The mission of the Immunity and Pathogenesis Division is to elucidate of the cellular and molecular mechanisms at the interface of infection, inflammation, and immunity. Our group has broad interest and expertise in microbial pathogenesis, innate immunity, inflammatory signaling pathways, and immunological memory. Our discoveries are being translated into innovative diagnostics, vaccines, and therapeutic strategies to improve human health.

We have projects related to respiratory diseases (influenza, parainfluenza, respiratory syncytial virus, asthma, and tuberculosis), sexually transmitted diseases (chlamydia trachomatis, human papilloma virus, and Zika virus), vector-borne diseases (lyme disease and emerging vector borne viruses) and inflammatory diseases (inflammatory bowel disease).

Our research division is structured as a collaborative and community environment, one that allows for frequent interactions between students, postdocs and faculty.

Immunity and Pathogenesis Division Faculty

    Dr. Griff Parks
  • Title: Interim Associate Dean of Research; Director, Burnett School of Biomedical Sciences and Professor
  • Office: BBS 101G
  • Phone: 407.266.7011
  • Investigating innate immune responses to RNA viruses, including parainfluenza virus, bunyavirus and Zika virus & development of novel virus vectors as vaccines and anti-cancer therapies
  • Send an Email
  • Biography:

    We study the replication and innate immune responses to Paramyxoviruses – a remarkably diverse family of negative-strand RNA viruses, some of which are the most ubiquitous disease-causing viruses of humans and animals. This work includes the development of vectors for therapy or vaccination that are based on novel properties of the viral genomes and proteins. In addition, we have expanded our focus to include viral immunology projects (interferon and complement) with the bioterrorism agent Nipah virus and the pathogenic bunyaviruses.

    Our lab projects can be divided into three general areas:

    1)    Interactions of negative strand RNA viruses with interferon and complement immune pathways. We address the questions of how these viruses first activate and then suppress important innate immune pathways in order to successfully replicate. This involves studies to understand the viral factors that induce interferon and complement responses, as well as the cellular sensors and pathways that respond, suppress replication, and neutralize virus.

    2)    Developing of novel viral vectors for tumor therapy. We are taking advantage of inherent properties of the viruses we study to design novel vectors for controlled killing of tumor cells. This includes modifying the viral glycoproteins to produce vectors with enhanced ability to spread through a population of tumor cells. In addition, viral mutants which are defective in suppression of innate immunity are being tested for their ability to spread in tumor cells while retaining restricted growth in normal cells.

    3)    Development of vaccine vectors based on paramyxoviruses. Viral vectors can be potent inducers of innate and adaptive immunity, but also can cause disease in some cases. We are exploiting unique properties of some of these paramyxoviruses to develop new delivery vehicles that balance attenuated replication with induction of strong immunity to an engineered antigen.

    Recent Publications

    1. Ganguli T, Johnson JB, Parks GD and Deora R. 2014. Bordetella BPS interactions with human complement pathways. Cellular Microbiol 16:1105-1118.
    2. Mayer AE, Johnson JB, and Parks GD. 2014. The neutralizing capacity of antibodies elicited by parainfluenza virus infection of African Green monkeys is dependent on complement. Virology 460:23-33.
    3. Khalil SM, Tonkin DR, Snead AT, Parks GD, Johnston RE, and White LJ. 2014. An alphavirus-based adjuvant enhances serum and mucosal antibodies, T cells and protective immunity to influenza virus in neonatal mice. J. Virol. 88:9182-9196.
    4. Johnson JB, Schmitt AP, and Parks GD. 2013. Point mutations in the paramyxovirus F protein that enhance fusion activity shift the mechanism of complement-mediated virus neutralization. J. Virol 87:9250-9259
    5. Parks GD and Alexander-Miller MA. 2013. Invited Review: Paramyxovirus activation and inhibition of innate immune pathways. J. Molec. Biol. 425:4872-4892.
    6. Johnson JB, Lyles DS, Alexander-Miller MA and Parks GD. 2012. Virion-associated CD55 is more potent than CD46 in mediating resistance of mumps virus and VSV to neutralization. J. Virol. 86:9929-9940.
    7. Biswas, M, Kumar S, Johnson J, Parks GD and Subbiah E. 2012. Incorporation of host complement regulatory proteins into Newcastle Disease virus enhances complement evasion. J. Virol. 86:12708-12716.
    8. Briggs CM and Parks GD. 2012. Mumps virus inhibits migration of primary human macrophages toward a chemokine gradient through a TNF-alpha dependent mechanism. Virology 433:245-252.
    9. Johnson JB, Aguilar H, Lee B, and Parks GD. 2011. Interactions of human complement with virus particles containing the Nipah virus glycoproteins. J. Virol. 85:5940-5948.
    10. Clark KM, Johnson JB, Kock ND, Mizel SB and Parks GD. 2011. Parainfluenza virus 5-based vaccine vectors expressing vaccinia virus VACV antigens provide long-term protection in mice from lethal intranasal VACV challenge. Virology 419:97-106.
    11. Briggs CM, Holder RC, Reid SD and Parks GD. 2011. Activation of human macrophages by bacterial components relieves the restriction on replication of an interferon-inducing parainfluenza virus 5 (PIV5) P/V mutant. Microbes and Infection. 13:359-368.
    12. Manuse MJ and Parks GD. 2010. TLR3-dependent upregulation of RIG-I leads to enhanced cytokine production from cells infected with the parainfluenza virus SV5. Virology 397: 231-241.
    13. Armilli S, Sharma SK, Yammani R, Reid SD, Parks GD, and Alexander-Miller MA. 2010. Nonfunctional lung effectors exhibit decreased calcium mobilization associated with reduced expression of ORAI1. J. Leuk Biol. 87:977-88.
    14. Manuse MJ, Briggs CM, and Parks GD. 2010. Replication-Independent activation of human plasmacytoid dendritic cells by the paramyxovirus SV5 requires TLR7 and autophagy pathways. Virology 405:383-389.
View Full Profile
    Dr. Mollie W. Jewett
  • Title: Associate Professor, Immunity and Pathogenesis Division Leader
  • Office: BBS 218
  • Phone: 407.266.7028
  • Our lab focuses on molecular mechanisms of gene regulation and pathogenesis of the Lyme disease spirochete, Borrelia burgdorferi & Lyme disease diagnostics
  • Send an Email
  • Biography:

    Lyme disease is the leading tick-borne bacterial disease in the world resulting in greater than 30,000 cases per year in the US alone. Lyme disease is caused by tick-bite transmission of the pathogenic spirochete Borrelia burgdorferi. An increased understanding of the molecular mechanisms that B. burgdorferi uses to survive throughout its infectious cycle is critical for the development of innovative diagnostic and therapeutic protocols to reduce the incidence of Lyme disease. One of the major difficulties blocking this effort has been genome-wide identification of the B. burgdorferi genes that are expressed in the mammalian host environment. Using in vivo expression technology (IVET) in B. burgdorferi for the first time we have identified B. burgdorferi genes that are expressed during an active mammalian infection. The in vivo-expressed candidate genes putatively encode proteins in various functional categories including antigenicity, metabolism, motility, nutrient transport and unknown functions.

    In addition to identifying promoters corresponding to annotated genes, our screen has identified in vivo-expressed transcripts that map within genes and on the antisense strand relative to annotated genes. We predict that some of these DNA sequences may represent promoters for regulatory RNAs. Research in our laboratory is directed at understanding B. burgdorferi infection mechanisms through genetic, biochemical and in vivo analyses of unique in vivo-expressed genes. Furthermore, because accurate diagnosis is currently the greatest challenge for the clinical management of Lyme disease  my lab is focused on development of a simplified, objective and sensitive approach for the detection of B. burgdorferi antibodies in infected patients.

    Recent publications

     

    1. Halpern MD, Molins CR, Schriefer M and Jewett MW. 2014.  Simple objective detection of human Lyme disease infection using immuno-PCR and a single recombinant hybrid antigen. Clin Vaccin Immunol, 21(8):1094-105.
    2. Ellis TC, Jain S, Linowski A, Rike K, Bestor A, Rosa PA, Halpern M, Kurhanewicz S and Jewett MW.  2013. In vivo expression technology identifies a novel virulence factor critical for Borrelia bugdorferi persistence in mice.  PLoS Pathogens, 29 Aug 2013, 10.1371/journal.ppat.1003567.
    3. Halpern MD, Jain S and Jewett MW. 2013.  Enhanced detection of host response antibodies to Borrelia burgdorferi using immune-PCR. Clin Vaccine Immunol, 9 Jan 2013 doi:10.1128/CVI.00630-12 [epub ahead of print].
    4. Chen HD, Jewett MW and Groisman EA. 2012. An allele of an ancestral transcription factor dependent on a horizontally acquired gene product. PLoS Genetics, Dec;8(12):e1003060. doi: 10.1371/journal.pgen.1003060. Epub 2012 Dec 27.
    5. Jain S, Sutchu S, Rosa PA, Byram R, Jewett MW. Borrelia burgdorferi harbors a transport system essential for purine salvage and mammalian infection. Infect Immun. 2012 Jun 18. [Epub ahead of print]
    6. Jewett MW, Jain S, Linowski AK, Sarkar A and Rosa PA. 2011. Molecular characterization of the Borrelia burgdorferi in vivo essential protein, PncA. Microbiology, 157(10):2831-2840.
    7. Chen HD, Jewett MW and Groisman EA. 2011. Ancestral genes can control the ability of horizontally-acquired loci to confer new traits. PLoS Genetics, Jul;7(7):e1002184. Epub 2011 Jul 21.
    8. Hayes BM, Jewett MW, Rosa PA. 2010. A lacZ reporter system for use in Borrelia burgdorferi. Appl. Environ. Microbiol. 76(22):7404-12.
    9. Bestor A, Stewart PE, Jewett MW, Sarkar A, Tilly K and Rosa PA. 2010. Using the Cre-lox recombination system to investigate lp54 gene requirement in the infectious cycle of Borrelia burgdorferi. Infect. Immun. 78(6):2397-407.
    10. Jewett MW1, Lawrence K, Bestor A, Byram R, Gherardini F and Rosa PA. 2009. GuaA and GuaB are essential for B. burgdorferi survival in the tick-mouse infectious cycle. J. Bacteriol. 191(20):6231-6241.
    11. Lawrence K, Jewett MW, Rosa PA, Gherardini F. 2009. Borrelia burgdorferi bb0426 encodes a 2′-deoxyribosyltransferase that plays a central role in purine salvage.  Mol. Microbiol., 72(6):1517-1529.

    For more publication information, please visit Pubmed.

