Ding Q, Ploss A. (2014) Visualizing hepatitis C virus infection in humanized mice. Immunol Methods. 410: 50-9. Pubmed

Ploss A. (2014) Mouse models for human infectious diseases. J Immunol Methods. 410:1-2. Pubmed

Billerbeck E, Labitt RN, Vega K, Frias-Staheli N, Dorner M, Xiao J, Rice CM, Ploss A. (2014) Insufficient IL-12 signaling favors differentiation of human CD4+ and CD8+ T cells into GATA-3+ and GATA-3+ T-bet+ subsets in humanized mice. Immunology. 143:202-18. Pubmed

von Schaewen M, Ploss A. (2014) Murine models of hepatitis C: What can we look forward to? Antiviral Res. 104:15-22. Pubmed

Horwitz JA, Halper-Stromberg A, Mouquet H,...Ploss A,...Nussenzweig MC. (2013) HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice. Proc Natl Acad Sci. 110: 16538-43. Pubmed

Anggakusuma, Colpitts CC, Schang LM,...Ploss A,...Steinmann E. (2013) Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells. Gut. 63: 1137-49. Pubmed

Dorner M, Horwitz JA, Donovan BM,...Ploss A. (2013) Completion of the entire hepatitis C virus life cycle in genetically humanized mice. Nature. 501: 237-41. Pubmed

Billerbeck E, Horwitz JA, Labitt RN,...Ploss A. (2013) Characterization of human antiviral adaptive immune responses during hepatotropic virus infection in HLA-transgenic human immune system mice. J Immunol. 191: 1753-64. Pubmed

Gruell H, Bournazos S, Ravetch JV, Ploss A, Nussenzweig MC, Pietzsch J. (2013) Antibody and antiretroviral pre-exposure prophylaxis prevent cervicovaginal HIV-1 infection in a transgenic mouse model. J Virol.  87: 8535-44. Pubmed

Vogt A, Scull MA, Friling T,...Ploss A. (2013) Recapitulation of the hepatitis C virus life-cycle in engineered murine cell lines. Virology. 444: 1-11. Pubmed

Guermonprez P, Helft J, Claser C,...Ploss A,...Nussenzweig MC. (2013) Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection. Nat Med. 19: 730-38. Pubmed

Horwitz JA, Dorner M, Friling T,...Ploss A. (2013) Expression of heterologous proteins flanked by NS3-4A cleavage sites within the hepatitis C virus polyprotein. Virology. 439: 23-33. Pubmed

Billerbeck E, de Jong Y, Dorner M, de la Fuente C, Ploss A. (2013) Animal models for hepatitis C. Animal models for hepatitis C. Curr Top Microbiol Immunol. 369: 49-86. Pubmed

Shi C, Ploss A. (2013) Hepatitis C virus vaccines in the era of new direct-acting antivirals. Expert Rev Gastroenterol Hepatol. 7: 171-85. Pubmed

Sandmann L, Ploss A. (2013) Barriers of hepatitis C virus interspecies transmission. Virology. 435: 70-80. Pubmed

Dorner M, Rice CM, Ploss A. (2013) Study of hepatitis C virus entry in genetically humanized mice. Methods. 59: 249-57. Pubmed

Klein F, Halper-Stromberg A, Horwitz JA,...Ploss A, Nussenzweig MC. (2012) HIV therapy by a combination of broadly neutralizing antibodies in humanized mice, Nature. 492: 118-22. Pubmed

Pietzsch J, Gruell H, Bournazos S,...Ploss A, Nussenzweig MC. (2012) A mouse model for HIV entry. Proc Natl Acad Sci. 109: 15859-64. Pubmed

Vaughan AM, Mikolajczak SA, Wilson EM,...Ploss A, Kappe SH. (2012) Complete plasmodium falciparum liver-stage development in liver-chimeric mice. J Clin Invest. 122: 3618-28. Pubmed

Schoggins JW, Dorner M, Feulner M...Ploss A, Rice CM. (2012) Development of fully infectious dengue reporter viruses for bioluminescent imaging and high throughput screening, Proc Natl Acad Sci. 109: 14610-15. Pubmed

