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Research

In our efforts we combine the basic research and utilize it to carry out applicatory projects. Current research of the Virogenetics group focuses on early steps of viral infection, namely (a) identification of viral attachment receptors / co-receptors, (b) identification of internalization pathways to the host cell, and (c) single virus trafficking in the cell. To make an example we mapped early events during infection with a number of coronaviruses.

In order to appropriately study the subject we utilize the most advanced ex vivo culture system HAE (human airway epithelium), which is constructed with fully differentiated, ciliated human epithelium growing on an interphase of air and liquid, to mimic the natural infection microenvironment.

The 3D cultures provide an excellent research model, and in order to excel it and broaden our expertise we are actively collaborating with other research groups, e.g., Amy Sims (University of North Carolina), Katja Wolthers (Universiteit van Amsterdam), Dirk Johmans (Catholic University of Leuven). We plan to further extend our expertise and to start the organoid lung cultures to study the biology of viral infection and to improve translation of ex vivo research to the clinic. As we try to map early events during viral infection, we developed a workbench for such research. This includes methods to visualize single viruses in context of the cell, receptors and markers of certain sub cellular structures / pathways. Even though we have started with members of Coronaviridae family we are now extending the study also to other viral species.

Our research efforts are aimed to understand the virus biology, yet we combine the know how and knowledge gained in such a way to carry out applicatory projects. Consequently, we are working on development of antiviral agents hampering virus entry / internalization. One of the examples of such activity is our fruitful collaboration with chemists from the group of prof. Maria Nowakowska, with whom we formed the interdisciplinary team working on novel polymeric drugs. Combining the know how gained on virus entry and early stages of infection we are able to precisely pinpoint the mechanism of action for such compounds, visualizing their activity in the cell. These efforts are rewarding, as we already developed several effective inhibitors, for which intellectual property is secured (e.g., P416749, P409016, P409015, PCT/PL2013/050032, PCT/PL2013/00064, P401707).

Further, some our innovations are already in the commercialization phase. The StartIt Vet company has been formed by investors to commercialize the HTCC molecule (cationically substituted chitosan), as anticoronaviral drug. Several other compounds were developed, inhibiting entry of influenza virus, human metapneumovirus, human rhinoviruses, human herpesviruses, and flaviviruses. For some of these we are currently negotiating the commercialization route with private investors and venture capital.

The second line of research is related to flaviviruses. This family of viruses encompasses several human and non human species, which cause severe disease in humans. The best known example is hepatitis C, which causes a world-wide pandemic. Yet, there are several other species that are of interest. These include tick-borne encephalitis, dengue virus, West Nile virus, and Zika virus.

In collaboration with excellent teams from AGH Krakow (group of prof. Jerzy Sillbering), Wroclaw (group of prof. Marcin Sienczyk), and Gdansk (group of prof. Adam Lesner), we initiated the work aimed to understand the biology of the virus.

It is also worth to mention that Virogenetics group gathers postdoctoral fellows, PhD students and MSc students. As one of my priorities is to enrich the experience of our team, we invite researchers to join us and to work on satellite projects. One of the best examples is dr Anna Kula-Pacurar, who returned to Poland and to start the research within her Polonez grant. She will bring her unique experience in elucidating the interactions between biomolecules. Further, dr Justyna Ciejka, previously working on virus entry inhibitors, currently tries to use the developed biomaterials for fast diagnostics and virus/vaccine purification within her own project. Dr Antonina Naskalska utilizing our experience with coronaviruses aims to develop virus-like particles, which are a perfect tool to safely study early events during coronaviral infection, but also in the future may be used in applicatory projects.

