Source: PENNSYLVANIA STATE UNIVERSITY submitted to NRP
BORDETELLA-HOST INTERACTIONS
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
COMPLETE
Funding Source
HATCH
Reporting Frequency
Annual
Accession No.
0225790
Grant No.
(N/A)
Cumulative Award Amt.
(N/A)
Proposal No.
(N/A)
Multistate No.
(N/A)
Project Start Date
Jul 1, 2011
Project End Date
Jun 30, 2016
Grant Year
(N/A)
Program Code
[(N/A)]- (N/A)
Recipient Organization
PENNSYLVANIA STATE UNIVERSITY
208 MUELLER LABORATORY
UNIVERSITY PARK,PA 16802
Performing Department
Veterinary & Biomedical Sciences
Non Technical Summary
Bordetella bronchiseptica is a major bacterial infectious agent of respiratory tracts and is amongst the greatest threats to the health of animals. B. bronchiseptica infection is endemic in many agricultural animals and has been found in pigs, sheep, rabbits, cows, horses, dogs, cats, rats and mice. The infection can lead to diseases such as Atrophic Rhinitis that causes an estimated $17 million in damages to U.S. pig farms annually. B. bronchiseptica infection also predisposes animals to many other respiratory tract infections. The current vaccines and therapies are not capable of eliminating infection from individual animals or herds. Understanding mechanisms of protective immunity against B. bronchiseptica infection and how this pathogen manipulates the immune response will greatly improve our ability to vaccinate and treat the various diseases it causes.
Animal Health Component
(N/A)
Research Effort Categories
Basic
(N/A)
Applied
(N/A)
Developmental
(N/A)
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
3113840109050%
3114010110050%
Knowledge Area
311 - Animal Diseases;

Subject Of Investigation
3840 - Laboratory animals; 4010 - Bacteria;

Field Of Science
1090 - Immunology; 1100 - Bacteriology;
Goals / Objectives
GOALS: Bordetella bronchiseptica is a Gram-negative respiratory pathogen that infects a wide range of animals. The infection is endemic in many populations of domestic animals and is associated with a variety of pathologies including atrophic rhinitis in pigs, snuffles in rabbits and kennel cough in dogs. In surveys, B. bronchiseptica has been isolated from 92% of SPF piggeries and 97% of non-SPF facilities in the U.S. The infection with B. bronchiseptica persists for the life in the infected animals, is notoriously difficult to clear by antibiotic treatment and is associated with decreased weight gain that is costly to producers. In addition, The B. bronchiseptica infection predisposes animals to subsequent infection with various other bacterial and viral pathogens. Several studies have shown limited vaccine efficacy in controlling symptoms of disease, but none has shown significant effects on the rate of infection, which remains high even in vaccinated herds. Despite the significance of B. bronchiseptica infections to animal health and agricultural economy, there is very little understanding of the molecular basis for the host immune responses and bacterial virulence, which limits our ability to develop efficient vaccines and therapeutic methods against the infection. Our long-term goal is to understand how the host immune system responds to the B. bronchiseptica infection and how the bacteria avoids clearance by it, and to improve our ability to design truly effective vaccines and therapies against this and other respiratory pathogens. OBJECTIVES: 1. Determine the roles of different subsets of T cells in clearance of Bordetella species. 2. Determine mechanisms regulating development and maintenance of memory T cells important in inhibition and clearance of Bordetella species. 3. Determine mechanisms in promoting efficient mucosal antibody response in prevention and clearance of Bordetella infection. 4. Determine roles of in phagocyte-mediated innate immune response in promoting T and B cell responses. 5. Examine molecular basis for host specificity and evasion of particular Bordetella isolates. EXPECTED OUTPUTS: Past surveys found that domestic animals in nearly every farm has been infected with B. bronchiseptica. The symptoms vary widely from one isolate to another. Present trends in agriculture may select for even more virulent strains. So increasing problems are likely. Our study might identify a better strategy to immunize animals for protection against the increased threats.
Project Methods
1. The roles of various T cell subpopulations will be studied using animal models deficient of the specific T cell subsets. Bacterial clearance and persistence in various anatomic sites of respiratory tracts in these genetically modified animals will be determined by cultures. The relative expression of various effector molecules, such as cytokines and antibodies, will be determined using immunological, molecular biological and biochemical methods. 2. Molecules important for generation and maintenance of memory T cells specific to the bordetella infection will be studied using genetically modified mice and antibody treatment. Ability of these differently manipulated mice in clearance of the primary and secondary bacteria infection will be assessed. Generation and maintenance of bordetella-specific memory T cells in respiratory tracts and lymphoid organs will be determined using enzyme-linked immunosorbent spot (ELISPOT) and flow cytometric staining assays. 3. Molecules important for generation and maintenance of memory antibody response to the bordetella infection will be studied using genetically modified mice. Generation and maintenance of bordetella-specific antibody-producing B cells in respiratory tracts will be determined using ELISPOT and flow cytometric staining assays. Ability of these differently manipulated mice in clearance of the primary and secondary bacteria infection will be assessed. 4. Ability of macrophages and other phagocytes in killing of bacterial cells will be examined using a variety of approaches including immune imaging techniques both in vitro and in vivo. Effects of the phagocytes in inducing T and B cell responses will be tested in animals by genetically and cellularly manipulating numbers and ability of the phagocytes involved in killing the bacteria and processing the bacteria-associated antigens. 5. Three closely related bordetella strains will be used to determine their abilities to infect model animals such as mice. The three strains include one that is considered a generalist (B. bronchiseptica) and the other two that are more specialized to infect humans (B. pertussis and B. parapertussis). Ability of the different strains in inducing and/or suppressing immune responses in animals will be determined and correlated with their persistence and survival ability. Critical virulence factors from a wide range of isolates responsible for their host specificity and evasion will be screened using the whole genome sequencing of the strains and further tested on animals by using strains deficient of specific virulent factors.

