Ciaran Skerry, PhD

NAME: Ciaran Skerry

eRA COMMONS USER NAME (credential, e.g., agency login):  CSKERRY1

POSITION TITLE: Research Associate

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable. Add/delete rows as necessary.)

1. A.    Personal Statement

My research has focused on translating basic science discoveries in bacterial pathogenesis into host-directed therapeutics. During my Ph.D. studies I found a live B. pertussis vaccine strain to effectively colonize mice and elicit immune responses without inducing pathology. Following this I sought to better understand the role of the attenuated virulence factors. To further my microbiology training I travelled to the Johns Hopkins University Center of TB Research. Here, I followed key discoveries on the hypoxic nature of the murine granuloma with work examining the potential of immunomodulators to improve antibiotic efficacy and granuloma penetration. We found that both HMG-CoA reductase inhibition and TNF inhibition in infected C3HeB/FeJ mice lead to metabolic reawakening of dormant M. tb and an increase in the bactericidal capacity of first-line drugs. Following this, I was recruited to the University of Maryland to continue my work on understanding host-pathogen interactions in B. pertussis. Here, we discovered that the host sphingosine-1-phosphate (S1P) signaling pathway is manipulated by infection. Following this, we found that administration of S1P receptor agonists reduced the inflammatory cytokine production and pulmonary histopathology observed in murine pertussis and prolonged survival following lethal infection. We have since found that this is due to their action on the S1P receptor 1 of myeloid cells. Our current studies on the mechanism of action of these drugs identified peptidoglycan recognition protein 4 (PGLYRP4) as being highly enriched in infected agonist treated mice. Further, we have found that PGLYRP4 is an essential component in the control of inflammation following B. pertussis infection. Here, we will use our expertise in B. pertussis pathogenesis to define the role of PGLYRP4 in both B. pertussis infection and in S1P receptor agonist mediated disease attenuation. Through this work, we will further our understanding of pertussis pathogenesis and PGLYRP biology, increase our understanding of the therapeutic effect of S1PR agonists and explore the possibility of PGLYRP4 based treatments.

A. Viginor L, Skerry, C, McCann M and Deveruex M (2015). Tuberculosis: An inorganic medicinal chemistry perspective. Curr. Med. Chem. 2015;22(18):2199-224 PMID: 25850770  

B. Scanlon, KM, Skerry, C and Carbonetti NH (2015). Novel therapies for the treatment of pertussis disease. Pathogens and Disease Nov;73(8):ftv074

B.         Positions and Honors

Positions and Employment

2006-2010       Graduate Student, Department of Immunology, National University of Ireland, Maynooth

2010-2014       Postdoctoral Fellow, Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD

2014-2017       Postdoctoral Fellow, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD

2017-present  Research Associate, Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD

Other Experience, Professional Memberships and Honors

2006-2010                   Recipient, John and Pat Hume Research Scholarship

2006-2010       Recipient, Irish Research Council for Science Engineering and Technology Scholarship (now Government of Ireland Postgraduate Scholarship

2006-2010                   Member, Irish Society for Immunology

2006-2010                   Member, British Society for Immunology

2010-present Member, American Society for Microbiology

2016-present  Member, International Bordetella Society

2017                            Invited Speaker, University of West Virginia

C.        Contributions to Science

1. 1.     Bordetella pertussis vaccine development.

For my Ph.D. thesis I was fortunate to be involved in the development of live, attenuated B. pertussis vaccine strain BPZE1. We characterized the safety and immunogenicity of this novel vaccine strain in mice. We showed BPZE1 to be safe in immunocompromised mice and capable of inducing long-lasting immune responses. We went on to use this strain as a tool to aid in characterization of B. pertussis virulence factors PT, DNT and TCT. BPZE1 is currently the lead product candidate for ILiAD Biotechnologies.

1. Skerry, CM, Cassidy, JP, English, K, Feunou-Feunou. P, Locht C, and, Mahon BP (2009). A live attenuated Bordetella pertussis candidate vaccine does not cause disseminating infection in gamma- interferon receptor knockout mice. Clin Vaccine Immunol. 2009 Sep;16(9):1344-51.PMID: 19625486
2. Skerry, CM, Mahon BP (2011). A live, attenuated Bordetella pertussis vaccine provides long-term protection against virulent challenge in a murine model. Clin Vaccine Immunol. 2009 Sep;16(9):1344-51. PMID:19625486

1. 2.     Mycobacterium tuberculosis vaccine development

During my time at the Johns Hopkins Center for TB Research we developed a vaccine candidate for central nervous system TB. For this, we screened our transposon mutant library for genes required for CNS invasion. From this screen we identified protein kinase D (pknD) as an essential gene for crossing the blood-brain barrier and in vitro screens showed the pknD sensor domain to be involved in triggering invasion of the brain microvascular endothelium. Vaccination with purified pknD (formulated in CFA) was found to protect against invasion of guinea-pig CNS. This was mediated by pknD neutralizing antibodies. In later studies, we identified TLR2 stimulating lipoproteins as contributing to HIV infectivity following M. tb vaccination.

1. A.    Skerry, C, Pokkali, S, Pinn, M, Be, NA, Harper, J, Karakousis PC and Jain SK (2013). Vaccination with recombinant Mycobacteirum tuberculosis PknD attenuates bacterial dissemination to the brain in guinea pigs. PLoS One June 11;8(6):e66310
2. B.    Skerry, C, Klinkenberg, LG, Page, KR and Karakousis PC. (2016). TLR-2-Modulating lipoproteins of the Mycobacterium tuberculosis complex enhance the HIV infectivity of CD4+ cells. PLoS One Jan. 25;11(1):e0147192

1. 3.     Use of molecular imaging techniques to further our understanding of TB pathogenesis

We identified a mouse model of TB infection that developed hypoxic granulomatous lesions similar to those observed in human disease. To show this, we developed nuclear imaging techniques capable of detecting and monitoring hypoxic lesions over time in live BSL-3 contained mice. Following this, we showed antibiotic pharmacodynamics in this model to more closely reflect that seen in humans than traditional mouse models.

