Janet G. Markle, Ph.D.

Assistant Professor

janet.markle@vumc.org
Faculty Appointments
Assistant Professor of Pathology, Microbiology and Immunology
Education
M.P.H., University of Waterloo, Ontario, CanadaPh.D., University of Toronto, Toronto, CanadaB.Med.Sc., University of Western Ontario, Ontario, Canada
Research Description
The Markle Lab is interested in understanding genetic determinants of immunity. Our studies are patient-based, and we focus on children with severe immune-mediated diseases. Our lab uses human whole exome and whole genome sequencing to discover monogenic (e.g. single gene) inborn errors of immunity in children with rare infectious, autoimmune, or auto-inflammatory diseases. We use a customized bioinformatic pipeline to sift through large genetic datasets to pinpoint candidate gene variants. Then, we study the impact of these variants on the expression and function of the encoded proteins. We aim to thoroughly characterize the functional impact of each variant at the molecular and cellular levels, and to this end we use both classical and cutting-edge techniques in molecular biology, protein biochemistry, in vitro cell culture approaches, and mass cytometry using patient leukocytes. Current projects include: inflammasome-activating mutations, mutations affecting cytokine receptors, novel candidate genes for intestinal inflammation, and characterizing the microbiota of patients with monogenic immune diseases. Our group uses both ‘dry-lab’ (computational) and wide variety of ‘wet-lab’ approaches and our interests lie at the crossroads of human genetics, human immunology, and host-microbe interactions.
Research Keywords
Immunology, Genetics, Inflammation, Infection
Publications
Yang R, Mele F, Worley L, Langlais D, Rosain J, Benhsaien I, Elarabi H, Croft CA, Doisne JM, Zhang P, Weisshaar M, Jarrossay D, Latorre D, Shen Y, Han J, Ogishi M, Gruber C, Markle J, Al Ali F, Rahman M, Khan T, Seeleuthner Y, Kerner G, Husquin LT, Maclsaac JL, Jeljeli M, Errami A, Ailal F, Kobor MS, Oleaga-Quintas C, Roynard M, Bourgey M, El Baghdadi J, Boisson-Dupuis S, Puel A, Batteux F, Rozenberg F, Marr N, Pan-Hammarström Q, Bogunovic D, Quintana-Murci L, Carroll T, Ma CS, Abel L, Bousfiha A, Di Santo JP, Glimcher LH, Gros P, Tangye SG, Sallusto F, Bustamante J, Casanova JL. Human T-bet Governs Innate and Innate-like Adaptive IFN-¿ Immunity against Mycobacteria. Cell [print-electronic]. 2020 Dec 12/23/2020; 183(7): 1826-1847.e31. PMID: 33296702, PMCID: PMC7770098, PII: S0092-8674(20)31453-7, DOI: 10.1016/j.cell.2020.10.046, ISSN: 1097-4172.

Reeve L, Preece K, Markle J, Casanova JL, Walls T. Do not let them slip through the net: Catching a case of leaky severe combined immunodeficiency. J Paediatr Child Health [print-electronic]. 2020 May; 56(5): 809-11. PMID: 31721334, DOI: 10.1111/jpc.14690, ISSN: 1440-1754.

Rosain J, Kong XF, Martinez-Barricarte R, Oleaga-Quintas C, Ramirez-Alejo N, Markle J, Okada S, Boisson-Dupuis S, Casanova JL, Bustamante J. Mendelian susceptibility to mycobacterial disease: 2014-2018 update. Immunol Cell Biol [print-electronic]. 2019 Apr; 97(4): 360-7. PMID: 30264912, PMCID: PMC6438774, DOI: 10.1111/imcb.12210, ISSN: 1440-1711.