Progress 07/01/11 to 06/30/16

Outputs
Target Audience:The target audience consists of immunologists, microbiologists and veterinarians. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?Several graduate students are involved with these projects, are being mentored by the investigator, and are being trained in immunology, microbiology and veterinary science. Faculty uses the basic concepts and newly acquired knowledge in this research to train undergraduate and pre-veterinary students in the mechanism of host pathogen interaction How have the results been disseminated to communities of interest?The publications listed under the "products" are available to the target audience and general public. What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? In the past year, we have been continuously focusing on the molecular and cellular mechanisms regulating local resident immune cells and their functions in the skin. We found that CCR10 is preferentially induced on skin-homing innate lymphoid cells in the skin-draining lymph nodes by CD207+ dendritic cells for their migration into the healthy skin, where the CCR10+ innate lymphoid cells maintain the immune balance of regulatory and effector T cells and prevent over-active inflammation in response to skin stimulations by allergens. In addition, we also found that during the skin immunization, memory CD8+ T cell formation in the skin is dependent on their expression of CCR10 and the skin-resident CD8+ T cells play important roles in promoting regulatory T cell survival in the skin. We have carried out the funded project for the Joint Non-Lethal Weapons Directorate (JNLWD) on long duration Taser exposure and continued collaboration and data analysis for Cornwall project. We have performed contract research for ArgentumCidalElectrics, Inc. on microbial efficacy of products.We have further investigated the genomics of Bordetella spp and have found that they can survive within a host cell using Type III secretion system. We have discovered a novel Bordetella spp. named Bordetella pseudohinzii and CRISPR system in Bordetella. We have also evaluated the efficacy of monoclonal antibodies in preventing Bordetella pertussis infections. Finally, we have identified a novel group of antibiotics that could be used against respiratory pathogens such as Francisella tularensis.

Publications

  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Raman JD, Lehman KK, Dewan K, Kirimanjeswara G. Povidone Iodine Rectal Preparation at Time of Prostate Needle Biopsy is a Simple and Reproducible Means to Reduce Risk of Procedural Infection. J Vis Exp. 2015 Sep 21;(103). doi: 10.3791/52670. PMID: 26436913
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Bendor L, Weyrich LS, Linz B, Rolin OY, Taylor DL, Goodfield LL, Smallridge WE, Kennett MJ, Harvill ET. Type Six Secretion System of Bordetella bronchiseptica and Adaptive Immune Components Limit Intracellular Survival During Infection. PLoS One. 2015 Oct 20;10(10):e0140743. doi: 10.1371/journal.pone.0140743. PMID: 26485303
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Ivanov YV, Shariat N, Register KB, Linz B, Rivera I, Hu K, Dudley EG, Harvill ET A newly discovered Bordetella species carries a transcriptionally active CRISPR-Cas with a small Cas9 endonuclease. BMC Genomics. 2015 Oct 26;16:863. doi: 10.1186/s12864-015-2028-9.PMID: 26502932
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Park J, Zhang Y, Chen C, Dudley EG, Harvill ET. Diversity of secretion systems associated with virulence characteristics of the classical bordetellae. Microbiology. 2015 Dec;161(12):2328-40. doi: 10.1099/mic.0.000197. PMID: 26459829
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Yeoh BS, Saha P, Singh V, Xiao X, Ying Y, Vanamala JK, Kennett MJ, Harvatine KJ, Joe B, Vijay-Kumar M. Deficiency of Stearoyl-CoA Desaturase-1 Aggravates Colitogenic Potential of Adoptively Transferred Effector T cells. Am J Physiol Gastrointest Liver Physiol. 2016 Sep 8:ajpgi.00174.2016. doi: 10.1152/ajpgi.00174.2016. PMID: 27609767.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Yu S, Allen JN, Dey A, Zhang L, Balandaram G, Kennett MJ, Xia M, Xiong N, Peters JM, Patterson A, Hankey-Giblin PA. The Ron Receptor Tyrosine Kinase Regulates Macrophage Heterogeneity and Plays a Protective Role in Diet-Induced Obesity, Atherosclerosis, and Hepatosteatosis. J Immunol. 2016 Jul 1;197(1):256-65. doi: 10.4049/jimmunol.1600450. PMID: 27233965.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Yeoh BS, Aguilera Olvera R, Singh V, Xiao X, Kennett MJ, Joe B, Lambert JD, Vijay-Kumar M. Epigallocatechin-3-Gallate Inhibition of Myeloperoxidase and Its Counter-Regulation by Dietary Iron and Lipocalin 2 in Murine Model of Gut Inflammation. Am J Pathol. 2016 Apr;186(4):912-26. doi: 10.1016/j.ajpath.2015.12.004. PMID: 26968114.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Moreau MR, Wijetunge DS, Bailey ML, Gongati SR, Goodfield LL, Hewage EM, Kennett MJ, Fedorchuk C, Ivanov YV, Linder JE, Jayarao BM, Kariyawasam S. Growth in Egg Yolk Enhances Salmonella Enteritidis Colonization and Virulence in a Mouse Model of Human Colitis. PLoS One. 2016 Mar 3;11(3):e0150258. doi: 10.1371/journal.pone.0150258. PMID: 26939126; PubMed: 4777358.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Singh V, Kumar M, San Yeoh B, Xiao X, Saha P, Kennett MJ, Vijay-Kumar M. Inhibition of Interleukin-10 Signaling Induces Microbiota-dependent Chronic Colitis in Apolipoprotein E Deficient Mice. Inflamm Bowel Dis. 2016 Apr;22(4):841-52. doi: 10.1097/MIB.0000000000000699. PMID: 26891260;
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Linz B, Ivanov YV, Preston A, Brinkac L, Parkhill J, Kim M, Harris SR, Goodfield LL, Fry NK, Gorringe AR, Nicholson TL, Register KB, Losada L, Harvill ET. Acquisition and loss of virulence-associated factors during genome evolution and speciation in three clades of Bordetella species. BMC Genomics. 2016 Sep 30;17(1):767. PMID: 27716057
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Ivanov YV, Linz B, Register KB, Newman JD, Taylor DL, Boschert KR, Le Guyon S, Wilson EF, Brinkac LM, Sanka R, Greco SC, Klender PM, Losada L, Harvill ET. Identification and taxonomic characterization of Bordetella pseudohinzii sp. nov. isolated from laboratory-raised mice. Int J Syst Evol Microbiol. 2016 Oct 4. doi: 10.1099/ijsem.0.001540. PMID: 27707434
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Fu Y, Yang J, and Xiong N. Cutting Edge: Skin CCR10+ CD8+ T cells support resident Treg cells through the B7.2/receptor axis to regulate local immune homeostasis and response. Journal of Immunology 196(12):4859-64. (2016). PMID: 27183612
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Yu S, Allen JN, Dey A, Zhang L, Balandaram G, Kennett MJ, Xia M, Xiong N, Peters JM, Patterson A, Hankey-Giblin PA. The RON receptor tyrosine kinase regulates macrophage heterogeneity and plays a protective role in diet-induced obesity, atherosclerosis, and hepatosteatosis. Journal of Immunology 197(1):256-65. (2016). PMID: 27233965
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Jie Yang, Shaomin Hu, Luming Zhao, Daniel H. Kaplan, Gary H. Perdew and Na Xiong. Selective programming of CCR10+ innate lymphoid cells in skin-draining lymph nodes for cutaneous homeostatic regulation. Nature Immunology. 17(1):48-56. Published online 02 November 2015 doi:10.1038/ni.3312 (2016) PMID: 26523865
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Goralski TD, Dewan KK, Alumasa JN, Avanzato V, Place DE, Markley RL, Katkere B, Rabadi SM, Bakshi CS, Keiler KC, Kirimanjeswara GS Inhibitors of Ribosome Rescue Arrest Growth of Francisella tularensis at All Stages of Intracellular Replication. Antimicrob Agents Chemother. 2016 Jun;60(6):3276-82. doi: 10.1128/AAC.03089-15. PMID: 26953190