View Full Profile
    Dr. Travis Jewett
  • Title: Associate Professor
  • Office: BBS 221
  • Phone: 407.266.7029
  • Send an Email
  • Biography:
    Relevance:
    The sexually transmitted bacterium Chlamydia trachomatis causes substantial morbidity in the US and world wide. Our research efforts are focused on understanding the virulence factors employed by Chlamydiae to cause disease.
    The Tarp effector:
    A C. trachomatis effector called Tarp, for translocated actin recruiting protein is a candidate virulence factor. Tarp is tyrosine phosphorylated by a host cell kinase and is associated with actin recruitment during Chlamydiae entry. Tarp protein domains have been identified and include:  i) an actin binding and nucleating domain, ii) a proline rich oligomerization domain and iii) a phosphorylation domain. How these protein domains function during and after bacterial entry is the primary focus of our laboratory.The actin binding domain:
    The Tarp orthologs harbor between 1 to 4 actin binding domains (ABDs). Recent studies suggest that different Tarp proteins have the capacity to nucleate actin filaments by alternative nucleation mechanisms.  Ongoing projects in our lab are concentrated on comparing the ability of  different Tarps to polymerize actin.The phosphorylation domain:
    The function of the Tarp phosphorylation domain remains largely unknown. Src-homology domain 2 (SH2) containing proteins are candidate Tarp interacting proteins and recently, PI3 kinase was implicated in association with phosphorylated Tarp. Modification of lipids by PI3K ultimately regulates a variety of cellular processes. We predict that Tarp recruitment of PI3K plays a vital role in the establishment of chlamydial infection. Projects are currently underway to examine the host cell signaling cascades activated following Tarp phosphorylation and the possible contribution these pathways have in establishing chlamydial infections.
    Recent Publications
    1. Jiwani S, Ohr RJ, Fisher ER, Hackstadt T, Alvarado S, Romero A, Jewett TJ. Chlamydia trachomatis Tarp cooperates with the Arp2/3 complex to increase the rate of actin polymerization. Biochem Biophys Res Commun. 2012 Apr 20;420(4):816-21. Epub 2012 March 23.
    2. Jewett TJ, Miller NJ, Dooley CA, Hackstadt T. The conserved Tarp actin binding domain is important for chlamydial invasion. PLoS Pathog. 2010 Jul 15;6(7):e1000997.
    3. Lutter EI, Bonner C, Holland MJ, Suchland RJ, Stamm WE, Jewett TJ, McClarty G, Hackstadt T. Phylogenetic Analysis of Chlamydia trachomatis Tarp and Correlation with Clinical Phenotype. Infect Immun. 2010 Sep;78(9):3678-88. Epub 2010 Jul 6.
View Full Profile
    Dr. Kai McKinstry
  • Title: Assistant Professor
  • Office: BBS 449
  • Phone: 407.266.7137
  • Strategies to generate protective memory T cell populations & T cell-mediated protection against influenza virus
  • Send an Email
  • Biography:

    Influenza A virus (IAV) represents a global health concern, particularly for at risk segments of the population including the very young and aged. In the United States alone, seasonal IAV infection is responsible for over 200,000 hospitalizations per year and an economic burden estimated to exceed 87 billion dollars during the flu season. Protection against IAV generated through current vaccine strategies is not optimal; studies conducted during the 2014-2015 flu season estimated only around 25% efficacy of immunization across all age groups.

    Most current vaccines aim to generate high titers of neutralizing antibodies that will recognize and bind to a specific pathogen thereby preventing infection. IAV vaccines target antibody production against the viral hemagglutinin (HA) and neuraminidase (NA) proteins that are key for facilitating entry into host cells and productive infection. However, IAV rapidly mutates to escape recognition by neutralizing antibodies and this largely underlies the need for annual vaccine reformulation, based on predictions of which HA and NA molecules will be expressed by seasonal IAV variants. Current vaccines against IAV are of very little protective efficacy in cases of mismatch between the HA and NA molecules present in the vaccine versus those expressed by circulating seasonal strains. Perhaps more importantly, current vaccines are ineffective when unexpected pandemic IAV strains, such as the ‘bird flu’ or ‘swine flu’, emerge during the flu season.

    CD4 T cells, traditionally labeled as the ‘helper’ cells of the immune system, have recently been shown to also exert several powerful anti-viral functions. Evidence from animal models of IAV infection and clinical studies suggest that memory CD4 T cells can provide strong protection against several pathogens, including IAV, even in the absence of neutralizing antibody.

    Dr. McKinstry’s lab is focused on two fundamental questions. First, how do memory CD4 T cells combat IAV? Our studies have identified that several specialized subsets of memory CD4 T cells contribute to viral clearance through unique mechanisms. Current research in the lab seeks to identify how to harness the anti-viral potential of memory CD4 T cells while minimizing immunopathology in the lung. Future work will determine whether protective memory CD4 T cell functions can be harnessed and optimized to combat other dangerous pathogens as well as cancers.

    The second focus of Dr. McKinstry’s research is understanding how the most protective memory CD4 T cells are be generated through vaccination. Current vaccines do not stimulate the formation of strong T cell immunity. Recent studies have defined that memory T cells able to survive long-term at sites of infection (or vaccination) are crucial for providing optimal protection upon rechallenge. The requirements for generating such ‘tissue-resident’ memory T cells are not clear but seem to be distinct from the signals that drive the generation of memory cells present in secondary lymphoid organs. Defining critical elements of the pathway supporting tissue-resident memory CD4 T cell generation in the lung (the site of IAV infection) will allow for innovative vaccine strategies to improve protection against IAV and other important respiratory pathogens.

     

    Publications: Peer-reviewed Journal Articles

    Torrado, E., Fountain, J., Tighe, M., Reiley, W., Pearl, J., Zak, D., Thompson, E., Aderem, A., Solache, A., McKinstry, K.K., Strutt, T., Swain, S., and A. Cooper. Interleukin 27 regulates CD4+ T cell phenotype and impacts protective immunity during Mycobacterium tuberculosis infection. Journal of Experimental Medicine, 212: 1449-63.

    Sell. S., Guest, I., McKinstry, K.K., Strutt, T.M., Kohlmeier, J.E., Brincks, E., Tighe, M., Blackman, M.A.,Woodland, D.L., Dutton, R.W., and S.L. Swain. 2014. Intraepithelial T-cell cytotoxicity, induced bronchus associated lymphoid tissue, and proliferation of pneumocytes in experimental mouse models of influenza. Viral Immunology, 27:484-96.

    McKinstry, K.K., Strutt, T.M., Bautista, B., Zhang, W., Kaung, Y., Cooper, A.M., and S.L. Swain. 2014. Effector CD4 T cell transition to memory requires late cognate interactions that induce autocrine IL-2. Nature Communications: 5:5377.

    • corresponding author

    Rudulier, C.D., McKinstry, K.K., Al-Yassin, G.A., Kroeger, D.R., and P. A. Bretscher. 2014. The number of responding CD4 T cells and the dose of antigen conjointly determine the Th1/Th2 phenotype by modulating B7/CD28 interactions. Journal of Immunology, 192: 5140-50.

    Jain, N., Miu, B., Jiang, J., McKinstry, K.K., Prince, A., Swain, S.L., Greiner, D., Thomas, C.J., Sanderson, M.J., Berg, L.J., and J. Kang. 2013. CD28 and ITK signals regulate autoreactive T cell trafficking. Nature Medicine, 19: 1632-37.