Vaughan AM, Kappe SH, Ploss A, Mikolajczak SA. (2012) Development of humanized mouse models to study human malaria parasite infection. Future Microbiol. 7: 657-65. Pubmed

Ploss A, Dubuisson J. (2012) New advances in the molecular biology of hepatitis C virus infection: towards the identification of new treatment targets, Gut. 61 Suppl 1: i25-35. Pubmed

Giang E, Dorner M, Prentoe JC,...Ploss A, Burton DR, Law M. (2012) Human broadly neutralizing antibodies to the envelope glycoprotein complex of hepatitis C virus. Proc Natl Acad Sci. 109: 6205-10. Pubmed

Ploss A, Evans M. (2012) Hepatitis C virus entry. Curr Opin Virol. 2: 14-19. Pubmed

Meng X, Schoggins J, Rose L,...Ploss A,...Xiang Y. (2012) C7L family of poxvirus host range genes inhibits antiviral activities induced by type I interferons and interferon regulatory factor 1. J Virology. 86: 4538-47. Pubmed

Schwartz RE, Trehan K, Andrus L, Ploss A,...Bhatia SN. (2012) Modeling hepatitis C virus infection using human induced pluripotent stem cells. Proc Natl Acad Sci. 109: 2544-48. Pubmed

Scull MA, Ploss A. (2012) Exiting from uncharted territory: Hepatitis C virus assembles in mouse cell lines. Hepatology. 55: 645-48. Pubmed

Dorner M, Ploss A. (2011) Deconstructing hepatitis C virus infection in small animal models. (2011) Ann N Y Acad Sci. 1245: 59-62. Pubmed

Marukian S, Andrus L, Sheahan TP,...Ploss A,...Dustin LB. (2011) Hepatitis C virus induces interferon-λ and interferon-stimulated genes in primary liver cultures. Hepatology. 54: 1913-23. Pubmed

Andrus L, Marukian S, Jones CT,...Ploss A,...Rice CM. (2011) Expression of paramyxovirus V proteins promotes replication and spread of hepatitis C virus in cultures of primary human fetal liver cells. Hepatology.  54: 1901-12. Pubmed

Dorner M, Horwitz JA, Robbins J,...Ploss A. (2011) A genetically humanized mouse model for hepatitis C virus infection. Nature. 474: 208-11. Pubmed

Washburn ML, Bility MT, Kovalev GI,...Ploss A,...Su L. (2011) A novel humanized mouse model with a human immune system and human liver supports Hepatitis C virus infection, immune responses, and hepatopathogenesis. Gastroenterology. 40: 1334-44. Pubmed

Billerbeck E, Barry WT, Mu K, Dorner M, Rice CM, Ploss A. (2011) Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor, GM-CSF and interleukin 3 expressing NOD SCID IL2RγNULL humanized mice. Blood. 117: 3076-86. Pubmed

De Jong YP, Rice CM, Ploss A. (2010) Evaluation of combination therapy against hepatitis C virus infection in human liver chimeric mice. J. Hepatol. 54: 848-50. Pubmed

Gerold G, Rice CM, Ploss A. (2010) Teaching new tricks to an old foe: murinizing Hepatitis C virus. Hepatology. 52: 2233-36. Pubmed

Sheahan T, Jones CT, Ploss A. (2010) Advances and challenges in studying hepatitis C virus in its native environment, Expert Rev Gastroenterol Hepatol. 4: 541-50. Pubmed

Kohaar I, Ploss A, Korol E,...Prokunina-Olsson L. (2010) Splicing diversity of human OCLN gene and its biological significance for hepatitis C virus (HCV) entry. J Virol. 84: 6987-94. Pubmed

De Jong YP, Rice CM, Ploss A. (2010) New horizons for studying human hepatotropic infections. J Clin Invest. 120: 650-53. Pubmed