Progress 10/01/14 to 09/30/15

Outputs
Target Audience:The target audience consists of immunologists, microbiologists and veterinarians. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?Several graduate are involved with these projects, are being mentored by the investigator and trained in immunology, microbiology and veterinary science. Faculty uses the basic concepts and newly acquired knowledge in this research to train undergraduate and pre-veterinary students in the mechanism of host pathogen interaction. How have the results been disseminated to communities of interest?The publications listed under the "products" are available to the target audience and general public. What do you plan to do during the next reporting period to accomplish the goals?We will continue to elucidate the basic mechanisms of immune responses in the skin and lungs. We will continue to investigate the host pathogen interactions using several bacterial disease models such as bordetellosis and tularemia. In addition, we will investigate the effect of diets on disease susceptibility and host resistance.

Impacts
What was accomplished under these goals? We have sequenced 53 genetically distinct isolates of Bordetella bronchispetica isolated from various terrestrial and aquatic hosts. In addition, we have sequenced six Bordetella hinzii isolated from avian and mammalian hosts. We have characterized the microbial communities present in the lower respiratory tract of healthy birds. On the host side, we found that CCR10 is preferentially induced on skin-resident innate lymphoid cells in the skin-draining lymph nodes for their migration into the healthy skin to maintain the immune balance and prevent over-active inflammation. In absence of skin innate lymphoid cells, imbalanced presence and dysregulated function of resident regulatory and effector T cells result in over-reactive and prolonged innate and memory responses in the skin. In addition to several publications, we filed a patent application with intention to commercialize this novel finding. In addition, in collaboration with other labs, we reported that an immune activating ligand promotes natural killer cell activation and tumor rejection.

Publications

  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Xiong N and Hu, S. Regulation of intestinal IgA responses (Review). Cell Mol Life Sci. 2015. 72(14):2645-55 (2015). doi: 10.1007/s00018-015-1892-4. Epub 2015 Apr 3 PMID: 25837997
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Deng, W., Gowen, B. G., Zhang, L., Wang, L., Lau, S., Iannello, A., Xu, J., Rovis, T. L., Xiong, N., and Raulet, D. H. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection. Science 2015 348(6230): 136-9 (2015). PMID: 25745066
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Finch ER, Kudva AK, Quickel MD, Goodfield LL, Kennett MJ, Whelan J, Paulson RF, Prabhu KS. Chemopreventive effects of dietary eicosapentaenoic acid supplementation in experimental myeloid leukemia.Cancer Prev Res (Phila). 2015 Oct;8(10): 989-99. doi: 10.1158/1940-6207.CAPR-15-0050. Epub 2015 Aug 19. PMID: 26290393
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: McDaniel KL, Restori KH, Dodds JW, Kennett MJ, Ross AC, Cantorna MT. Vitamin A-deficient hosts become nonsymptomatic reservoirs of Escherichia coli-like enteric infections. Infect Immun. 2015 Jul;83 (7):2984-91. doi: 10.1128/IAI.00201-15. Epub 2015 May 11. PMID: 25964475
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Park J, Zhang Y, Chen C, Dudley EG, Harvill ET. Diversity of secretion systems associated with virulence characteristics of the classical Bordetellae. Microbiology. 2015 Oct 9. doi: 10.1099/mic.0.000197. PMID: 26459829.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Bolotin S, Harvill ET, Crowcroft NS. What to do about pertussis vaccines? Linking what we know about pertussis vaccine effectiveness, immunology and disease transmission to create a better vaccine. Pathog Dis. 2015 Nov;73(8). pii: ftv057. doi: 10.1093/femspd/ftv057. Epub 2015 Aug 6. PMID: 26253079.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Hester SE, Goodfield LL, Park J, Feaga HA, Ivanov YV, Bendor L, Taylor DL, Harvill ET. Host specificity of ovine Bordetella parapertussis and the role of complement. PLoS One. 2015 Jul 9;10 (7):e0130964. doi: 10.1371/journal.pone.0130964. eCollection 2015. PMID: 26158540
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Register KB, Ivanov YV, Jacobs N, Meyer JA, Goodfield LL, Muse SJ, Smallridge WE, Brinkac L, Kim M, Sanka R, Harvill ET, Losada L. Draft Genome sequences of 53 genetically distinct isolates of Bordetella bronchiseptica representing 11 terrestrial and aquatic hosts. Genome Announc. 2015 Apr 23;3(2). pii: e00152-15. doi: 10.1128/genomeA.00152-15. PMID: 25908122
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Register KB, Ivanov YV, Harvill ET, Brinkac L, Kim M, Losada L. Draft genome sequences of six Bordetella hinzii isolates acquired from avian and mammalian hosts. Genome Announc. 2015 Mar 19;3(2). pii: e00081-15. doi: 10.1128/genomeA.00081-15. PMID: 25792043
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Shabbir MZ, Malys T, Ivanov YV, Park J, Shabbir MA, Rabbani M, Yaqub T, Harvill ET. Microbial communities present in the lower respiratory tract of clinically healthy birds in Pakistan. Poult Sci. 2015 Apr;94(4):612-20. doi: 10.3382/ps/pev010. Epub 2015 Feb 9. PMID: 25667427.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Register KB, Ivanov YV, Harvill ET, Davison N, Foster G. Novel, host-restricted genotypes of Bordetella bronchiseptica associated with phocine respiratory tract isolates. Microbiology. 2015 Mar;161(Pt 3):580-92. doi: 10.1099/mic.0.000035. Epub 2015 Jan 27. PMID: 25627438


Progress 10/01/13 to 09/30/14

Outputs
Target Audience: The tartget audience consists of immunologists and veterinarians. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Several graduate students are involved with these projects, are being mentored by the investigators, and are being trained in immunology. Faculty use the basic concepts involved in this research to train undergraduates and preveterinary students in the mechanisms of host pathogen interactions. How have the results been disseminated to communities of interest? The publications listed under "Products" are all available to the target audience. What do you plan to do during the next reporting period to accomplish the goals? We will continue to explore mechanisms of host pathogen interaction to answer important questions such as: Which bacterial factors determine host specificity? How do animal pathogens adapt to infect humans? What determines the severity of dysfunctions and lesions? And, how do bacteria avoid host defenses to cause persistent infections, sometimes throughout the life of the host?

