Innate immunity in mycobacterial infections
M. tuberculosis and non-tuberculous mycobacteria are highly prevalent human pathogens worldwide which cause significant morbidity and mortality, particularly in AIDS patients. They are intracellular pathogens of mononuclear phagocytes. Dr. Schlesinger’s research focuses on innate immunity in mycobacterial infections by studying human mononuclear phagocyte interactions with pathogenic mycobacteria, particularlyM. tuberculosis.
The laboratory uses a variety of approaches (cell biology, immunology, molecular biology and biochemistry) to study the role of mycobacterial surface glycoconjugates in complement activation and in binding to phagocyte receptors. It also focuses on the mechanism of phagocytosis of mycobacteria by macrophages, the intracellular trafficking pathway of mycobacterial products and the ability of intracellular mycobacteria to regulate the biosynthesis and expression of macrophage class II molecules, accessory molecules for antigen presentation and molecules involved in cellular adhesion.
The laboratory utilizes novel in vitro models that include surfactant components to study innate immune responses to these pathogens in the air spaces of the lung.
The lab also studies the iron-dependent metabolic pathways in mycobacteria by using trivalent metals to inhibit these pathways. Newly characterized clinical isolates of M. tuberculosis and mutant strains of bacteria are utilized for these studies.
Finally, the lab is interested in pathogenesis of the category A biodefense agent, Francisella tularensis. This work involves examining receptor-mediated interactions between the bacteria and human macrophages.
- Guirado E, Schlesinger LS. Modeling the Mycobacterium tuberculosis granuloma – the critical battlefield in host immunity and disease. Front Immunol. 4:98, 2013. PMID:23626591.
- Yang L, Sinha T, Carlson TC, Keiser TL, Torrelles JB, Schlesinger LS. Changes in the Major Cell Envelope Components of Mycobacterium tuberculosis during in vitro growth. Glycobiology. Epub.
- Abu Khweek A, Caution K, Akhter A, Abdulrahman BA, Tazi M, Hassan H, Majumdar N, Doran A, Guirado E, Schlesinger LS, Shuman H, Amer AO. A bacterial protein promotes the recognition of the Legionella pneumophila vacuole by autophagy. Eur J Immunol. 43:1333-44, 2013. PMID:23420491
- Azad AK, Curtis A, Papp A, Webb A, Knoell D, Sadee W, Schlesinger LSS. Allelic mRNA expression imbalance in C-type lectins reveals a frequent regulatory SNP in the human surfactant protein A (SP-A) gene. Genes and Immunity 14:99-106, 2013. PMID:23328842.
- Dai S, Curry HM, Leander R, Schlesinger LS.Fine tuning inflammation at the front door: Macrophage Complement Receptor 3-mediates phagocytosis and immune suppression for Francisella tularensis. PLoS Pathogens. 9:e1003114, 2013. PMID:23359218
- Young NA, Friedman AK, Kaffenberger B, Rajaram MVS, Birmingham DJ, Schlesinger LS, Wu L-C, Jarjour WN. Novel estrogen target gene ZAS3 is overexpressed in systemic lupus erythematosus. Mol Immunol. 54:23-31, 2013. PMID 23178823.
- Gomez DI, Twahirwa M, Schlesinger LS, Restrepo BI. Reduced Mycobacterium tuberculosis association with monocytes from diabetes patients that have poor glucose control. Tuberculosis. 93:192-197, 2013. PMID: 23028991.
- Leander R, Dai S, Schlesinger LS, Friedman A. A mathematical model of CR3/TLR2 crosstalk in the context of Francisella tularensis infection. PLoS Comput Bio. 8:e1002757. PMID 23133361.
- Guirado E, Arcos J, Knaup R, Reeder R, Cotton C, Patel T, Betz B, Pfaller S, Torrelles JB, Schlesinger LS. Characterization of clinical and environmental Mycobacterium avium spp. isolates and their interaction with human macrophages. PLoS ONE. One. 7:e45411, 2012. PMCID: PMC3446901.
- Nguyen HA, Rajaram MVS, Meyer D, Schlesinger LS. Pulmonary surfactant protein-A and surfactant lipids up-regulate IRAK-M, a negative regulator of TLR-mediated inflammation in human macrophages. Am J Physiol Lung Cell Mol Physiol. 303:L608-16, 2012. PMCID: PMC3469587
- Azad AK, Sadee W, Schlesinger LS. Innate immune gene polymorphisms in tuberculosis. Infect Immun. 80:3343-59, 2012. PMCID: PMC3457569.
- Julian MW, Shao G, Schlesinger LS, Huang Q, Cosmar DG, Bhatt NT, Culver DA, Baughman RP, Wood KL, Crouser ED. Nicotine treatment improves TLR2 and TLR9 responsiveness in active pulmonary sarcoidosis. Chest. Epub.
- Cremer TJ, Fatehchand K, Shah P, Gillette D, Patel H, Marsh RL, Besecker BY, Rajaram MVS, Kanneganti TD, Schlesinger LS, Butchar JP, Tridandapani S. MiR-155 induction by microbes/microbial ligands requires NF-kB-dependent de novo protein synthesis. Front. Cell. Inf. Microbiol. 2:73, 2012. PMCID: PMC3417573.
- Akhter A, Caution K, Abu Khweek A, Tazi M, Abdulrahman BA, Abdelaziz DH, Voss OH, Doseff AI, Hassan H, Azad A, Schlesinger LS, Wewers MD, Gavrilin MA, Amer AO. Caspase-11 promotes the fusion of phagosomes harboring pathogenic bacteria with lysosomes by modulating actin polymerization. Immunity. 37:35-47, 2012. PMCID: PMC3408798.