    Strutt, T.M., McKinstry, K.K., Marshall, N.B., Vong, A.M., Dutton, R.W., and S.L. Swain. 2013. Multipronged CD4 T cell effector and memory responses cooperate to provide potent immunity against respiratory viruses. Immunological Reviews, 255: 149-64. (invited review)

    McKinstry, K.K., Dutton, R.W., Swain, S.L., and T. M. Strutt. 2013. Memory CD4 T cell-mediated immunity against influenza A virus: more than a little helpful. Archivum Immunologiae et Therapiae Experimentalis, 61: 341-53. (invited review)

    • corresponding author

    Hamada, H., Bassity, E., Flies, A., Strutt, T.M., de Luz Garcia-Hernandez, M., McKinstry, K.K., Zou, T., Swain, S.L., and R.W. Dutton. 2013. Multiple redundant effector mechanisms of CD8+ T cells protect against influenza infection. Journal of Immunology, 190: 296-306.

    Strutt, T.M., McKinstry, K.K., Kaung, Y., Bradley, L.M., and S.L. Swain. 2012. Memory CD4+ T cell-mediated protection depends on secondary effectors that are distinct from and superior to primary effectors. Proceedings of the National Academy of Sciences (USA), 109: E2551-60.

    • co-first author
    • corresponding author

    McKinstry K.K., Strutt, T.M., Kaung, Y., Brown, D.M., Sell, S., Dutton, R.W., and S.L. Swain. 2012. Memory CD4+ T-cells protect against influenza by multiple synergizing mechanisms. Journal of Clinical Investigation, 122: 847-56.

    • corresponding author
    • featured commentary in Journal of Clinical Investigation
    • featured as a Research Highlight in Nature Reviews Immunology

    Swain, S.L., McKinstry, K.K., and T. M. Strutt. 2012. Expanding roles for CD4+ T cells in immunity to viruses. Nature Reviews Immunology, 12: 136-48. (invited review)

    McKinstry, K.K., Strutt, T.M., and S.L. Swain. 2011. Hallmarks of CD4 T cell immunity against influenza. Journal of Internal Medicine, 269: 507-518. (invited review)

    • corresponding author

    McKinstry, K.K., Strutt, T.M., and S.L. Swain. 2010. Regulation of CD4 T cell contraction during pathogen challenge. Immunological Reviews, 236: 110-24. (invited review)

    Strutt, T.M., McKinstry, K.K., Dibble, J.P., Winchell, C., Kuang, Y., Curtis, J.D., Huston, G., Dutton, R.W., and S.L. Swain. 2010. Memory CD4 T cells induce innate responses independent of pathogen. Nature Medicine, 16: 558-64.

    • co-first author
    • selected and reviewed by Faculty of 1000
    • featured as a Research Highlight in Nature Reviews Immunology

    McKinstry, K.K., Strutt, T.M., and S.L. Swain. 2010. The potential of CD4 T cell memory. Immunology, 130: 1-9. (invited review)

    • corresponding author

    McKinstry, K.K., Strutt, T.M., Buck, A., Curtis, J.D., Dibble, J.P., Huston, G., Tighe, M., Hamada, H., Sell, S., Dutton, R.W., and S.L. Swain. 2009. IL-10 deficiency unleashes an influenza-specific Th17 response and enhances survival against high dose challenge. Journal of Immunology, 182: 7353-63.

    • corresponding author
    • selected and reviewed by Faculty of 1000

    Hamada H, Garcia-Hernandez L., Reome, J.B., Misra, S.K., Strutt, T.M., McKinstry, K.K., Cooper, A.M., Swain, S.L., and R.W. Dutton. 2009. Tc17, a unique subset of CD8 T cells that can protect against lethal influenza challenge. Journal of Immunology 182: 3469-81.

    Strutt, T.M., McKinstry, K.K., and S.L. Swain. 2009. Functionally diverse subsets in CD4 T cell responses against influenza. Journal of Clinical Immunology 29: 145-50. (invited review)

    Jelley-Gibbs, D.M., Strutt, T.M., McKinstry, K.K., and S.L. Swain. 2008. Influencing the fates of CD4 T cells on the path to memory: lessons from influenza. Immunology and Cell Biology 86: 343-52. (invited review)

    McKinstry, K.K., Strutt, T.M., and S.L. Swain. 2008. The effector to memory transition of CD4 T cells. Immunologic Research 40: 114-27. (invited review)

    • corresponding author

    McKinstry, K.K., Golech, S., Lee, W.H., Huston, G., Weng, N.P., and S.L. Swain. 2007. Rapid default transition of CD4 T cell effectors to functional memory cells. Journal of Experimental Medicine 204: 2199-211.

    • corresponding author

    Li, X., McKinstry, K.K., Swain, S.L., and D.K. Dalton. 2007. IFN-gamma acts directly on activated CD4+ T cells during mycobacterial infection to promote apoptosis by inducing components of the intracellular apoptosis machinery and by inducing extracellular proapoptotic signals. Journal of Immunology 179: 939-49.

    Jelley-Gibbs, D.M., Dibble, J.P., Brown, D.M., Strutt, T.M., McKinstry, K.K., and S.L. Swain. 2007. Persistent depots of influenza antigen fail to induce a cytotoxic CD8 T cell response. Journal of Immunology 178: 7563-70.

    Swain, S.L., Agrewala, J.N., Brown, D.M., Jelley-Gibbs, D.M., Golech, S., Huston, G., Jones, S.C, Kamperschroer, C., Lee, W-H., McKinstry, K.K., Roman, E., Strutt, T. and N. Weng. 2006. CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza. Immunological Reviews 211: 8-22. (invited review)

    Strutt, T., Uzonna, J., McKinstry, K.K., and P. Bretscher. 2006. Activation of thymic T cells by MHC alloantigen requires syngeneic, activated CD4+ T cells and B cells as APC. International Immunology 18: 719-28.

     

    Publications: Book Chapters

    S.L. Swain, Strutt, T.M., and K.K. McKinstry. 2015.  Immunity to Viral Infection: CD4 T Cell Immunity to Viral Infection. In Encyclopedia of Immunobiology. Ed. Christine Biron.  Chapter 14026 (Accepted).