Impacts
What was accomplished under these goals? Bordetella infections remain a significant problem in both people and animals. And, while transmission of pathogens has been notoriously difficult to study under laboratory conditions, we have a model system with which to study both transmission and clearance of these important bacterial pathogens. This year, we studied the mechanisms of clearance of the Bordetella by examining the role of IL-1alpha/beta (α/β) and the inflammasome in generation of the interleukin-1 (IL-1) response. We found that IL-1(beta)β is required for mediating the clearance of Bordetella from the lungs of mice. Alternatively, IL-1a is not required. In fact, when infected with B. pertussis and compared to wild-type mice, IL-1beta(β)- and IL-1R-deficient mice display chronic inflammation with inflammatory infiltrates, increased IFN(gamma)γ, and a normal IL-17A response. Unexpectedly, the cleavage of precursor IL-1(beta)β to its mature form did not require caspase-1 during primary infections even though it is required by bone marrow-derived macrophages exposed to live bacteria. Although IL-1R signaling is required, caspase-1 inflammasome is not required for protective immunity against a B. pertussis challenge following vaccination with heat-killed whole cell B. pertussis. Generally, we found that caspase-1-independent host factors are involved in the processing of protective IL-1(beta)β responses that are critical for bacterial clearance and vaccine-mediated immunity. These results will help guide the process of vaccine development. In related studies we have developed a mouse model of transmission of a natural pathogen, Bordetella bronchiseptica. This imparts a clear advantage to use this system to assess the impact of host immune functions. We found that B. bronchiseptica transmits efficiently between mice deficient in Toll-Like Receptor 4 (TLR4). In fact, TLR4-mutant mice are susceptible to initial colonization, and exhibit higher levels of pathogen growth and shedding. Heavy neutrophil infiltration distinguished TLR4-deficient responses, and neutrophil depletion did not affect respiratory CFU load, but decreased bacterial shedding. The effect of TLR4 response on transmission may explain the extensive variation in TLR4 agonist potency observed among closely related subspecies of Bordetella. This transmission model will enable mechanistic studies of how pathogens spread from one host to another, the defining feature of infectious disease.