Publications:
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    1. Milewska A, Kindler E, Vkovski P, Zeglen S, Ochman M, Thiel V, Rajfur Z, Pyrc K.(2018) APOBEC3-mediated restriction of RNA virus replication. Scientific Reports. in press.
    2. A Milewska, P Nowak, K Owczarek, A Szczepanski, M Zarebski, A Hoang-Bujnowicz, K Berniak, J Wojarski, S Zeglen, Z Baster, Z Rajfur, Pyrc K (2018) Entry of human coronavirus NL63 to the cell. Journal of Virology. 92(3). pii: e01933-17.
    3. Pachota M, Klysik K, Synowiec A, Ciejka J, Szczubialka K, Pyrc K, Nowakowska M. (2017) Inhibition of herpes simplex viruses by cationic dextran derivatives. Journal of Medicinal Chemistry. 60(20):8620-8630.
    4. Burmistrz M, Rodriguez Martinez JI, Krochmal D, Staniec D, Pyrc K. (2017) crRNAs in Porphyromonas gingivalis CRISPR-Cas I-C system. Journal of Bacteriology. 199(23). pii: e00275-17.
    5. Skalniak L, Zak K, Guzik K, Magiera K, Musielak B, Pachota M, Szelazek B, Kocik J, Grudnik P, Tomala M, Krzanik S, Pyrc K, Dömling A, Dubin G, Holak T. (2017) Small-molecule inhibitors of PD-1/PD-L1 immune checkpoint alleviate the PD-L1-induced exhaustion of T-cells. Oncotarget. 8(42):72167-72181.
    6. Sheahan TP, Sims AC, Graham RL, Menachery VD, Gralinski LE, Case JB, Leist SR, Pyrc K, Feng JY, Trantcheva I, Bannister R, Park Y, Babusis D, Clarke MO, Mackman RL, Spahn JE, Palmiotti CA, Siegel D, Ray AS, Cihlar T, Jordan R, Denison MR, Baric RS (2017) Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Science Translational Medicine, Vol. 9, Issue 396, eaal3653.
    7. Skorenski M, Pachota M, Pyrc K, Sienczyk M, Oleksyszyn J (2017) Novel Peptidyl α-Aminoalkylphosphonates as Inhibitors of Hepatitis C Virus NS3/4A Protease. Antiviral Research. 144:286-298.
    8. Ciejka J, Wolski K, Nowakowska M, Pyrc K, Szczubiałka K. (2017) Biopolymeric nano/microspheres for selective and reversible adsorption of coronaviruses. Materials Science & Engineering C. 76:735-742.
    9. Szelazek B, Kabala W, Kus K, Zdzalik M, Twarda-Clapa A, Golik P, Burmistrz M, Florek D, Wladyka B, Pyrc K, Dubin G. (2017) Structural characterization of HCoV‑NL63 N-protein. Journal of Virology. 91(11). pii: e02503-16.
    10. Gruba N*, Rodriguez Martinez JI*, Grzywa R, Wysocka M, Skoreński M, Burmistrz M, Łęcka M, Lesner A#, Sieńczyk M#Pyrc K#. (2016) Substrate profiling of Zika virus NS2B-NS3 protease. FEBS Letters. 590(20):3459-3468.
    11. Szychowska M, Siwek W, Pawolski D, Karani AA, Pyrc K, Bochtler M (2016) Type III CRISPR complexes from Thermus thermophilus. Acta Biochimica Polonica. 63(2):377-86.
    12. Milewska A, Kaminski K, Ciejka J, Kosowicz K, Zeglen S, Wojarski J, Nowakowska M, Szczubialka K#, Pyrc K# (2016) HTCC: broad range inhibitor of coronavirus entry. PLoS One. 11(6):e0156552
    13. Ciejka J, Milewska A, Wytrwal M, Wojarski J, Golda A, Ochman M, Nowakowska M, Szczubialka K, Pyrc K# (2016) Novel polyanions inhibiting replication of influenza viruses. Antimicrobial Agents and Chemotherapy (AAC). 60(4):1955-66.
    14. Szczubialka K., Pyrc K, Nowakowska M. (2016) In search for effective and definitive treatment of Herpes Simplex Virus Type 1 (HSV-1) infections. RSC Advances. 6, 1058-1075.
    15. Benedyk M., Mydel P., Płaza K., Gawron K., Milewska A., Maresz K., Koziel J., Jotwani R., Pyrc K, & Potempa J. (2016) Gingipains: critical factors in the development of aspiration pneumonia caused by Porphyromonas gingivalis. Journal of Innate Immunity. 8(2):185-98.
    16. Burmistrz M, Dudek B, Staniec D, Rodriguez Martinez JI, Bochtler M, Potempa J, Pyrc K#. (2015). Functional analysis of Porphyromonas gingivalis W83 CRISPR-Cas systems. Journal of Bacteriology. 197(16):2631-41.
    17. Burmistrz MPyrc K#. (2015). CRISPR/Cas systems in prokaryotes. Polish Journal of Microbiology. In press.