    McKinstry K.K., and Strutt T.M. 2014. Regulation and Maintenance of Adaptive Immunity. In Pathobiology of Human Disease. Ed. Linda M. McManus and Richard N. Mitchell, p. 20-35.

    Strutt, T.M., McKinstry, K.K., and S.L. Swain. 2011. Control of innate immunity by memory CD4 T cells. In 3rd Crossroads between Innate and Adaptive Immunity. Ed. B. Pulendran, S. Schoenberger, and P. Katsikis, p 57-68.

    McKinstry, K., Ismail, N., Peters, N., Strutt, T. and P. Bretscher. 2005. Non-interference, independence and coherence of immune responses: Implications for macroimmunology and strategies of intervention. In Altered Immunoregulation and Human Disease. Ed. Reginald M. Gorczynski, p 93-113.

View Full Profile
    Dr. Kyle Rohde
  • Title: Assistant Professor
  • Office: BBS 238
  • Phone: 407.266.7124
  • Studies (i) Pathogenesis and gene regulation in Mycobacterium tuberculosis and M. abscessus (ii) Antibiotic drug discovery targeting Mycobacteria (iii)Mechanisms of drug resistance in pathogenic Mycobacteria (iv) Diagnostic tools for detection of drug resistant TB
  • Send an Email
  • Biography:

    Background

    Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), infects ~9 million new people and claims ~1.5 million lives each year.  This ongoing global health crisis stems from the lack of an effective vaccine, inadequate diagnostics and drug regimens, emergence of multi-drug resistant strains, and synergism with HIV infection.  Thus, there is an urgent need to better understand how Mtb causes disease in order to develop reliable diagnostics, protective vaccines, and fast-acting drugs effective against Mtb.

    An important key to the success of Mtb as an intracellular pathogen is the ability to survive inside macrophages which are capable of killing most bacteria.  Mtb is able to prevent trafficking to acidic, degradative lysosomes and adapt its metabolism and physiology to survive inside a specialized compartment.  Long-term growth in this niche requires that Mtb regulate gene expression in response to cues and stresses encountered within macrophages.  Another defining feature of TB disease is the development of latent infections in which asymptomatic patients harbor dormant Mtb bacteria for years which can reactivate upon suppression of the immune system.

    Research Areas

    My lab is exploiting several approaches to address to root causes of the TB health crisis.

    1) Mtb genetics and Host Interactions:   How does TB survive inside hostile macrophages? What genes are required for Mtb to grow and cause disease?  How does Mtb regulate its genes in response to host-derived stresses?  Do different strains of Mtb use different strategies to be successful?  Answers to these questions will help to identify vulnerable targets for new drugs.

    • A)  Transcriptional adaptation of Mtb required for survival in macrophages. We developed a novel RNA amplification and microarray methodology to monitor mycobacterial global gene expression within macrophages.  This allowed high-resolution temporal profiling of Mtb genes actively modulated during macrophage invasion in response to host-derived cues/stressors.  For example, we found that acidification of the Mtb vacuole is a major trigger of the early transcriptional responses. Future studies will characterize specific regulatory pathways involved in Mtb intracellular survival and stress responses relevant during human infections.  Gene products and pathways that are essential for adaptation within the host represent potential new drug targets.
    • B)  Functional Evolution of Mtb Transcriptional Regulatory Networks.  This project is exploring the impact of genomic diversity among clinical isolates on Mtb pathogenesis, specifically intracellular survival and gene expressionThus far, studies of Mtb have mainly focused on a few lab strains, despite evidence of important genetic and phenotypic differences among clinical isolates.  By extending our microarray studies to a panel of 17 phylogenetically diverse clinical isolates, we found that the genetic diversity of clinical isolates has a significant impact on global gene expression, affecting basal transcript levels in vitro and responses to intracellular cues encountered during macrophage invasion. Coupled with the distinct abilities of strains to survive inside macrophages, these observations suggest that dysregulation of gene expression is a powerful potential mechanism by which genomic diversity could influence Mtb-host interactions. Future work will focus initially on selected virulence regulators with strain-dependent expression patterns to begin to identify the underlying mechanisms and significance of lineage-specific gene regulation.  We are collaborating with Dr. Stefan Niemann of the National Reference Center for Mycobacteria in Borstel, Germany.

    2) Point-of-care diagnostics: We are developing DNA-based molecular diagnostics, called binary deoxyribozyme sensors, designed to allow fast, cheap, and accurate detection of Mtb in sputum samples in point-of-care settings.  These tools will also permit detection of drug-resistant strains of Mtb to guide the rational design of drug therapy regimens.  This project is in collaboration with Dr. Dmitry Kolpashchikov (UCF, Department of Chemistry).

    3) TB Drug Discovery:   Our aim is to discover novel chemical compounds capable of killing Mtb under conditions that mimic the in vivo environment during infection.  Our current screening of a library of thousands of marine natural products against “glow in the dark” Mtb we engineered to be fluorescent has already revealed several promising “hit” compounds.  Additional studies will hopefully uncover many more so-called lead compounds that may help effectively treat TB.  This NIH-funded project is a collaboration with Dr. Amy Wright of Harbor Branch Oceanographic Institute and Dr. Pappachan Kolattukudy of the Burnett School of Biomedical Sciences, UCF.

    By taking a multifaceted approach to improve our understanding of this disease and add to our arsenal of tools aimed at this pathogen, we hope to make a significant contribution to the fight against TB.  