Publications

  • Type: Journal Articles Status: Published Year Published: 2013 Citation: Kudva AK, Kaushal N, Mohinta S, Kennett MJ, August A, Paulson RF, Prabhu KS. Evaluation of the stability, bioavailability, and hypersensitivity of the omega-3 derived anti-leukemic prostaglandin: ?(12)-prostaglandin J3. PLoS One. 2013 Dec 2;8(12):e80622. doi: 10.1371/journal.pone.0080622. eCollection 2013. PubMed PMID: 24312486; PubMed Central PMCID: PMC3846793.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Gandhi UH, Kaushal N, Hegde S, Finch ER, Kudva AK, Kennett MJ, Jordan CT, Paulson RF, Prabhu KS. Selenium suppresses leukemia through the action of endogenous eicosanoids. Cancer Res. 2014 Jul 15;74(14):3890-901. doi:10.1158/0008-5472.CAN-13-3694. Epub 2014 May 28. PubMed PMID: 24872387; PubMed Central PMCID: PMC4102641.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Kaushal N, Kudva AK, Patterson AD, Chiaro C, Kennett MJ, Desai D, Amin S, Carlson BA, Cantorna MT, Prabhu KS. Crucial role of macrophage selenoproteins in experimental colitis. J Immunol. 2014 Oct 1;193(7):3683-92. doi:10.4049/jimmunol.1400347. Epub 2014 Sep 3. PubMed PMID: 25187657; PubMed Central PMCID: PMC4170023
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Xia M, Hu S, Fu Y, Jin W, Yi Q, Matsui Y, Yang J, McDowell MA, Sarkar S, Kalia V, Xiong N. CCR10 regulates balanced maintenance and function of resident regulatory and effector T cells to promote immune homeostasis in skin. J Allergy Clin Immunol. 134(3):634-644.e10. doi: 10.1016/j.jaci.2014.03.010 (2014)
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Cai Y, Xue F, Fleming C, Yang J, Ding C, Ma Y, Liu M, Zhang HG, Zheng J, Xiong N, Yan J. Differential Developmental Requirement and Peripheral Regulation for Dermal V?4 and V?6T17 Cells in Health and Inflammation. Nat Commun. 5:3986 (2014).
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Wang J, Lindholt JS, Sukhova GK, Shi MA, Xia M, Chen H, Xiang M, He A, Wang Y, Xiong N, Libby P, Wang JA, Shi GP. IgE actions on CD4+ T cells, mast cells, and macrophages participate in the pathogenesis of experimental abdominal aortic aneurysms. EMBO Mol Med. 6(7):952-69. doi: 10.15252/emmm.201303811 (2014).
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Gorgojo J, Harvill ET, Rodr�guez ME. Bordetella parapertussis survives inside human macrophages in lipid raft enriched phagosomes. Infect Immun. 2014 Sep 29. pii: IAI.02553-14. [Epub ahead of print] PubMed PMID: 25267839.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Place DE, Muse SJ, Kirimanjeswara GS, Harvill ET. Caspase-1-independent interleukin-1? is required for clearance of Bordetella pertussis infections and whole-cell vaccine-mediated immunity. PLoS One. 2014 Sep 8;9(9):e107188. doi: 10.1371/journal.pone.0107188. eCollection 2014. PubMed PMID: 25198773; PubMed Central PMCID: PMC4157866.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Harvill ET, Goodfield LL, Ivanov Y, Smallridge WE, Meyer JA, Cassiday PK, Tondella ML, Brinkac L, Sanka R, Kim M, Losada L. Genome Sequences of Nine Bordetella holmesii Strains Isolated in the United States. Genome Announc. 2014 Jun 19;2(3). pii: e00438-14. doi: 10.1128/genomeA.00438-14. PubMed PMID: 24948754; PubMed Central PMCID: PMC4064020.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Bart MJ, Harris SR, Advani A, Arakawa Y, Bottero D, Bouchez V, Cassiday PK, Chiang CS, Dalby T, Fry NK, Gaillard ME, van Gent M, Guiso N, Hallander HO, Harvill ET, He Q, van der Heide HG, Heuvelman K, Hozbor DF, Kamachi K, Karataev GI, Lan R, Luty?ska A, Maharjan RP, Mertsola J, Miyamura T, Octavia S, Preston A, Quail MA, Sintchenko V, Stefanelli P, Tondella ML, Tsang RS, Xu Y, Yao SM, Zhang, S, Parkhill J, Mooi FR. Global population structure and evolution of Bordetella pertussis and their relationship with vaccination. MBio. 2014 Apr 22;5(2):e01074. doi: 10.1128/mBio.01074-14. PubMed PMID: 24757216; PubMed Central PMCID: PMC3994516.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Hewlett EL, Burns DL, Cotter PA, Harvill ET, Merkel TJ, Quinn CP, Stibitz ES. Pertussis pathogenesis--what we know and what we don't know. J Infect Dis. 2014 Apr 1;209(7):982-5. doi: 10.1093/infdis/jit639. Review. PubMed PMID: 24626533; PubMed Central PMCID: PMC3952676.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Rolin O, Smallridge W, Henry M, Goodfield L, Place D, Harvill ET. Toll-like receptor 4 limits transmission of Bordetella bronchiseptica. PLoS One. 2014 Jan 30;9(1):e85229. doi: 10.1371/journal.pone.0085229. eCollection 2014. PubMed PMID:24497924; PubMed Central PMCID: PMC3907416.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Rolin O, Muse SJ, Safi C, Elahi S, Gerdts V, Hittle LE, Ernst RK, Harvill ET, Preston A. Enzymatic modification of lipid A by ArnT protects Bordetella bronchiseptica against cationic peptides and is required for transmission. Infect Immun. 2014 Feb;82(2):491-9. doi: 10.1128/IAI.01260-12. Epub 2013 Oct 14. PubMed PMID: 24478065; PubMed Central PMCID: PMC3911393.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Weyrich LS, Feaga HA, Park J, Muse SJ, Safi CY, Rolin OY, Young SE, Harvill ET. Resident microbiota affect Bordetella pertussis infectious dose and host specificity. J Infect Dis. 2014 Mar;209(6):913-21. doi: 10.1093/infdis/jit597. Epub 2013 Nov 13. PubMed PMID: 24227794; PubMed Central PMCID: PMC3935476.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Smallridge WE, Rolin OY, Jacobs NT, Harvill ET. Different effects of whole-cell and acellular vaccines on Bordetella transmission. J Infect Dis. 2014 Jun 15;209(12):1981-8. doi: 10.1093/infdis/jiu030. Epub 2014 Jan 16. PubMed PMID: 24443545; PubMed Central PMCID: PMC4038146.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Harvill ET, Goodfield LL, Ivanov Y, Meyer JA, Newth C, Cassiday P, Tondella ML, Liao P, Zimmerman J, Meert K, Wessel D, Berger J, Dean JM, Holubkov R, Burr J, Liu T, Brinkac L, Kim M, Losada L. Genome Sequences of 28 Bordetella pertussis U.S. Outbreak Strains Dating from 2010 to 2012. Genome Announc. 2013 Dec 19;1(6). pii: e01075-13. doi: 10.1128/genomeA.01075-13. PubMed PMID: 24356839; PubMed Central PMCID: PMC3868863.


Progress 10/01/12 to 09/30/13

Outputs
Target Audience: Our Target Audience is the veterinary and biomedical research community, with special relevance to those interested in Immunology, Infectious Diseases, Microbiology, Bacteriology, Genomics and Genetics. The journals in which we publish reach these and other broad groups of Agricultural and Public Health researchers, clinicians and others interested in these topic areas. Changes/Problems: The lack of college and university support for graduate students, and the reduction in federal grants will combine to negatively impact our ability to train great students and produce great science. What opportunities for training and professional development has the project provided? In addition to the training of undergraduate, graduate and postdoctoral researchers, we have presented our work at national and international meetings. How have the results been disseminated to communities of interest? Results have been disseminated via peer-reviewed publications, review articles and presentations at national and international meetings. What do you plan to do during the next reporting period to accomplish the goals? We will extend our work and aggressively promote this exciting science.

Impacts
What was accomplished under these goals? We have established a pipeline beginning with Veterinary outreach to farmers in Pakistan and Pennsylvania, identifying diseases of unknown etiology. We then carefully sample sick animals and relevant control animal, such as healthy animals from the same flock/herd. Samples are returned to the lab in cold chain and processed to isolate DNA and/or RNA, which is delivered to sequencing facilities. DNA sequence data is analyzed via metagenomic approaches to identify every organism present in the samples. A comparison of the various organisms in each sample has allowed us to assess the differences between animals housed in different conditions (I.e. Closed house versus free range) and in different health conditions. In several cases we have identified microbial agents associated with diseased states, and some of these represent new pathogens and others represent known pathogens associated with new diseases. This work is in preparation for two initial research articles. We expect to see four more submitted over the coming six months. We collaborate across the university on infectious disease, cancer, metabolic, and other studies to perform histological analysis of tissue samples in order to score experimental and control lesions. This allows us to determine the effectiveness of the immune response or treatment and/ or the virulence of the pathogen, invasiveness of the cancer, etc. Information from these studies will benefit animal and human health by helping to evaluate specific aspects of the immune system, the toxicity or pathogenicity of certain agents and the effectiveness of various treatments and vaccines. Now that this pipeline is established we expect to be able to use it to study any new disease that may emerge amongst animals.