    18. Huang X, Dong W, Milewska A, Golda A, Qi Y, Zhu Q, Marasco W, Baric R, Sims A#, Pyrc K#, Li W#, Sui J#. (2015). HCoV-HKU1 Spike protein uses O-acetylated sialic acid as an attachment receptor determinant and employs HE protein as a receptor-destroying enzyme. Journal of VirologyIn press.
    19. Zabieglo K, Majewski P, Majchrzak-Gorecka M, Wlodarczyk A, Grygier B, Zegar A, Kapinska-Mrowiecka M, Naskalska A, Pyrc K, Dubin A, Wahl S, Cichy J#. (2015). The inhibitory effect of secretory leukocyte protease inhibitor (SLPI) on formation of neutrophil extracellular traps. Journal of Leukocyte Biology. In press.
    20. Pyrc K#. (2015). Ludzkie koronawirusy. Postępy Nauk Medycznych. t. XXVIII, nr 4B, 2015.
    21. Naskalska A, Pyrc K#. (2015) Virus Like Particles as Immunogens and Universal Nanocarriers. Polish Journal of Microbiology. 64(1):3-13.
    22. Zuwala K, Golda A, Kabala W, Burmistrz M, Zdzalik M, Nowak P, Kedracka-Krok S, Zarebski M, Dobrucki J, Florek D, Zeglen S, Wojarski J, Potempa J, Dubin G, Pyrc K#. (2015) The nucleocapsid protein of human coronavirus NL63. PLoS One.
    23. Milewska A, Zarebski M, Nowak P, Stozek K, Potempa J, Pyrc K#. (2014) Human coronavirus NL63 utilize heparan sulfate proteoglycans for attachment to target cells. Journal of Virology. doi: 10.1128/JVI.02078-14.
    24. Gawron K, Łazarz–Bartyzel K, Łazarz M, Stęplewska K, Pyrc K, Potempa J, Chomyszyn–Gajewska M. In vitro testing the potential of a novel chimeric IgG variant for inhibiting collagen fibrils formation in recurrent hereditary gingival fibromatosis. Journal of Physiology and Pharmacology. In press.
    25. Koziel J, Bryzek D, Sroka A, Maresz K, Glowczyk I, Bielecka E, Kantyka T, Pyrc K, Svoboda P, Pohl J, Potempa J. (2014) Citrullination Alters Immunomodulatory Function of LL-37 Essential for Prevention of Endotoxin-Induced Sepsis. Journal of Immunology2014 Apr 25
    26. Florek D, Burmistrz M, Potempa J, Pyrc K. Stability of infectious human coronavirus NL63 (2014) Journal of Virological Methods. 2014 Apr 18. pii: S0166-0934(14)00136-0. doi: 10.1016/j.jviromet.2014.04.001.
    27. Maresz K, Hellvard A, Sroka A, Adamowicz K, Bielecka E, Koziel J, Gawron K, Mizgalska D, Marcinska K, Benedyk M, Pyrc K, Quirke A, Jonsson R, Alzabin S, Venables P, Nguyen K, Mydel P, Potempa J. Porphyromonas gingivalis Facilitates the Development and Progression of Destructive Arthritis through Its Unique Bacterial Peptidylarginine Deiminase (PAD). (2013) PloS Pathogens9(9): e1003627. doi:10.1371/journal.ppat.1003627.
    28. Pyrc K, Stozek K, Galan W, Potempa J. HexaPrime: a novel method for detection of coronaviruses. (2013) Journal of Virological Methods188 (1–2), pp. 29–36 doi: 10.1016/j.jviromet.2012.11.039.
    29. Milewska A, Ciejka J, Kaminski K, Karewicz A, Bielska D, Zeglen S, Karolak W, Nowakowska M, Potempa J, Bosch BJ, Pyrc K#, Szczubialka K#. 2012. Novel polymeric inhibitors of HCoV-NL63. Antiviral Research. doi: 10.1016/j.antiviral.2012.11.006
    30. Kantyka T*, Pyrc K*, Gruca M, Smagur J, Plaza K, Guzik K, Zeglen S, Ochman M, Potempa J. 2012. Staphylococcus aureus proteases degrade lung surfactant protein A potentially impairing innate immunity of the lung. 2012. Journal of Innate Immunity2012.
    31. Pyrc K, Milewska A, Kantyka T,  Sroka A, Maresz K, Kozieł J, Nguyen KA, Enghild JJ., Knudsen AD, Potempa J. Inactivation of epidermal growth factor by Porphyromonas gingivalis as a potential mechanism for periodontal tissue damage. (2013) Infection and Immunity81(1):55 doi: 10.1128/​IAI.00830-12.
    32. Milewska A, Pyrc K. 2012 Human RIG-1/Mda5 and TLR3 signaling pathways and their role in antiviral response during mucosal infections, Recent Research Developments in Virology. ISBN: 978-81-7895-563-6, Transworld Research Network
    33. Dubin G., Koziel J., Pyrc K., Wladyka B., Potempa J. Bacterial proteases in disease – role in intracellular survival, evasion of coagulation/fibrinolysis innate defenses, toxicoses and viral infections. Current Pharmacuethical Design (2012). [Epub ahead of print].
