Research Interests

• Retroviruses
• Gene therapy
• Diamond Blackfan Anemia
• Heme transporters

Research Activities

Retroviruses represent a major concern for human and animal health because they cause devastating diseases such as immune deficiency, anemia and neurological disorders. Their ability to carry non-viral genes, however, has made them attractive candidates for gene therapy studies. The major goals of my laboratory are to understand how the envelope (Env) protein of retroviruses, specifically feline leukemia viruses (FeLVs), interacts with host cell surface receptors to gain entry, and how this interaction causes disease. FeLVs are one of the most significant causes of death in young cats worldwide, with approximately 18 per cent of sick cats being FeLV positive. FeLVs can also efficiently infect human hematopoietic stem cells, making FeLV an attractive vector for human gene therapy. There are four subgroups of FeLVs - A, B, C and T - that cause distinct feline diseases and show striking similarity to human diseases. This similarity makes them attractive models to study related human diseases. Current studies in my laboratory include developing FeLV vectors with modified Envs that can efficiently and specifically infect human CD34+ hematopoietic stem cells, identifying co-factors/co-receptors used by FeLVs, and investigating the receptor adaptation of pathogenic FeLVs during their emergence in FeLV infected cats.

The second goal of my laboratory is to investigate the role of the human subgroup C FeLV receptor FLVCR1 in Diamond Blackfan Anemia (DBA). This is a fatal infant anemia characterized by a specific disruption in development of erythroid colony-forming units (CFU-E). We have found that disruption in FLVCR1 disrupts erythroid development at the CFU-E stage but does not disrupt myeloid cell development, which mimics the hematological features observed in DBA. Furthermore, we have found that DBA erythroid cells express alternatively spliced FLVCR1 transcripts that encode proteins that are defective in cellular and surface expression. In addition, we have found that the ribosomal protein RPS19, which is mutated in 25 per cent of DBA patients, regulates FLVCR1. Our studies suggest that DBA may be caused by a dysfunction in FLVCR1 as a consequence of alternative splicing of its transcript. Current studies in my laboratory include: understanding the mechanism of alternatively splicing of FLVCR1 transcript in DBA; how RPS19 regulates FLVCR1; how the FLVCR1 related FLVCR2 protein is involved in erythropoiesis; and developing a diagnostic test and long-term treatment for DBA.

External Funding

• Canadian Institutes of Health Research
• SickKids Foundation
• Ontario Premier Research Excellence Award

Achievements

Ontario Premier Research Excellence Award

Publications

Ramachandran N, Munteanu I, Wang P, Aubourg P, Rilstone JJ, Israelian N, Naranian T, Paroutis P, Guo R, Ren ZP, Nishino I, Chabrol B, Pellissier JF, Minetti C, Udd B, Fardeau M, Tailor CS, Mahuran DJ, Kissel JT, Kalimo H, Levy N, Manolson MF, Ackerley CA, Minassian BA. VMA21 deficiency causes an autophagic myopathy by compromising V-ATPase activity and lysosomal acidification. Cell. 2009 Apr 17;137(2):235-46.

Shalev Z, Duffy SP, Adema KW, Prasad R, Hussain N, Willett BJ, Tailor CS. Identification of a feline leukemia virus variant that can use THTR1, FLVCR1 and FLVCR2 for infection. J Virol. 2009 Apr 15. [Epub ahead of print]

Jandu N, Ho NK, Donato KA, Karmali MA, Mascarenhas M, Duffy SP, Tailor C, Sherman PM. Enterohemorrhagic Escherichia coli O157:H7 gene expression profiling in response to growth in the presence of host epithelia. PLoS ONE. 2009;4(3):e4889. Epub 2009 Mar 18.

Rey MA, Duffy SP, Brown JK, Kennedy JA, Dick JE, Dror Y, Tailor CS. Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis. Haematologica. 2008 Nov;93(11):1617-26.

Rey M, Prasad R, Tailor CS. The C domain in the surface envelope glycoprotein of subgroup C feline leukemia virus is a second receptor binding domain. Virology 370: 273-284 (2008)

Brown JK, Fung CW, Tailor CS. Comprehensive mapping of receptor functioning domains in subgroup C feline leukemia virus receptor FLVCR1. J.Virol 80:1742-1751 (2006)

Tailor CS, Lavillette D, Marin M, Kabat D. Cell Surface receptors for gammaretroviruses. Curr. Top. Microbiol. Immunol. 281:29-106 Review 2003.

Tailor CS, Marin M, Nouri A, Kabat D. Truncated forms of the dual-function human ASCT2 neutral amino acid transporter/retroviral receptor are translationally initiated at multiple alternative CUG and GUG codons. J. Biol. Chem. 276: 27221-27230, 2001.

Tailor CS, Nouri A, Kabat D. Cellular and species resistance to murine amphotropic, gibbon ape and feline subgroup C leukemia viruses is strongly influenced by receptor expression levels and by receptor masking mechanisms. J. Virol. 74: 9797-9801, 2000.

Tailor CS, Nouri A, Kabat D. A comprehensive approach to mapping the interacting surfaces of murine amphotropic and feline subgroup B leukemia viruses with their cell surface receptors. J. Virol. 74: 237-244, 2000.

Tailor CS Willett BJ, Kabat D. A putative cell surface receptor for anemia-inducing feline leukemia virus subgroup C is a member of a transporter superfamily. J. Virol 73: 6500-6505, 1999.

Tailor CS, Nouri A, Zhao Y, Takeuchi Y, Kabat D. A sodium dependent neutral amino acid transporter mediates infections of feline and baboon endogenous retroviruses and simian type D retroviruses. J. Virol. 73: 4470-4474, 1999.

Tailor CS, Nouri A, Lee CG, Kozak CA, Kabat D. Cloning and characterization of a cell surface receptor for xenotropic and polytropic murine leukemia viruses. Proc. Natl. Acad. Sci. USA 96: 927-932, 1999.