Publications

  • Type: Journal Articles Status: Published Year Published: 2012 Citation: Narayan K, Sylvia KE, Malhotra N, Yin CC, Martens G, Vallerskog T, Kornfeld H, Xiong N, Cohen NR, Brenner MB, Berg LJ, Kang J; Immunological Genome Project Consortium. Intrathymic programming of effector fates in three molecularly distinct ?? T cell subtypes. Nat Immunol. 13(5):511-8 (2012)
  • Type: Journal Articles Status: Published Year Published: 2013 Citation: Hu S, Xiong N. Programmed downregulation of CCR6 is important for establishment of epidermal ??T cells by regulating their thymic egress and epidermal location. Journal of Immunology. 190(7):3267-75 (2013)
  • Type: Journal Articles Status: Published Year Published: 2012 Citation: Hester SE, Lui M, Nicholson T, Nowacki D, and Harvill ET, (2012)Identification of a CO2 responsive regulon in Bordetella PLoS ONE, 2012;7(10):e47635.
  • Type: Journal Articles Status: Published Year Published: 2012 Citation: Zhang X, Weyrich LS, Lavine JS, Karanikas AT, Harvill ET. (2012)Lack of Cross-protection against Bordetella holmesii after Pertussis Vaccination. Emerg Infect Dis. 2012 Nov;18(11):1771-9.
  • Type: Journal Articles Status: Published Year Published: 2012 Citation: Park J, Zhang Y, Buboltz AM, Zhang X, Schuster SC, Ahuja U, Liu M, Miller JF, Sebaihia M, Bentley SD, Parkhill J, Harvill ET. (2012) Comparative genomics of the classical Bordetella subspecies: the evolution and exchange of virulence-associated diversity amongst closely related pathogens. BMC Genomics. 13(1):545.
  • Type: Journal Articles Status: Published Year Published: 2013 Citation: Weyrich LS, Harvill ET (2013) Teaching Ethical Aptitude to Graduate Student Researchers Accountability in Research, 2013;20(1):5-12.
  • Type: Journal Articles Status: Published Year Published: 2012 Citation: Lass S, Hudson PJ, Thakar J, Saric J, Harvill ET, Albert R, Perkins SE. (2013) Generating super-shedders: co-infection increases bacterial load and egg production of a gastrointestinal helminth. J R Soc Interface. 2012 Dec 19;10(80):20120588.
  • Type: Journal Articles Status: Published Year Published: 2013 Citation: Berger JT, Carcillo JA, Shanley TP, Wessel DL, Clark A, Holubkov R, Meert KL, Newth CJ, Berg RA, Heidemann S, Harrison R, Pollack M, Dalton H, Harvill E, Karanikas A, Liu T, Burr JS, Doctor A, Dean JM, Jenkins TL, Nicholson CE (2013) Critical Pertussis Illness in Children: A Multicenter Prospective Cohort Study Pediatr Crit Care Med. 2013 Apr 2.
  • Type: Journal Articles Status: Published Year Published: 2013 Citation: Pinkerton M, Chinchilli V, Banta E, Craig T, August A, Bascom R, Cantorna M, Harvill ET, Ishmael FT. (2013) Differential expression of microRNAs in exhaled breath condensates of patients with asthma, patients with chronic obstructive pulmonary disease, and healthy adults. J Allergy Clin Immunol. 2013 Apr 26. doi:pii: S0091-6749(13)00426-0.
  • Type: Journal Articles Status: Awaiting Publication Year Published: 2013 Citation: Hester SE, Park J, Goodfield LL, Feaga HA, Preston A and Harvill ET. (2013) Horizontally Acquired Divergent O-antigen Contributes to Escape from Cross-Immunity in the Classical Bordetellae BMC Microbiology. In revision.
  • Type: Journal Articles Status: Published Year Published: 2013 Citation: Harvill ET. (2013) Cultivating Our Frienemies: Viewing Immunity As Microbiome Management mBio 2013 Mar 26;4(2).


Progress 10/01/11 to 09/30/12

Outputs
OUTPUTS: Understanding the mechanism by which pathogens modulate and suppress host defenses is critical for developing successful strategies to fight respiratory infections, the leading cause of morbidity and mortality in humans and animals. Bordetella pertussis, a Gram-negative bacterium and the causative agent of whooping cough in humans, expresses several virulence factors that aid in infection and disease pathogenesis. For example, B. pertussis expresses pertussis toxin (Ptx), which we have established as a critical determinant required to down-regulate inflammatory responses. We have shown that Ptx induces IL-10 by an IL-1 receptor signaling-dependent mechanism and contributes to the regulation of innate and adaptive immune responses. It was further established that adaptive immunity to B. pertussis was also dependent on IL-1R signaling. IL-6, a potent pro-inflammatory cytokine, on the other hand was found to be critical for recruitment of innate immune cells to the lungs, generation of protective inflammatory responses and ultimately the bacterial clearance. It is interesting that a similar requirement for IL-1 and IL-6 was also observed for a seemingly distant respiratory pathogen, Francisella tularensis. F. tularensis was found to induce IL-10 as a way to establish infection and resist innate immune defense-mediated bacterial clearance. Thus, respiratory pathogens appear to adopt a similar mechanism of down regulation innate immune defenses by inducing anti-inflammatory cytokines. While, B. pertussis requires IL-1 receptor signaling for the induction of IL-10, F. tularensis appear to require Type I Interferon signaling. Furthermore, we also established that chemokine receptor 10 (CCR10) was critical for recruitment of lymphocytes to mucosal surfaces and lymphocyte memory functions. These results underscore a fine balance between pro- and anti-inflammatory environments at the interface of pathogens and immune defenses at mucosal surfaces and provide a window for therapeutic interventions. These results were published in well respected and widely read scientific journals for the consumption by the research immunity. PARTICIPANTS: Eric T. Harvill, Mary J. Kennett, Na Xiong and Girish Soorappa Kirimanjeswara TARGET AUDIENCES: Immunologists and Veterinarians PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.

Impacts
IL-1 family of cytokines signal through IL-1 receptor. We utilized mice that lack IL-1R to explore the role of IL-1 in mucosal immunity. We demonstrated that IL-1R(-/-) mice failed to clear B. pertussis efficiently. Although a robust antibody response was observed in these mice, they had a deficiency in IL-17 response, a cytokine known to be critical for clearing of several pathogens including B. pertussis. Further experiments revealed that IL-1beta signals through IL-1R and induction of IL-1beta was independent of classical mediator Caspase-1. Interestingly, IL-1R-mediated signaling led to the induction of IL-10. IL-10 was found to be a critical mediator of immune suppression facilitating bacterial persistence. F. tularensis was also found to induce IL-10, which was shown to inhibit pro-inflammatory IL-17 response. The latter was demonstrated to be critical for bacterial clearance. Surprisingly, IL-10 induction by F. tularensis was not dependent on IL-1R signaling but on type I IFN signaling. Taken together, these data suggest that respiratory pathogens seem to have evolved different mechanisms to induce IL-10. We also established a mechanism by which innate and adaptive immune responses are induced by mucosal pathogens. Recruitment of leukocytes is a critical first step in containing and clearing pathogens. Our data indicate that CCR10 is a key sensing molecule on leukocytes and is responsible for guiding these cells to the site of infection. CCR10 was also found to be important for maintenance of memory B cells at the mucosal surface. Lastly, we used IL-12 as an adjuvant to enhance the mucosal immune responses of vaccines against respiratory pathogens. FopA, an outre membrane protein produced by F. tularensis, was found not to induce protective immune response. In contrast, addition of a pro-inflammatory cytokine IL-12 dramatically altered the efficacy of the subunit vaccines paving way for including of IL-12 as a potential adjuvant in other subunit vaccines such as pertussis vaccines.

