22. Ohno T, Nishimura M (2004) Detection of a new cerebral malaria susceptibility locus, using CBA mice. Immunogenetics 56: 675–678. 23. Sauer JD, Sotelo-Troha K, von Moltke J, Monroe KM, Rae CS, et al. (2011) The N-ethyl-N-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides. Infect Immun 79: 688–694. 24. Hong CJ, Tsai PJ, Cheng CY, Chou CK, Jheng HF, et al. (2010) ENU mutagenesis identifies mice with morbid obesity and severe hyperinsulinemia caused by a novel mutation in leptin. PLoS One 5: e15333. 25. Miller G, Neilan M, Chia R, Gheryani N, Holt N, et al. (2010) ENU mutagenesis reveals a novel phenotype of reduced limb strength in mice lacking fibrillin 2. PLoS One 5: e9137. 26. Fernandez L, Marchuk DA, Moran JL, Beier DR, Rockman HA (2009) An N- ethyl-N-nitrosourea mutagenesis recessive screen identifies two candidate regions for murine cardiomyopathy that map to chromosomes 1 and 15. Mamm Genome 20: 296–304. 27. Chan ER, Lavender H, Li G, Haviernik P, Bunting KD, et al. (2009) An ENU- induced recessive mutation in Mpl leads to thrombocytopenia with overdom- inance. Exp Hematol 37: 276–284. 28. Thomis DC, Gurniak CB, Tivol E, Sharpe AH, Berg LJ (1995) Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 270: 794–797. 29. Baptista FG, Pamplona A, Pena AC, Mota MM, Pied S, et al. (2010) Accumulation of Plasmodium berghei-infected red blood cells in the brain is crucial for the development of cerebral malaria in mice. Infect Immun 78: 4033–4039. 30. North RJ, Jung YJ (2004) Immunity to tuberculosis. Annu Rev Immunol 22: 599–623. 31. Simmons CP, Clare S, Ghaem-Maghami M, Uren TK, Rankin J, et al. (2003) Central role for B lymphocytes and CD4+ T cells in immunity to infection by the attaching and effacing pathogen Citrobacter rodentium. Infect Immun 71: 5077–5086. 32. Higgins LM, Frankel G, Douce G, Dougan G, MacDonald TT (1999) Citrobacter rodentium infection in mice elicits a mucosal Th1 cytokine response and lesions similar to those in murine inflammatory bowel disease. Infect Immun 67: 3031–3039. 33. Simmons CP, Goncalves NS, Ghaem-Maghami M, Bajaj-Elliott M, Clare S, et al. (2002) Impaired resistance and enhanced pathology during infection with a noninvasive, attaching-effacing enteric bacterial pathogen, Citrobacter roden- tium, in mice lacking IL-12 or IFN-gamma. J Immunol 168: 1804–1812. 34. WHO (2010) Guidelines for the treatment of malaria, 2nd Edition. pp 37–47. 35. Lackner P, Part A, Burger C, Dietmann A, Broessner G, et al. (2009) Glatiramer acetate reduces the risk for experimental cerebral malaria: a pilot study. Malar J 8: 36. 36. Morrell CN, Srivastava K, Swaim A, Lee MT, Chen J, et al. (2011) Beta interferon suppresses the development of experimental cerebral malaria. Infect Immun 79: 1750–1758. 37. Franklin BS, Ishizaka ST, Lamphier M, Gusovsky F, Hansen H, et al. (2011) Therapeutical targeting of nucleic acid-sensing Toll-like receptors prevents experimental cerebral malaria. Proc Natl Acad Sci U S A 108: 3689–3694. 38. Cabrales P, Zanini GM, Meays D, Frangos JA, Carvalho LJ (2011) Nitric Oxide Protection Against Murine Cerebral Malaria Is Associated With Improved Cerebral Microcirculatory Physiology. J Infect Dis. 39. Balachandar S, Katyal A (2011) Peroxisome proliferator activating receptor (PPAR) in cerebral malaria (CM): a novel target for an additional therapy. Eur J Clin Microbiol Infect Dis 30: 483–498. 40. Cornejo MG, Boggon TJ, Mercher T (2009) JAK3: a two-faced player in hematological disorders. Int J Biochem Cell Biol 41: 2376–2379. A Jak3 Mutation Protects against Cerebral Malaria 41. Notarangelo LD, Mella P, Jones A, de Saint Basile G, Savoldi G, et al. (2001) Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiency. Hum Mutat 18: 255–263. 