    Recent Publications:

     

    1. Wright AE, Killday KB, Chakrabarti D, Guzmán E, Harmody D, McCarthy PJ, Pitts T, Pomponi S, Reed JK, Roberts BF, Rodrigues Felix C, Rohde KH.  2017.  Dragmacidin G, a Bioactive Bis-Indole Alkaloid from a Deep-Water Sponge of the Genus Spongosorites.  Marine DrugsIn press
    2. Rohde KH, Michaels HA, Nefzi A, 2016. Synthesis and Antitubercular Activity of 1,2,4-Trisubstituted Piperazines.  Bioorganic and Medicinal Chemistry Letters.  26(9):2206-9.
    3. Sandhaus S, Annamalai T, Welmaker G, Houghten RA, Paz C, Garcia PK, Andres A, Narula G, Rodrigues Felix C, Geden S, Netherton M, Gupta R, Rohde KH, Giulianotti MA, Tse-Dinh YC. 2016.  Small molecule inhibitors targeting topoisomerase 1 as novel antituberculosis agents.  Antimicrob Agents Chemother.. Apr 25. pii: AAC.00288-16. [Epub ahead of print].
    4. Liu Y, Tan S, Huang L, Abramovitch R, Rohde KH, Zimmerman M, Chen C, Dartois V, VanderVen B, and Russell DG. 2016. Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo.  J Exp Med.   213(5):809-25.
    5. Cox AJ, Bengtson HN, Gerasimova YV, Rohde KH, Kolpashchikov DM. 2016.  DNA Antenna Tile-Associated Deoxyribozyme Sensor with Improved Sensitivity.  Chembiochem.  17 (21); 2038-2041.
    6. Cox AJ, Bengtson HN, Rohde KH, Kolpashchikov DM. 2016.  DNA nanotechnology for nucleic acid analysis: Multifunctional molecular DNA machine for RNA detection.  ChemComm.  52 (99): 14318-14321.
    7. Stout MB, Swindell WR, Zhi X, Rohde KH, List EO, Berryman DE, Kopchick JJ, Gesing A, Fang Y, and Masternak MM. 2015.  Transcriptome profiling reveals divergent expression shifts in brown and white adipose tissue from long-lived GHRKO mice.  Oncotarget.  6(29): 26702-15.
    8. Gerasimova YV, Cornett EM, Edwards E, Su X, Rohde KH, Kolpashchikov D.M. 2013. Deoxyribozyme Cascade for Visual Detection of Bacterial RNA. Chembiochem. Nov 4;14(16):2087-90.
    9. Sakamoto K, Kim MJ, Rhoades ER, Allavena RE, Ehrt S, Wainwright HC, Russell DG, Rohde KH.  2013.  Mycobacterial trehalose dimycolate reprograms macrophage global gene expression and activates matrix metalloproteinases.  Infect Immun.  81(3): 764-76.
    10. Rohde KH*, Veiga DFT, Caldwell S, Balázsi G, Russell DG. 2012.  Linking the Transcriptional Profiles and the Physiological States of Mycobacterium tuberculosis during an Extended Intracellular Infection. PLoS Pathog 8(6): e1002769. doi:10.1371/journal.ppat.1002769. *corresponding author
    11. Abramovitch RB, Rohde KH, Hsu FF and Russell DG. 2011.  aprABC: A Mycobacterium tuberculosis complex-         specific locus that modulates pH-driven adaptation to the macrophage phagosome.  Mol Microbiol.  May;80(3):678-94.
    1. Homolka S, Niemann S, Russell DG, Rohde KH. 2010. Functional Genetic Diversity among Mycobacterium tuberculosis Complex Clinical Isolates: Delineation of Conserved Core and Lineage-Specific Transcriptomes during Intracellular Survival. PLoS Pathog. 6(7): e1000988. doi:10.1371/journal.ppat.1000988.
    2. Hagedorn M, Rohde KH, Russell DG, Soldati T. 2009. Infection by tubercular mycobacteria is spread by nonlytic ejection from their amoeba hosts. Science. 323(5922): 1729-1733.
    1. Schwab U, Rohde KH, Wang Z, Chess PR, Notter RH, Russell DG. 2009. Transcriptional responses of Mycobacterium tuberculosis to lung surfactant. Microb Pathog. 46(4): 185-193.
    1. Rohde KH, Abramovitch RB, Russell DG. 2007. Mycobacterium tuberculosis invasion of macrophages: Linking bacterial gene expression to environmental cues. Cell Host and Microbe. 2: 352-364.
    1. Russell DG, Purdy GE, Owens RM, Rohde KH, and Yates RM. 2005. Mycobacterium tuberculosis and the Four-Minute Phagosome.  ASM News.  71 (10); 459-463.
View Full Profile
    Dr. Tara Strutt
  • Title: Assistant Professor
  • Office: BBS 442
  • Phone: 407.266.7144
  • Memory CD4 T cell regulation of inflammatory responses & Protective roles of innate lymphoid cells during respiratory virus infection
  • Send an Email
  • Biography:

    My ongoing and future research endeavors are centered on two lines of research, both of which strive to gain further insights into how CD4 T cells function to protect against influenza A virus (IAV).

    The first is focused on understanding the cellular and molecular mechanisms by which memory CD4 T cells enhance early innate inflammatory cytokines and chemokines that correlate with early control of IAV. Such knowledge has broad translational impact as it could also provide insight into how CD4 T cells promote immune mediated inflammatory autoimmune diseases.

    The second research avenue is centered on the hypothesis that memory CD4 T cells, in addition to orchestrating and participating in more rapid and effective anti-viral recall responses, orchestrate accelerated healing in infected or damaged tissue through enhanced activation and mobilization of innate cells involved in tissue repair processes. The beneficial role of memory CD4 T cells in promoting tissue repair has not previously been appreciated and has broad translational application.

    The ultimate goal of research in my lab is to gain insight into how immune cells participate in vaccine induced protection. Understanding how immune cells function to mediate protection is key to the development of novel and innovative vaccination strategies against pathogens, such as IAV, for which vaccines that induce long-lived universal protection have yet to be formulated. Research leading to the development of novel strategies to protect individuals from potential pandemic or circulating strains of influenza that differ from the predicted vaccine strain is of paramount importance as influenza remains a serious public health concern.