Publications

  • Xiong, N., Y. Fu, S. Hu, M. Xia, and J. Yang. 2012. CCR10 and its ligands in regulation of epithelial immunity and diseases. Protein Cell 3:571-80.
  • Xia, M., N. Guerra, G. K. Sukhova, K. Yang, C. K. Miller, G. P. Shi, D. H. Raulet, and N. Xiong. 2011. Immune activation resulting from NKG2D/ligand interaction promotes atherosclerosis. Circulation 124:2933-43.
  • Weyrich, L. S., O. Y. Rolin, S. J. Muse, J. Park, N. Spidale, M. J. Kennett, S. E. Hester, C. Chen, E. G. Dudley, and E. T. Harvill. 2012. A Type VI Secretion System Encoding Locus Is Required for Bordetella bronchiseptica Immunomodulation and Persistence In Vivo. PLoS One. 7(10):e45892.
  • Sharda, D. R., J. L. Miller-Lee, G. M. Kanski, J. C. Hunter, C. H. Lang, M. J. Kennett, and D. H. Korzick. 2012. Comparison of the agar block and Lieber-DeCarli diets to study chronic alcohol consumption in an aging model of Fischer 344 female rats. J Pharmacol Toxicol Methods (In Press).
  • Werner, J. R., D. M. Jenkins, W. B. Murray, E. L. Hughes, D. A. Bienus, and M. J. Kennett. 2012. Human electromuscular incapacitation devices characterization: a comparative study on stress and the physiological effects on swine. J Strength Cond Res. 26:804-10.
  • Gorgojo, J., Y. Lamberti, H. Valdez, E. T. Harvill, and M. E. Rodriguez. 2012. Bordetella parapertussis survives the innate interaction with human neutrophils by impairing bactericidal trafficking inside the cell through a lipid raft-dependent mechanism mediated by the lipopolysaccharide O antigen. Infect. Immun. (In Press).
  • Barchinger, S. E., X. Zhang, S. E. Hester, M. E. Rodriguez, and E. T. Harvill. 2012. sigE facilitates the adaptation of Bordetella bronchiseptica to stress conditions and lethal infection in immunocompromised mice. BMC Microbiol. 2012 12:179.
  • Ahuja, U., M. Liu, S. Tomida, J. Park, P. Souda, J. Whitelegge, H. Li, E. T. Harvill, J. Parkhill, and J. F. Miller. 2012. Phenotypic and Genomic Analysis of Hypervirulent Human-associated Bordetella bronchiseptica. BMC Microbiol. 12:167.


Progress 10/01/10 to 09/30/11

Outputs
OUTPUTS: The broad goal of our work is to understand the interactions of bacterial pathogens with the immune system. Successful bacterial pathogens have developed ways of manipulating and evading the mammalian immune system. For example, several pathogens are known to promote the production of factors such Interleukin 10 (IL-10), an anti-inflammatory cytokine, to avoid induction of the host inflammatory response. Bordetella species are Gram negative respiratory pathogens of humans and animals that differentially modulate the immune systems of their hosts. Both Bordetella pertussis and B. parapertussis cause a chronic coughing illness called whooping cough. These bacteria may persist for weeks within the human respiratory tract and have different strategies for evading the immune response. Despite high coverage for childhood vaccination, pertussis causes substantial morbidity and mortality in US children, especially among infants. We examined how cytokines/receptors is involved in regulation of innate and adaptive immune response and found that the cytokine IL-6 influences the adaptive immune responses against the Bordetella pertussis. IL-6 is involved in regulating antibody generation, pulmonary leukocyte accumulation, and T cell cytokine production in response to B. pertussis as well as the generation of effective vaccine-induced immunity against this pathogen. In addition, we also studied how cytokine IL-1 receptor-mediated signals contribute to immune responses against different strains of bordetella infections and found that pertussis toxin contributes to IL-1beta induction by B. pertussis, which is involved in IL-10 induction through IL-1R signaling. IL-10 treatment reduced B. pertussis numbers in IL-1R(-/-) mice, suggesting that IL-10 responses regulated by the IL-1R signals are important in inflammation and bacterial growth. We also provided data to demonstrate Interleukin-12 as a safe and effective adjuvant to be used with either whole cell or subunit vaccines and intranasal delivery of vaccines as an effective delivery strategy againt respiratory infections. The results of the projects were disseminated to the general research communities by publishing the results in leading peer-reviewed journals. PARTICIPANTS: Eric T. Harvill, Mary J. Kennett, Na Xiong and Girish Soorappa Kirimanjeswara TARGET AUDIENCES: Immunologists, Veterinarians PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.