A.  Harper* J, Skerry*, C, Davis, SL, Tasneen, R, Weir, M, Kramnik, I, Bishai, WR, Pomper MG, Neurmberger, EL and Jain SK (2012). Mouse model of necrotic tuberculosis granulomas develops hypoxic lesions. J. Infect. Dis. Feb. 15;205(4):595-602

1. 4.     Development of host-directed therapies for TB

Antibiotic resistance is a major problem in the treatment of M. tb infections.For this reason, we sought to develop host-targeting drugs, which could improve the efficacy of existing antibiotics. M. tb may reside within hypoxic lesions which are difficult to penetrate with antibiotics. We discovered that TNF-α inhibitors reactivated metabolically dormant bacterium making them more susceptible to antibiotic killing. However, the severe immune-suppression associated with TNF-inhibition was undesirable. Following this, we sought to take advantage of the immunomodulatinig effect of HMG-CoA reductase inhibitors. We found that this class of molecules could increase the bactericidal activity of first-line anti-TB drugs. Work that is being carried forward in human trials currently.

A. Skerry, C, Harper, J, Klunk, M, Bishai, WR and Jain SK (2012). Adjunctive TNF inhibition with standard treatment enhances bacterial clearance in a murine model of necrotic TB granulomas. PLoS One. 7;(6):e39680

B. Skerry, C, Pinn, ML, Bruiners, N, Pine, R, Gennaro, ML and Karakousis PC (2014). Simvastatin increases the in vivo activity of the first-line tuberculosis regimen. J. Antimicrob Chemother. Sep. 69(9):2453-7

5. Development of host-directed therapeutics for B. pertussis

In response to the urgent need for improved anti-pertussis therapeutics we sought to develop host-acting molecules that reduce the inflammatory pathology associated with disease. We found that agonists of sphingosine-1-phosphate receptors significantly reduced inflammatory cytokine production and lung histopathology. Further, these agonists were shown to prolong survival in a model of lethal neonate infection. We then determined that this phenomenon was due to the activity of agonists on the S1P1 receptor of myeloid cells and was not pertussis-toxin sensitive.

1. A.    Skerry, C, Scanlon, K, Rosen, H and Carbonetti NH (2015). Sphingosine-1-phosphate receptor agonism reduces Bordetella pertussis-mediated lung pathology. J. Infect Dis. Jun 15;211(12):1883-1886     
2. B.    Skerry, C, Scanlon, K, Ardanuy, J, Roberts, D, Zhang, L, Rosen H and Carbonetti NH (2017). Reduction of pertussis inflammatory pathology by therapeutic treatment with sphingosine-1-phosphate receptor ligands by a pertussis toxin-insensitive mechanism. J Infect Dis. Jan 15;215(2):278-286

C.   Scanlon, KM, Snyder YG, Skerry, C, and Carbonetti, NH (2017). Fatal pertussis in the neonatal mouse model is associated with pertussis-toxin mediated pathology beyond the airways. Infect Immun. Aug 7 IAI.00355-17

Complete list of publications is available in MyBibliography:

https://www.ncbi.nlm.nih.gov/pubmed/?term=skerry+ciaran

D.         Additional Information: Research Support and/or Scholastic Performance

No funding in the past 3 years

Completed research support

None in the last 3 years

Microbiology, Immunology, Bordetella, bordetella pertussis, host-pathogen, host-directed, sphingosine-1-phosphate, peptidoglycan, peptidoglycan recognition protein,

CM. Skerry, JP. Cassidy, K. English, P. Feunou-Feunou, C. Locht and BP. Mahon (2009). A live attenuated Bordetella pertussis vaccine does not cause disseminating infection in IFN-g receptor knockout mice. Clinical Vaccine Immunology 16:1344-51

C. Skerry*, J. Harper*, SL. Davis, R. Tasneen, M. Weir, I. Kramnik, WR. Bishai, MG. Pomper, EL. Nuermberger, and SK. Jain (2012). Mouse model of necrotic TB granulomas develops hypoxic lesions. Journal of Infectious Diseases 205:595-602

C. Skerry, J. Harper, M. Klunk, WR. Bishai and SK. Jain (2012). Adjunctive TNF Inhibition with Standard Treatment Enhances Bacterial Clearance in a Murine Model of Necrotic TB Granulomas. PLoS ONE 7:e39680

C. Skerry, S. Pokkali, M. Pinn, NA. Be, J. Harper, PC. Karakousis and SK. Jain (2013). Vaccination with recombinant Mycobacterium tuberculosis PknD attenuates bacterial dissemination to the brain in guinea pigs. PLoS ONE 8:66310

C. Skerry, M. Pinn, N. Bruiners, R. Pine, ML. Gennaro and PC. Karakousis (2014). Simvastatin increases the in vivo activity of the first-line tuberculosis regimen. Journal of Antimicrobial Chemotherapy 69:2453-7

C. Skerry, K. Scanlon, J. Ardanuy, D. Roberts, L. Zhang, H. Rosen and NH Carbonetti (2017). Therapeutic treatment with sphingosine-1-phosphate receptor ligands reduces pertussis inflammatory pathology by a pertussis toxin-insensitive mechanism. Journal of Infectious Diseases 215:278-86