    34. Dijkman R, Jebbink MF, Deijs M, Milewska APyrc K, Buelow E, van der Bijl A, van der Hoek L. Replication dependent downregulation of cellular ACE2 protein expression by Human Coronavirus NL63. Journal of General Virology (2012) doi:10.1099/vir.0.043919-0.
    35. Pyrc K, Stozek K, Wojcik K, Gawron K, Zeglen S, Karolak W, Wojarski J, Ochman M, Hubalewska-Mazgaj M, Bochenek G, Sanak M, Zembala M, Szczeklik A, Potempa J. 2012. Use of Sensitive, Broad-Spectrum Molecular Assays and Human Airway Epithelium Cultures for Detection of Respiratory Pathogens. PLoS ONE 7(3): e32582.
    36. Pyrc K, Strzyz P, Milewska A, Golda A, Schildgen O, Potempa J; 2011; Porphyromonas gingivalis enzymes enhance infection with human metapneumovirus in vitro. Journal of General Virology. Journal of General Virology (2011) 92(Pt 10):2324-32
    37. Pyrc K, Milewska A, Potempa J;  Development of loop-mediated isothermal amplification assay for detection of human coronavirus-NL63. Journal of Virological Methods (2011) 175(1): 133-136.
    38. Golda A, Malek N, Dudek B, Zeglen S, Wojarski J, Ochman M, Kucewicz E, Zembala M, Potempa J, Pyrc K; Infection with human coronavirus NL63 enhances streptococcal adherence to epithelial cells. Journal of General Virology (2011) 92(6):1358-68.
    39. Pyrc K; Hunting the bugs. (Poland)  Rzeczpospolita 03-12-2010, (Austria) Der Standard 02-02-2011.
    40. Pyrc K, Sims AC, Dijkman R, Jebbink M, Long C, Deming D, Donaldson E, Vabret A, Baric R, van der Hoek L, Pickles R; Culturing the Unculturable: Human Coronavirus HKU1 Infects, Replicates, and Produces Progeny Virions in Human Ciliated Airway Epithelial Cell Cultures. Journal of Virology. (2010) 84(21):11255-63.
    41. Pyrc K; A la caza de los virus. 2010, El Pais, 09-02-2010
    42. Pyrc K; Ludzki koronawirus NL63 - Obraz kliniczny i charakterystyka molekularna. Postępy Mikrobiologii (2008), 47,3, 257-262.
    43. Dijkman R, Jebbink MF, El Idrissi NB, Pyrc K, Müller MA, Kuijpers TW, Zaaijer HL, van der Hoek L.; Human coronavirus NL63 and 229E seroconversion in children; Journal of clinical microbiology (2008) 46(7):2368-73.
    44. Golda A, Pyrc K; Recent antiviral strategies against human coronavirus – related respiratory illness; Current Opinion in Pulmonary Medicine. 2008, 14 (3), 248-253
    45. de Vries M, Pyrc K, Berkhout R, Vermeulen-Oost W, Dijkman R, Jebbink MF, Bruisten S, Berkhout B, van der Hoek L; Human parechovirus type 1, 3, 4, 5 and 6 detection in picornavirus cultures; Journal of clinical microbiology (2008) 46(2):759-762.
    46. Pyrc K, Jebbink MF, Berkhout B, van der Hoek L; Detection of new viruses by VIDISCA: virus discovery based on cDNA-amplified fragment length polymorphism (2008) in: SARS-and Other Coronaviruses, Laboratory Protocols; Methods in Molecular Biology, Vol. 454, Ed. Cavanagh, Dave, ISBN: 978-1-58829-867-6

    • 2018. P.424871. Use of copolimers for the treatment of infections caused by HSV-1 virus.
    • P. 416 749. The use of cationially modified dextran for the treatment of infections caused by HSV-1 virus.
    • P. 409 016: The use of polymers in the treatment and prevention of infections caused by influenza virus.
    • P. 409 015: The use of polymers in the treatment and prevention of infections caused by human metapneumovirus virus.
    • PCT/PL2013/050032. Method of RNA viruses identification and its application.
    • PCT/PL2013/00064. The use of chitosan polymer in the treatment and prevention of infections caused by coronaviruses.
    • P 401 707. Method for identification of RNA viruses and its application.
    • P 399 246. Application of chitosan derivatives for treatment and prophylaxis od coronaviral infection.

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