- Dai S, Mohapatra NP, Schlesinger LS, Gunn JS. The acid phosphatase AcpA is secreted in vitro and in macrophages by Francisella spp. Infect. Immun. 80:1088-97, 2012. PMCID: PMC3294640.
- Mishra M, Byrd MS, Sergeant S, Azad A, Parsek MR, McPhail L, Schlesinger LS, Wozniak DJ. Pseudomonas aeruginosa Psl polysaccharide reduces neutrophil phagocytosis and the oxidative response by limiting complement-mediated opsonization. Cell Micro. 14:95-106, 2012.
- Rajaram MVS, Ni B, Morris JD, Brooks MN, Carlson TK, Torrelles JB, Schlesinger LS. M. tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAP Kinase-Activated Protein Kinase 2 (MK2) and miR125b. PNAS. 108:17408-17413, 2011. Selected for Faculty of 1000, top 2% in Biology and Medicine. PMCID: PMC3198317.
- Keiser TL, Azad AK, Guirado E, Bonacci R, Schlesinger LS. A comparative transcriptional study of the putative mannose donor biosynthesis genes in virulent Mycobacterium tuberculosis and attenuated Mycobacterium bovis BCG strains. Infect Immun. 79: 4668-73, 2011. PMCID: PMC3257929.
- Torrelles JB, Sieling PA, Arcos, J, Knaup R, Bartling C, Rajaram MVS, Stenger S, Modlin RL, Schlesinger LS. Structural differences in lipomannans from pathogenic and non-pathogenic mycobacteria that impact CD1b-restricted T cell responses. JBC. 286:35438-46, 2011. PMCID: PMC3195570.
- Abdulrahman BA, Khweek AA, Akhter A, Caution K, Kotrange S, Abdelaziz DHA, Newland C, Rosales-Reyes R, Kopp B, McCoy K, Montione R, Schlesinger LS, Gavrilin M, Wewers MD, Valvano MA, Amer AO. Autophagy stimulation by rapamycin suppresses lung inflammation and infection by Burkholderia cenocepacia in a model of cystic fibrosis. Autophagy. 7:1359-1370, 2011. PMCID: PMC3359483.
- Betz BE, Azad AK, Morris JD, Rajaram MV, Schlesinger LS. β-glucans inhibit intracellular growth of Mycobacterium bovis BCG but not virulent Mycobacterium tuberculosis in human macrophages. Microbial Pathogenesis. 51:233-242, 2011. PMCID: n/a.
- Arcos J, Sasindran SJ, Fujiwara N, Turner J, Schlesinger LS, Torrelles, JB. Human lung hydrolases delineate Mycobacterium tuberculosis-macrophage interactions and the capacity to control infection. J Immunol. 187:372-381, 2011.
- Sow FB, Nandakumar S, Velu V, Kellar KL, Schlesinger LS, Amara RR, Lafuse WP, Shinnick TM, Sable SB. Mycobacterium tuberculosis components stimulate production of the antimicrobial peptide hepcidin. Tuberculosis 91:314-321, 2011.
- Dwivedi V, Manickam C, Patterson R, Dodson K, Murtaugh M, Torrelles JB, Schlesinger LS, Renukaradhya GJ. Cross-protective immunity to porcine reproductive and respiratory syndrome virus by intranasal delivery of a live virus vaccine with a potent adjuvant. Vaccine 29:4058-4066, 2011.
- Day J, Friedman A, Schlesinger LS. Modeling the host response to inhalation anthrax. J. Theoretical Bio. 276:199-208, 2011. PMCID: PMC3253853.
- Dai S, Mohapatra NP, Schlesinger LS, Gunn JS. Regulation of Francisella tularensis virulence. Frontiers in Cellular and Infection Microbiology. 1:1-10, 2011. PMCID: PMC3109300.
- Brooks MN, Rajaram MVS, Azad AK, Amer A, Valdivia-Arenas MA, Park J-H, Nunez G, Schlesinger LS. NOD2 controls the nature of the inflammatory response and subsequent fate of Mycobacterium tuberculosis and M. bovis BCG in human macrophages. Cell Microbiol. 13:402-418, 2011. PMCID: PMC3259431.
- Wang S-H, Powell DA, Nagaraja HN, Morris JD, Schlesinger LS, Turner J. Evaluation of a modified interferon gamma release assay for the diagnosis of latent tuberculosis infection in adult and pediatric populations that enables delayed processing. Scand J Infect Dis. 42:845-850, 2010. PMCID: PMC3249229.
- Clay CD, Gunn JS, SchlesingerLS. Antibody-independent classical complement pathway activation by wildtype and LPS O-antigen mutant Francisella tularensis strains. Mol Immun. 47:2245, 2010 (Abs).
- Rajaram MVS, Morris JD, Brooks MN, Torrelles JB, Azad AK, Schlesinger LS. Mycobacterium tuberculosis activates human macrophage PPARγ linking mannose receptor recognition to regulation of immune responses. J Immunol. 185:929-942, 2010 (featured). PMCID: PMC3014549.
- Mohapatra NP, Soni S, Rajaram M, Dang PMC, Reilly TJ, El-Benna J, Schlesinger LS, Gunn JS. Francisella acid phosphatases inactivate the NADPH oxidase in human phagocytes. J. Immunol. 184:5141-5150, 2010. PMCID: PMC2952287.
- Torrelles JB, Schlesinger LS. Diversity in Mycobacterium tuberculosis mannosylated cell wall determinants impacts adaptation to the host. Tuberculosis. 90:84-93, 2010. PMCID: PMC2855779.
- Sweet L, Singh PP, Azad AK, Rajaram MVS, Schlesinger LS, Schorey JS. Mannose receptor-dependent delay in phagosome maturation by Mycobacterium avium glycopeptidolipids. Infect. Immun. 78:518-526, 2010. PMCID: PMC2798179.