42. Rudin W, Favre N, Bordmann G, Ryffel B (1997) Interferon-gamma is essential for the development of cerebral malaria. Eur J Immunol 27: 810–815. 43. Yanez DM, Manning DD, Cooley AJ, Weidanz WP, van der Heyde HC (1996) Participation of lymphocyte subpopulations in the pathogenesis of experimental murine cerebral malaria. J Immunol 157: 1620–1624. 44. Hansen DS, Bernard NJ, Nie CQ, Schofield L (2007) NK cells stimulate recruitment of CXCR3+ T cells to the brain during Plasmodium berghei- mediated cerebral malaria. J Immunol 178: 5779–5788. 45. Mitchell AJ, Hansen AM, Hee L, Ball HJ, Potter SM, et al. (2005) Early cytokine production is associated with protection from murine cerebral malaria. Infect Immun 73: 5645–5653. 46. Hermsen C, van de Wiel T, Mommers E, Sauerwein R, Eling W (1997) Depletion of CD4+ or CD8+ T-cells prevents Plasmodium berghei induced cerebral malaria in end-stage disease. Parasitology 114(Pt 1): 7–12. 47. Yanez DM, Batchelder J, van der Heyde HC, Manning DD, Weidanz WP (1999) Gamma delta T-cell function in pathogenesis of cerebral malaria in mice infected with Plasmodium berghei ANKA. Infect Immun 67: 446–448. 48. Finley R, Weintraub J, Louis JA, Engers HD, Zubler R, et al. (1983) Prevention of cerebral malaria by adoptive transfer of malaria-specific cultured T cells into mice infected with Plasmodium berghei. J Immunol 131: 1522–1526. 49. McCall MB, Roestenberg M, Ploemen I, Teirlinck A, Hopman J, et al. (2010) Memory-like IFN-gamma response by NK cells following malaria infection reveals the crucial role of T cells in NK cell activation by P. falciparum. Eur J Immunol 40: 3472–3477. 50. Kudlacz E, Perry B, Sawyer P, Conklyn M, McCurdy S, et al. (2004) The novel JAK-3 inhibitor CP-690550 is a potent immunosuppressive agent in various murine models. Am J Transplant 4: 51–57. 51. Meyer DM, Jesson MI, Li X, Elrick MM, Funckes-Shippy CL, et al. (2010) Anti- inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond) 7: 41. 52. Frucht DM, Gadina M, Jagadeesh GJ, Aksentijevich I, Takada K, et al. (2001) Unexpected and variable phenotypes in a family with JAK3 deficiency. Genes Immun 2: 422–432. 53. Roberts JL, Lengi A, Brown SM, Chen M, Zhou YJ, et al. (2004) Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation. Blood 103: 2009–2018. 54. Zhou YJ, Chen M, Cusack NA, Kimmel LH, Magnuson KS, et al. (2001) Unexpected effects of FERM domain mutations on catalytic activity of Jak3: structural implication for Janus kinases. Mol Cell 8: 959–969. 55. Yamaoka K, Saharinen P, Pesu M, Holt VE, 3rd, Silvennoinen O, et al. (2004) The Janus kinases (Jaks). Genome Biol 5: 253. 56. Royer Y, Staerk J, Costuleanu M, Courtoy PJ, Constantinescu SN (2005) Janus kinases affect thrombopoietin receptor cell surface localization and stability. J Biol Chem 280: 27251–27261. 57. Rane SG, Reddy EP (2000) Janus kinases: components of multiple signaling pathways. Oncogene 19: 5662–5679. 58. O’Shea JJ, Gadina M, Schreiber RD (2002) Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 109 Suppl: S121–131. 59. Balling R (2001) ENU mutagenesis: analyzing gene function in mice. Annu Rev Genomics Hum Genet 2: 463–492. 60. Fortin A, Diez E, Rochefort D, Laroche L, Malo D, et al. (2001) Recombinant congenic strains derived from A/J and C57BL/6J: a tool for genetic dissection of complex traits. Genomics 74: 21–35. 61. Gros P, Skamene E, Forget A (1981) Genetic control of natural resistance to Mycobacterium bovis (BCG) in mice. J Immunol 127: 2417–2421. PLoS ONE | www.plosone.org 13 February 2012 | Volume 7 | Issue 2 | e31012