Impacts
Using a murine model of infection, we established that IL-6 influences the adaptive immune responses against the Bordetella pertussis. IL-6(-/-) mice showed a protracted infectious course and were less efficiently protected by B. pertussis vaccination than wild-type mice. Pulmonary leukocyte recruitment and splenic or pulmonary T cell cytokine responses to B. pertussis, including Th1 and Th17 cytokine production, were lower in IL-6(-/-) mice than in wild-type mice. Adoptive transfer of immune wild-type CD4(+) cells ameliorated the defect of IL-6(-/-) mice in the control of B. pertussis numbers. In addition, IL-1 receptor-mediated signals in immune response to different strains of Bordetella infections were studied. We found that following inoculation with B. pertussis, but not B. parapertussis, IL-1R(-/-) mice showed elevated bacterial numbers and more extensive inflammatory pathology than wild-type mice, which is associated with elevated levels of gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) but lower levels of IL-10 in the infected IL-1R(-/-) mice with the former. The lack of severe disease in B. parapertussis-infected IL-1R(-/-) mice was due to the extreme requirement for IL-1R in pathology induced by pertussis toxin (Ptx), which is expressed only by B. pertussis. Ptx contributes to IL-1beta induction by B. pertussis, which is involved in IL-10 induction through IL-1R signaling. IL-10 treatment reduced B. pertussis numbers in IL-1R(-/-) mice, suggesting that the lower IL-10 responses partially account for the uncontrolled inflammation and bacterial growth in these mice. We also studied how chemokine receptor CCR10 is involved in regulation of IgA antibody production at the mucosal sites, which is important in preventing the establishment of infection at entry sites. We found that although CCR10 is not critical in the acute phase of IgA production in primary response to pathogen infection, CCR10-deficient long-lived IgA-producing plasma cells and IgA(+) memory B cells generated against the infection could not be maintained properly in intestines. Consequently, IgA memory responses to the pathogen reinfection were severely impaired in CCR10-/- mice, elucidating critical roles of CCR10 in the intestinal IgA memory maintenance, which could help in design of vaccines against intestinal and other mucosal pathogens. At the front of development of efficient vaccines, we demonstrated that a whole cell preparation of Yersinia pestis, combined with IL-12 and delivered by intranasal route induced a sterilizing immune response that was effective in preventing pneumonic plague in a mouse model. Similarly, a vaccine containing outer membrane protein (FopA) of Francisella tularensis combined with IL-12 and delivered by intranasal route mounted a robust humoral and cell-mediated response that was effective in preventing lethal pneumonic tularemia. These results indicate that the use of an adjuvant such as IL-12 and intranasal delivery of vaccines is a very effective and safe strategy against respiratory infections. These results could now be extended to evaluate the vaccine candidates against Bordetella bronchispetica.

Publications

  • Hu, S., K. Yang, J. Yang, M. Li, and N. Xiong. 2011. Critical roles of chemokine receptor CCR10 in regulating memory IgA responses in intestines. Proc. Natl. Acad. Sci. U. S. A. (In Press).
  • Sun, J., G. K. Sukhova, J. Zhang, H. Chen, S. Sjoberg, P. Libby, M. Xia, N. Xiong, B. D. Gelb, and G. P. Shi. 2011. Cathepsin K Deficiency Reduces Elastase Perfusion-Induced Abdominal Aortic Aneurysms in Mice. Arterioscler. Thromb. Vasc. Biol. (In Press).
  • Jin, Y., M. Xia, C. M. Saylor, K. Narayan, J. Kang, D. L. Wiest, Y. Wang, and N. Xiong. 2010. Cutting edge: Intrinsic programming of thymic γδT cells for specific peripheral tissue localization. J. Immunol. 185:7156-60.
  • Jin, Y., M. Xia, A. Sun, C. M. Saylor, and N. Xiong. 2010. CCR10 is important for the development of skin-specific gammadeltaT cells by regulating their migration and location. J. Immunol. 185:5723-31.
  • Hicky, A. J., K. R. Hazlett, G. S. Kirimanjeswara, and D. W. Metzger. 2011. Identification of Francisella tularensis outer membrane protein A (FopA) as a protective antigen for Tularemia. Vaccine 40:6941-6947
  • Zhang, X., T. Goel, L. L. Goodfield, S. J. Muse, and E. T. Harvill. 2011. Decreased leukocyte accumulation and delayed Bordetella pertussis clearance in IL-6-/- mice. J. Immunol. 186:4895-904.
  • Long, G. H., D. Sinha, A. F. Read, S. Pritt, B. Kline, E. T. Harvill, P. J. Hudson, and O. N. Bjornstad. 2010. Identifying the age cohort responsible for transmission in a natural outbreak of Bordetella bronchiseptica. PLoS Pathog. 6(12):e1001224.
  • Burr, J. S., T. L. Jenkins, R. Harrison, K. Meert, K. J. Anand, J. T. Berger, J. Zimmerman, J. Carcillo, J. M. Dean, C. J. Newth, D. F. Willson, R. C. Sanders, Jr., M. M. Pollack, E. Harvill, and C. E. Nicholson. 2011. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Collaborative Pediatric Critical Care Research Network (CPCCRN). The Collaborative Pediatric Critical Care Research Network Critical Pertussis Study: collaborative research in pediatric critical care medicine. Pediatr. Crit. Care Med. 4:387-92.
  • Lavine, J., H. Broutin, E. T. Harvill, and O. N. Bjornstad. 2010. Imperfect vaccine-induced immunity and whooping cough transmission to infants. Vaccine 29:11-6.
  • Zhang, X., S. E. Hester, M. J. Kennett, A. T. Karanikas, L. Bendor, D. E. Place, and E. T. Harvill. 2011. Interleukin-1 receptor signaling is required to overcome the effects of pertussis toxin and for efficient infection- or vaccination-induced immunity against Bordetella pertussis. Infect. Immun. 79:527-41.
  • Sae-Tan, S., K. A. Grove, M. J. Kennett, and J. D. Lambert. 2011. (-)-Epigallocatechin-3-gallate increases the expression of genes related to fat oxidation in the skeletal muscle of high fat-fed mice. Food Funct. 2:111-6.
  • Thomas, G. A., W. J. Kraemer, M. J. Kennett, B. S. Comstock, C. M. Maresh, C. R. Denegar, J. S. Volek, and W. C. Hymer. 2011. Immunoreactive and bioactive growth hormone responses to resistance exercise in men who are lean or obese. J. Appl. Physiol. 111:465-72.
  • Grove, K. A., S. Sae-Tan, M. J. Kennett, and J. D. Lambert. 2011. (-)-Epigallocatechin-3-gallate Inhibits Pancreatic Lipase and Reduces Body Weight Gain in High Fat-Fed Obese Mice. Obesity (Silver Spring) (In Press).
  • Heiderstadt, K. M. and M. J. Kennett. 2011. IACUC issues related to animal models of aging. ILAR J. 52:106-9.
  • Zhu, B., R. Bai, M. J. Kennett, B. H. Kang, F. J. Gonzalez, and J. M. Peters. 2010. Chemoprevention of chemically induced skin tumorigenesis by ligand activation of peroxisome proliferator-activated receptor-beta/delta and inhibition of cyclooxygenase 2. Mol. Cancer Ther. 9:3267-77.
  • Markell, L. M., R. Perez-Lorenzo, K. E. Masiuk, M. J. Kennett, and A. B. Glick. 2010. Use of a TGFbeta type I receptor inhibitor in mouse skin carcinogenesis reveals a dual role for TGFbeta signaling in tumor promotion and progression. Carcinogenesis 31:2127-35.