Boisson-Dupuis S, Ramirez-Alejo N, Li Z, Patin E, Rao G, Kerner G, Lim CK, Krementsov DN, Hernandez N, Ma CS, Zhang Q, Markle J, Martinez-Barricarte R, Payne K, Fisch R, Deswarte C, Halpern J, Bouaziz M, Mulwa J, Sivanesan D, Lazarov T, Naves R, Garcia P, Itan Y, Boisson B, Checchi A, Jabot-Hanin F, Cobat A, Guennoun A, Jackson CC, Pekcan S, Caliskaner Z, Inostroza J, Costa-Carvalho BT, de Albuquerque JAT, Garcia-Ortiz H, Orozco L, Ozcelik T, Abid A, Rhorfi IA, Souhi H, Amrani HN, Zegmout A, Geissmann F, Michnick SW, Muller-Fleckenstein I, Fleckenstein B, Puel A, Ciancanelli MJ, Marr N, Abolhassani H, Balcells ME, Condino-Neto A, Strickler A, Abarca K, Teuscher C, Ochs HD, Reisli I, Sayar EH, El-Baghdadi J, Bustamante J, Hammarström L, Tangye SG, Pellegrini S, Quintana-Murci L, Abel L, Casanova JL. Tuberculosis and impaired IL-23-dependent IFN-¿ immunity in humans homozygous for a common TYK2 missense variant. Sci Immunol. 2018 Dec 12/21/2018; 3(30): PMID: 30578352, PMCID: PMC6341984, PII: 3/30/eaau8714, DOI: 10.1126/sciimmunol.aau8714, ISSN: 2470-9468.

Martínez-Barricarte R, Markle JG, Ma CS, Deenick EK, Ramírez-Alejo N, Mele F, Latorre D, Mahdaviani SA, Aytekin C, Mansouri D, Bryant VL, Jabot-Hanin F, Deswarte C, Nieto-Patlán A, Surace L, Kerner G, Itan Y, Jovic S, Avery DT, Wong N, Rao G, Patin E, Okada S, Bigio B, Boisson B, Rapaport F, Seeleuthner Y, Schmidt M, Ikinciogullari A, Dogu F, Tanir G, Tabarsi P, Bloursaz MR, Joseph JK, Heer A, Kong XF, Migaud M, Lazarov T, Geissmann F, Fleckenstein B, Arlehamn CL, Sette A, Puel A, Emile JF, van de Vosse E, Quintana-Murci L, Di Santo JP, Abel L, Boisson-Dupuis S, Bustamante J, Tangye SG, Sallusto F, Casanova JL. Human IFN-¿ immunity to mycobacteria is governed by both IL-12 and IL-23. Sci Immunol. 2018 Dec 12/21/2018; 3(30): PMID: 30578351, PMCID: PMC6380365, PII: 3/30/eaau6759, DOI: 10.1126/sciimmunol.aau6759, ISSN: 2470-9468.

Metz KA, Teng X, Coppens I, Lamb HM, Wagner BE, Rosenfeld JA, Chen X, Zhang Y, Kim HJ, Meadow ME, Wang TS, Haberlandt ED, Anderson GW, Leshinsky-Silver E, Bi W, Markello TC, Pratt M, Makhseed N, Garnica A, Danylchuk NR, Burrow TA, Jayakar P, McKnight D, Agadi S, Gbedawo H, Stanley C, Alber M, Prehl I, Peariso K, Ong MT, Mordekar SR, Parker MJ, Crooks D, Agrawal PB, Berry GT, Loddenkemper T, Yang Y, Maegawa GHB, Aouacheria A, Markle JG, Wohlschlegel JA, Hartman AL, Hardwick JM. KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy-lysosome defect. Ann Neurol [print-electronic]. 2018 Nov; 84(5): 766-80. PMID: 30295347, PMCID: PMC6295419, DOI: 10.1002/ana.25351, ISSN: 1531-8249.

de Jong SJ, Créquer A, Matos I, Hum D, Gunasekharan V, Lorenzo L, Jabot-Hanin F, Imahorn E, Arias AA, Vahidnezhad H, Youssefian L, Markle JG, Patin E, D'Amico A, Wang CQF, Full F, Ensser A, Leisner TM, Parise LV, Bouaziz M, Maya NP, Cadena XR, Saka B, Saeidian AH, Aghazadeh N, Zeinali S, Itin P, Krueger JG, Laimins L, Abel L, Fuchs E, Uitto J, Franco JL, Burger B, Orth G, Jouanguy E, Casanova JL. The human CIB1-EVER1-EVER2 complex governs keratinocyte-intrinsic immunity to ß-papillomaviruses. J Exp Med [print-electronic]. 2018 Sep 9/3/2018; 215(9): 2289-310. PMID: 30068544, PMCID: PMC6122964, PII: jem.20170308, DOI: 10.1084/jem.20170308, ISSN: 1540-9538.