     

    Publications:

    1. Swain, S. L., Strutt, T.M., and K.K. McKinstry. 2015. “Immunity to Viral Infection: CD4 T Cell Immunity to Viral Infection”. In Biron (Ed) Encyclopedia of Immunobiology. Oxford: Elsevier (In Press).
    1. Torrado, E., Fountain, J., Tighe, M., Reiley, W., Pearl, J.E., Zak, D.E., Thompson, E.G., Aderem, A., Solache, A., McKinstry, K., Strutt, T., Swain, S., and A.M. 2015. Cooper. Interleukin 27 regulates CD4 T cell phenotype and impacts protective immunity during Mycobacterium tuberculosis Journal of Experimental Medicine 212:1449-63.
    1. McKinstry, K.K.*, Strutt, T.M.*, Bautista, B. Zhang, W., Kuang, Y., Cooper, A.M., and S.L. Swain. 2014. Effector CD4 T cell transition to memory requires late cognate interactions that induce autocrine IL-2. Nature Communications 5:5377 doi: 10.1038/ncomms6377. *Authors contributed equally.
    1. Stewart S., Guest, I., McKinstry, K.K., Strutt, T.M., Kohlmeier, J.E., Brincks, E., Tighe, M., Blackman, M.A., Woodland, D.L., Dutton, R.W., and S.L. Swain. Intraepithelial T-cell cytotoxicity, induced bronchus associated lymphoid tissue, and proliferation of pneumocytes in experimental mouse models of influenza. Viral Immunology. 27:484-96.
    1. McKinstry K.K., and Strutt T.M. 2014. “Regulation and Maintenance of Adaptive Immunity”. In L.M. McManus, R.N. Mitchell (Eds.) Pathobiology of Human Disease. San Diego: Elsevier; p.20-35.
    1. Strutt, T.M., McKinstry, K.K., Marshall, N.B., Vong, A.M., Dutton, R.W., and S.L. Swain. 2013. Multipronged CD4 T cell effector and memory responses cooperate to provide potent immunity against respiratory virus. Immunological Reviews 255:149-64.
    1. McKinstry, K.K., Dutton, R.W., Swain, S.L., and M. Strutt. 2013. Memory CD4 T cell-mediated immunity against influenza A virus: more than a little helpful. Archivum Immunologiae et Therapiae Experimentalis 61:341-53.
    1. Hamada, H., Bassity, E., Flies, A., Strutt, T.M., Garcia-Hernandez, M-L., McKinstry, K.K., Zou, T., Swain, S.L., and R.W. Dutton. 2013. Multiple effector mechanisms of CD8+ T cells protect against influenza infection.   Journal of Immunology 190:296-306.
    1. Strutt, T.M., McKinstry, K.K., Kuang, Y., Bradley, L.M., and S.L. Swain. 2012. Memory CD4+ T cell-mediated protection depends on secondary effectors that are distinct from and superior to primary effectors. Proceedings from the National Academy of Sciences 109:E2551-60.
    1. Pearl, J.E., Torrado, E., Tighe, M., Fountain, J.J., Solache, A., Strutt, T., Swain, S., Appelberg, R., and A. Cooper. 2012. Nitric oxide inhibits accumulation of CD4+CD44hiTbet+CD69lo T cells in mycobacterial infection. European Journal of Immunology 42: 3267-79.
    1. McKinstry, K.K.*, Strutt, T.M.*, Kuang, Y., Brown, D.M., Sell, S., Dutton, R.W., and S.L. Swain. 2012. Memory CD4+ T-cells protect against influenza by multiple synergizing mechanisms. Journal of Clinical Investigation 122: 2847-2856. *Authors contributed equally.
    1. Swain, S.L., McKinstry, K.K., and M. Strutt. 2012. Expanding roles for CD4+ T cells in immunity to viruses. Nature Reviews Immunology 12:136-148.
    1. Strutt, T.M., McKinstry, K.K., and S.L. Swain. Crossroads between innate and adaptive immunity III: Control of innate immunity by memory CD4+ T cells”. In B. Pulendran, P.D. Katsikis, and S.P. Schoenberger (Eds.) Advances in Experimental Medicine and Biology Vol.780: 57-68.
    1. McKinstry K.K., Strutt T.M., and S.L. Swain. 2011. Hallmarks of CD4+ T cell immunity against influenza. The Journal of Internal Medicine 269:507-18.
    1. Strutt, T.M., McKinstry, K.K., Dibble, J.P., Winchell, C., Kuang, Y., Curtis, J.D., Huston, G., Dutton, R.W., and S.L. Swain. 2010. Memory CD4+ T cells induce innate responses independent of pathogen. Nature Medicine 16: 558-564.
    1. McKinstry, K.K., Strutt, T.M.,L. Swain. 2010. The potential of CD4+ T cell memory. Immunology 130:1-9.
    1. McKinstry, K.K., Strutt, T.M.,L. Swain. 2010. Regulation of CD4+ T cell contraction during pathogen challenge. Immunological Reviews 236: 110-124.
    1. McKinstry, K.K.*, Strutt, T.M.*, Buck, A., Curtis, J., Dibble, J., Huston, G., Hamada, H., Dutton, R.W., Sell, S., and S.L. Swain. 2009. IL-10 deficiency unleashes an influenza specific TH-17 response and enhances survival against high dose challenge. Journal of Immunology 182:7353-63. *Authors contributed equally.
    1. Hamada, H., Garcia-Hernandez, M-L., Reome, J., Misra, S.K., Strutt, T.M., McKinstry, K.K., Cooper, A.M., Swain, S.L., and R.W. Dutton. 2009. Tc17, a unique subset of CD8+ T cells that can protect against lethal influenza challenge. Journal of Immunology 182: 3469-81.
    1. Strutt, T.M., McKinstry, K.K., and S.L. Swain. 2009. Functionally diverse subsets in CD4+ T cell responses against influenza. Journal of Clinical Immunology 29:145-50.
    1. Jelly-Gibbs, D. M., Strutt, T.M., McKinstry, K.K., and S.L. Swain. 2008. Influencing the fates of CD4+ T cells on the path to memory: lessons from influenza. Immunology and Cell Biology 86:343-52.
    1. K.K., Strutt, T.M., and S.L. Swain. 2008. The effector to memory transition of CD4+ T cells. Immunologic Research 40:114-27.
    1. Jelly-Gibbs, D.M., Dibble, J.P., Brown, D.M., Strutt, T.M., McKinstry, K.K., and S.L. Swain. 2007. Persistent depots of influenza antigen fail to induce a cytotoxic CD8+ T cell response. Journal of Immunology 178:7563-70.
    1. Powell, T.J.*, Strutt, T.*, Reome, J., Hollenbaugh, J.A., Roberts, A.D., Woodland, D.L., Swain, S.L., Dutton, R. W. 2007. Priming with cold-adapted influenza A does not prevent infection but elicits long-lived protection against supralethal challenge with heterosubtypic virus. Journal of Immunology 178:1030-8. *Authors contributed equally.
    1. Swain, S.L., Agrewala, J.N., Brown, D.M., Jelley-Gibbs, D.M., Golech, S., Huston, G., Jones, S.C, Kamperschroer, C., Lee, W-H., McKinstry, K.K., Roman, E., Strutt, T. and N. Weng. 2006. CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza. Immunological Reviews 211:8-22.
    1. Strutt, T.M., Uzonna, J., McKinstry, K.K, and P. Bretscher. 2006. Activation of thymic T cells by MHC alloantigen requires syngeneic, activated CD4+ T cells and B cells as APC. International Immunology 18:719-28.
    1. McKinstry, K., Ismail, N., Peters, N., Strutt, T.M., and P. Bretscher. 2005. Non-interference, independence and coherence of immune responses: Implications for macro immunology and strategies of intervention. In R.M. Gorczynski (Ed) Altered Immunoregulation and Human Disease. Kerala: Research Signpost; p. 93-113.
    1. Strutt, T. and P. Bretscher. 2005. Cooperation between CD4+ T helper cells is required for the generation of alloantigen-specific, IFN-g-producing human CD4+ T cells. Immunology and Cell Biology 83:175-81.
View Full Profile
    Dr. Justine Tigno-Aranjuez
  • Title: Assistant Professor
  • Office: BBS 338
  • Phone: 407.266.7142
  • Post-translational modifications occurring in innate immune signaling pathways involved in inflammatory disease with a particular focus on NOD2 signaling & Molecular mechanisms underlying the pathogenesis of inflammatory bowel disease (IBD) and allergic asthma
  • Send an Email
  • Biography:

     

    Post-translational Modifications (PTMs) Driving Inflammatory Disease

     
    Genome-wide association studies (GWAS) and next-generation sequencing technologies (NGS) have greatly expanded our knowledge of disease-associated genetic variants. However, for many of these variants, the underlying molecular mechanisms and cellular pathways influencing disease development are, yet, unknown. One avenue that can contribute to the functional understanding of such disease-related associations is the study of post-translational modifications (PTMs). PTM involves the attachment of biochemical functional groups or moieties, often affecting a protein’s localization, stability, and function. Determining how a disease-associated variant influences or is influenced by PTMs is an appealing strategy not only because it may give insight into a protein’s regulation and function, and therefore, point to involvement of a certain biological pathway, but also, as many PTMs are enzymatically regulated, it allows for pharmaceutical targeting of such PTMs. Therefore, identifying and understanding the roles of PTMs in various disease states will be important if one wants to determine an underlying molecular defect, identify a novel drug target, and manipulate signaling pathways for clinical benefit.
     
    Majority of my work will focus on signaling mediated through the bacterial peptidoglycan sensor NOD2. Our research on this pathway has led to the discovery that RIP2, the NOD2-associated kinase, undergoes inducible tyrosine autophosphorylation. This led to the identification of RIP2 as the tyrosine kinase mediating this PTM, reclassifying it as a dual-specificity kinase. These findings encouraged us to conduct a small molecule screen for inhibitors of RIP2’s tyrosine kinase activity, a direction which led to the identification of FDA-approved drugs (Erlotinib and Gefitinib) which could be repurposed for inhibiting NOD2/RIP2 hyperactive states such as asthma, EAE, arthritis, and certain settings of IBD (WT NOD2 background). My latest work demonstrates that targeting RIP2’s kinase activity in vivo (using Gefitinib or a novel RIP2 specific inhibitor) is protective in three inflammatory disease states: a spontaneous ileitis model, a DSS colitis model, and an MDP-induced peritonitis model. I am also currently funded to understand how RIP2 may play a role in the pathogenesis of allergic asthma. These studies nicely illustrate the feasibility, broad applicability and clinical relevance of studying PTMs in inflammatory disease, a direction which I hope to continue in the future.
     

    Recent Publications

     
    Tigno-Aranjuez, J.T., Benderitter, P., Rombouts, F., Deroose, F., Bai, X., Mattioli, B., Cominelli, F., Pizarro, T.T., Hoflack, J., and D.W. Abbott. “In vivo inhibition of RIP2 kinase alleviates inflammatory disease”. J. Biol. Chem. 2014. 289:29651-64.

    Jun, J., Kertesy, S., Jones, M., Marinis, J.M., Cobb, B.A., Tigno-Aranjuez, J.T. and D.W. Abbott. “Innate immune-directed NF-κB signaling requires site-specific NEMO ubiquitination”. Cell Reports. 2013. 4:352-61.

    Tigno-Aranjuez, J.T. and D.W. Abbott. “Transcriptomics identifies a discrete ubiquitin-regulated network driving NOD2-dependent signaling”. Mol. Cell. Biol. 2013. 33:146-58

    Tigno-Aranjuez, J.T. and D.W. Abbott. “Ubiquitination and Phosphorylation in the Regulation of NOD2 signaling and NOD2-mediated Disease”. Biochim Biophys Acta. 2012. 1823:2022-8

    Tigno-Aranjuez, J.T., Asara, J.M., and D.W. Abbott. “Inhibition of RIP2’s tyrosine kinase activity limits NOD2-driven cytokine responses”. Genes Dev. 2010. 24:2666-77.

View Full Profile

 

Immunity and Pathogenesis Affiliate Faculty

Dr. Kenneth Alexander, M.D., Ph.D., Nemours Children’s Hospital

Dr. Nyla Dil, D.V.M.,  Ph.D., COM Medical Education

Dr. Le-Chu Su, M.D., Ph.D., COM Internal Medicine

Dr. Bradley Willenberg, Ph.D., COM Internal Medicine