Shabaana A. Khader, Ph.D.
Molecular Microbiology and Microbial Pathogenesis Program
314 362 1232
Room 10240, McDonnell Pediatric Research Building
Tuberculosis, lung, cytokines, host pathogen interactions, immune cells, macrophages, vaccines
Understanding lung host immunity to intracellular pathogens
Tuberculosis (TB) kills more than 2 million people worldwide every year. The widely used TB vaccine, Bacille Calmette Guerin (BCG) has variable efficacy and has prompted the search for more effective vaccines. Although significant progress has been made in identifying protective Mycobacterium tuberculosis (Mtb) antigen candidates, our poor understanding of how immune responses mediate protection in the lung remains a major hurdle to successful vaccine design.
The major goal of my lab is to define the basic requirements for induction of protective immunity in the lung against pulmonary pathogens such as Mtb. Our past work has described a novel role for the cytokine Interleukin-17 (IL-17) in vaccine-induced immunity against tuberculosis. More recent work from my lab has utilized this information to target and boost lung Th17 responses to improve vaccine-induced immunity against tuberculosis. We have identified that mucosal immunization with Mtb antigen induces a population of lung-resident Th17 cells. IL-17 made by Th17 cells mediate protection in the host by inducing formation of lymphoid follicles in the lung to initiate T cell localization near infected macrophage for Mtb control. In contrast, IL-17 is a potent proinflammatory cytokine and expression of this cytokine during TB is associated with induction of neutrophil accumulation and associated lung pathology. Thus, current approaches in the Khader lab are focused on enhancing lung Th17 responses to improve vaccine strategies for TB, without inducing the pathological effects of IL-17 mediated lung inflammation. We use cutting edge approaches involving the use of alternative routes of immunization, use of novel Th17 adjuvants, and altering the location of Th17 cells in the lung, as new ways to boost vaccine-induced immunity against TB.
S.A. Khader, G. Bell, J.E.Pearl, J.J. Fountain, J-M.Moreno, G.E. Ciley, F.Shen, S.M. Eaton, S.L.Gaffen, S.S.Swain, R.M.Locksley, T. Randall, L.Haynes and A.M.Cooper. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nature Immunology. 2007. Apr,8(4):369-377.
S.A.Khader*, J.Rangel-Moreno, J.J.Fountain, C.Martino, W.Reiley, J.E.Pearl, G.Winslow, D.L.Woodland, T.D.Randall and A.M. Cooper. Pulmonary expression of homeostatic chemokines is essential for protective immunity to Mycobacterium tuberculosis infection. J.Immunol. 2009. Dec 15;183(12):8004-14. PMCID: PMC2799945.
S.A.Khader*, L.Guglani, J.Rangel-Moreno, J.J Fountain, C.Martino, J. E.Pearl, Y. Lin, W.Ouyang, T.Randall and A.M.Cooper* . IL-23 is required for long-term containment of Mycobacterium tuberculosis growth in the lung. The Journal of Immunology.2011. Nov 15;187(10):5402-7. PMCID: PMC3208087.
Slight SR, Rangel-Moreno J, Gopal R, Lin Y, Fallert Junecko BA, Mehra S, Selman M, Becerril-Villanueva E, Baquera-Heredia J, Pavon L, Kaushal D, Reinhart TA, Randall TD, Khader SA*. CXCR5+ T helper cells mediate protective immunity against tuberculosis. J Clin Invest. 2013 Jan 2. doi:pii: 65728. 10.1172/JCI65728.
R.Gopal, J.Rangel-Moreno, S.Slight, Y.Lin, H.F.Nawar, B.A. Fallert Junecko, T.A. Reinhart4, J.Kolls,T.D. Randall, T.D. Connell and S.A. Khader*. Interleukin-17-dependent CXCL-13 mediates mucosal vaccine-induced immunity against tuberculosis. Mucosal Immunology. 2013. doi:10.1038/mi.2012.135.
Highlighted as a featured article in the journal.
S.R. Slight, L.Monin, R.Gopal, L.Avery, M.Davis, H.Cleveland, Tim.D. Oury, J.Rangel-Moreno, S.A.Khader*. Short Communication: Interleukin-10 restrains Interleukin-17 to limit lung pathology following pulmonary infection with Francisella tularensis LVS. American Journal of Pathology. 2013 Nov;183(5):1397-404.
R.Gopal, L.Monin, D.Torres, S.Slight, S.Mehra, K.McKenna, B.A.Fallert Junecko, T.A.Reinhart, J.Kolls, R.Bez-Saldaa, A.Cruz-Lagunas, T.S.Rodrguez-Reyna, N.P.Kumar, P.Tessier, J.Roth, M.Selman, E.Becerril-Villanueva, J.Baquera-Heredia, B.Cumming, V.O.Kasprowicz, A.JC. Steyne, S. Babu, D.Kaushal, J.Ziga, T.Vogl, J.Rangel-Moreno and S.A. Khader*. S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis. The American Journal of Respiratory and Critical Care Medicine. Am J Respir Crit Care Med. 2013 Nov 1;188(9):1137-46.
D.Torres-Garca, A.Cruz-Lagunas, M.C.Garca-Sancho, R.Fernndez-Plata, R.Baez-Saldaa, C.Mendoza-Milla, A.Carrera-Eusebio, S.Ramrez-Bravo5, L.Campos, J.Angeles, G.Vargas-Alarcn, J.Granados, R.Gopal, S.A.Khader, E.J.Yunis, J.Zuiga. Variants in toll-like receptor 9 gene influence susceptibility to tuberculosis in a Mexican population. Journal of Translational Medicine. J Transl Med. 2013 Sep 21;11(1):220. [Epub ahead of print].
R.Gopal, J.Rangel-Moreno, B.Fallert Junecko, D.Mallon, K.Chen, D.Pociask, T.D. Connell, T.A.Reinhart, J.F.Alcorn, T.M.Ross, J.K.Kolls, and S.A.Khader*. Short Communication: Mucosal pre-exposure to Th17-inducing adjuvants exacerbates pathology following influenza infection. American Journal of Pathology. Oct 31. doi:pii: S0002-9440(13)00667-6. 10.1016/j.ajpath.2013.09.012. [Epub ahead of print].
Last Updated: 3/10/2014 9:47:14 AM