Kong XF, Martinez-Barricarte R, Kennedy J, Mele F, Lazarov T, Deenick EK, Ma CS, Breton G, Lucero KB, Langlais D, Bousfiha A, Aytekin C, Markle J, Trouillet C, Jabot-Hanin F, Arlehamn CSL, Rao G, Picard C, Lasseau T, Latorre D, Hambleton S, Deswarte C, Itan Y, Abarca K, Moraes-Vasconcelos D, Ailal F, Ikinciogullari A, Dogu F, Benhsaien I, Sette A, Abel L, Boisson-Dupuis S, Schröder B, Nussenzweig MC, Liu K, Geissmann F, Tangye SG, Gros P, Sallusto F, Bustamante J, Casanova JL. Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Nat Immunol [print-electronic]. 2018 Sep; 19(9): 973-85. PMID: 30127434, PMCID: PMC6130844, PII: 10.1038/s41590-018-0178-z, DOI: 10.1038/s41590-018-0178-z, ISSN: 1529-2916.

Guérin A, Kerner G, Marr N, Markle JG, Fenollar F, Wong N, Boughorbel S, Avery DT, Ma CS, Bougarn S, Bouaziz M, Béziat V, Della Mina E, Oleaga-Quintas C, Lazarov T, Worley L, Nguyen T, Patin E, Deswarte C, Martinez-Barricarte R, Boucherit S, Ayral X, Edouard S, Boisson-Dupuis S, Rattina V, Bigio B, Vogt G, Geissmann F, Quintana-Murci L, Chaussabel D, Tangye SG, Raoult D, Abel L, Bustamante J, Casanova JL. IRF4 haploinsufficiency in a family with Whipple's disease. Elife. 2018 Mar 3/14/2018; 7: PMID: 29537367, PMCID: PMC5915175, PII: 32340, DOI: 10.7554/eLife.32340, ISSN: 2050-084X.

Parvaneh N, Barlogis V, Alborzi A, Deswarte C, Boisson-Dupuis S, Migaud M, Farnaria C, Markle J, Parvaneh L, Casanova JL, Bustamante J. Visceral leishmaniasis in two patients with IL-12p40 and IL-12Rß1 deficiencies. Pediatr Blood Cancer [print-electronic]. 2017 Jun; 64(6): PMID: 27873456, DOI: 10.1002/pbc.26362, ISSN: 1545-5017.

Martínez-Barricarte R, de Jong SJ, Markle J, de Paus R, Boisson-Dupuis S, Bustamante J, van de Vosse E, Fleckenstein B, Casanova JL. Transduction of Herpesvirus saimiri-Transformed T Cells with Exogenous Genes of Interest. Curr Protoc Immunol. 2016 Nov 11/1/2016; 115: 7.21C.1-7.21C.12. PMID: 27801513, DOI: 10.1002/cpim.15, ISSN: 1934-368X.

Itan Y, Shang L, Boisson B, Ciancanelli MJ, Markle JG, Martinez-Barricarte R, Scott E, Shah I, Stenson PD, Gleeson J, Cooper DN, Quintana-Murci L, Zhang SY, Abel L, Casanova JL. The mutation significance cutoff: gene-level thresholds for variant predictions [letter]. Nat Methods. 2016 Feb; 13(2): 109-10. PMID: 26820543, PMCID: PMC4980758, PII: nmeth.3739, DOI: 10.1038/nmeth.3739, ISSN: 1548-7105.

Itan Y, Shang L, Boisson B, Patin E, Bolze A, Moncada-Vélez M, Scott E, Ciancanelli MJ, Lafaille FG, Markle JG, Martinez-Barricarte R, de Jong SJ, Kong XF, Nitschke P, Belkadi A, Bustamante J, Puel A, Boisson-Dupuis S, Stenson PD, Gleeson JG, Cooper DN, Quintana-Murci L, Claverie JM, Zhang SY, Abel L, Casanova JL. The human gene damage index as a gene-level approach to prioritizing exome variants. Proc Natl Acad Sci U S A [print-electronic]. 2015 Nov 11/3/2015; 112(44): 13615-20. PMID: 26483451, PMCID: PMC4640721, PII: 1518646112, DOI: 10.1073/pnas.1518646112, ISSN: 1091-6490.