Jones CT, Catanese MT, Law LMJ,...Ploss A,...Rice CM. (2010) Real-time imaging of hepatitis C virus infection using a fluorescent cell-based reporter system. Nat Biotechnol. 28: 167-71. Pubmed

Ploss A, Khetani SK, Jones CT,...Bhatia SN. (2010) Persistent hepatitis C virus infection in microscale primary human hepatocyte cultures. Proc Natl Acad Sci. 107: 3141-45. Pubmed

Akondy RS, Monson ND, Miller JD,...Ploss A,...Ahmed R. (2009) The yellow fever virus vaccine induces a broad and polyfunctional human memory CD8+ T cell response. J Immunol. 183: 7919-30. Pubmed

Ploss A, Rice CM. (2009) Towards a small model for Hepatitis C. EMBO Rep. 10: 1220-27. Pubmed

Legrand N, Ploss A, Balling R,...Ziegler P. (2009) Humanized mice for modeling human infectious disease: challenges, progress, and outlook. Cell Host Microbe. 6: 5-9. Pubmed

Strowig T, Gurer C, Ploss A,...Münz C. (2009) Priming of protective T cell responses against virus-induced tumors in mice with human immune system components. J Exp Med. 206: 1423-34. Pubmed

Ploss A, Evans MJ, Gaysinskaya VA,...Rice CM. (2009) Human occludin is a hepatitis C virus entry factor required for infection of mouse cells, Nature. 457: 882-86. Pubmed

Biswas PS, Pedicord V, Ploss A, Menet E, Leiner I, Pamer EG. (2007) Pathogen-specific CD8 T cell responses are directly inhibited by IL-10. J Immunol. 179: 4520-28. Pubmed

Lindenbach BD, Meuleman P, Ploss A,...Rice CM. (2006) Cell culture-grown hepatitis C virus is infectious in vivo and can be recultured in vitro. Proc Natl Acad Sci. 103: 3805-09. Pubmed

Ploss A, Leiner I, Pamer EG. (2005) Distinct regulation of H2-M3 restricted memory T cell responses in lymph node and spleen. J Immunol. 175: 5998-6005. Pubmed

Ploss A, Tran A, Menet E, Leiner I, Pamer EG. (2005) Cross-recognition of N-formyl methionine peptides is a general characteristic of H2-M3 restricted CD8+ T cells. Infect Immun. 73: 4423-26. Pubmed

Dao T, Guo D, Ploss A,...Sant'Angelo DB. (2004) Development of CD1d-restricted NKT cells in the mouse thymus. Eur J Immunol. 34: 3542-52. Pubmed

Wong P, Lara-Tejero M, Ploss A, Leiner I, Pamer EG. (2004) Rapid development of T cell memory. J Immunol. 172: 7239-45. Pubmed

Ploss A, Lauvau G, Contos B,...Pamer EG. (2003) Promiscuity of MHC class Ib restricted T cell responses. J Immunol. 171: 5948-55. Pubmed

Kerksiek KM, Ploss A, Leiner I, Busch DH, Pamer EG. (2003) H2-M3 restricted T cells respond to secondary antigen exposure. J Immunol. 170: 1862-69. Pubmed

Reuss FU, Heber R, Ploss A, Berdel B. (2001) Amphotropic murine leukemia virus replication in human mammary epithelial cells and the formation of cytomegalovirus-promoter recombinants. Virology. 291: 91-100. Pubmed

Book chapters:

Ploss A. (2012) Hepatitis C virus and use of reverse genetics in drug design, in A. Bridgen (Ed.) Chapter 3: Reverse Genetics of RNA Viruses: Applications and Perspectives, pages 64-90, Wiley-Blackwell

Ploss A, Pamer EG. (2005) Immunologic Memory. In: Meyers, R.A., ed. Encyclopedia of Molecular Cell Biology and Molecular Medicine, WILEY-VCH Verlag GmbH & Co., Weinheim. p. 383

Ploss A, Pamer EG. (2004) Memory, in S.H.E. Kaufmann (Ed.) Novel Vaccination Strategies, WILEY-VCH, Weinheim, New York, pp.73



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