Okada S, Markle JG, Deenick EK, Mele F, Averbuch D, Lagos M, Alzahrani M, Al-Muhsen S, Halwani R, Ma CS, Wong N, Soudais C, Henderson LA, Marzouqa H, Shamma J, Gonzalez M, Martinez-Barricarte R, Okada C, Avery DT, Latorre D, Deswarte C, Jabot-Hanin F, Torrado E, Fountain J, Belkadi A, Itan Y, Boisson B, Migaud M, Arlehamn CSL, Sette A, Breton S, McCluskey J, Rossjohn J, de Villartay JP, Moshous D, Hambleton S, Latour S, Arkwright PD, Picard C, Lantz O, Engelhard D, Kobayashi M, Abel L, Cooper AM, Notarangelo LD, Boisson-Dupuis S, Puel A, Sallusto F, Bustamante J, Tangye SG, Casanova JL. IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations. Science [print-electronic]. 2015 Aug 8/7/2015; 349(6248): 606-13. PMID: 26160376, PMCID: PMC4668938, DOI: 10.1126/science.aaa4282, ISSN: 1095-9203.

Motta VN, Markle JG, Gulban O, Mortin-Toth S, Liao KC, Mogridge J, Steward CA, Danska JS. Identification of the inflammasome Nlrp1b as the candidate gene conferring diabetes risk at the Idd4.1 locus in the nonobese diabetic mouse. J Immunol [print-electronic]. 2015 Jun 6/15/2015; 194(12): 5663-73. PMID: 25964492, PII: jimmunol.1400913, DOI: 10.4049/jimmunol.1400913, ISSN: 1550-6606.

Markle JG, Frank DN, Adeli K, von Bergen M, Danska JS. Microbiome manipulation modifies sex-specific risk for autoimmunity. Gut Microbes [print-electronic]. 2014 Jul 7/1/2014; 5(4): 485-93. PMID: 25007153, PII: 29795, DOI: 10.4161/gmic.29795, ISSN: 1949-0984.

Celaj A, Markle J, Danska J, Parkinson J. Comparison of assembly algorithms for improving rate of metatranscriptomic functional annotation. Microbiome. 2014; 2: 39. PMID: 25411636, PMCID: PMC4236897, PII: 2049-2618-2-39, DOI: 10.1186/2049-2618-2-39, ISSN: 2049-2618.

Markle JG, Mortin-Toth S, Wong AS, Geng L, Hayday A, Danska JS. ¿d T cells are essential effectors of type 1 diabetes in the nonobese diabetic mouse model. J Immunol [print-electronic]. 2013 Jun 6/1/2013; 190(11): 5392-401. PMID: 23626013, PMCID: PMC3836168, PII: jimmunol.1203502, DOI: 10.4049/jimmunol.1203502, ISSN: 1550-6606.

Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, von Bergen M, McCoy KD, Macpherson AJ, Danska JS. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science [print-electronic]. 2013 Mar 3/1/2013; 339(6123): 1084-8. PMID: 23328391, PII: science.1233521, DOI: 10.1126/science.1233521, ISSN: 1095-9203.

Xiong X, Frank DN, Robertson CE, Hung SS, Markle J, Canty AJ, McCoy KD, Macpherson AJ, Poussier P, Danska JS, Parkinson J. Generation and analysis of a mouse intestinal metatranscriptome through Illumina based RNA-sequencing. PLoS One [print-electronic]. 2012; 7(4): e36009. PMID: 22558305, PMCID: PMC3338770, PII: PONE-D-12-00232, DOI: 10.1371/journal.pone.0036009, ISSN: 1932-6203.

Mulvihill EE, Allister EM, Sutherland BG, Telford DE, Sawyez CG, Edwards JY, Markle JM, Hegele RA, Huff MW. Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance. Diabetes [print-electronic]. 2009 Oct; 58(10): 2198-210. PMID: 19592617, PMCID: PMC2750228, PII: db09-0634, DOI: 10.2337/db09-0634, ISSN: 1939-327X.

Beyea MM, Heslop CL, Sawyez CG, Edwards JY, Markle JG, Hegele RA, Huff MW. Selective up-regulation of LXR-regulated genes ABCA1, ABCG1, and APOE in macrophages through increased endogenous synthesis of 24(S),25-epoxycholesterol. J Biol Chem [print-electronic]. 2007 Feb 2/23/2007; 282(8): 5207-16. PMID: 17186944, PII: S0021-9258(20)68814-7, DOI: 10.1074/jbc.M611063200, ISSN: 0021-9258.