Jan Pohl

Centers for Disease Control and Prevention

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Matthew S. Reed

University of Wisconsin–Madison

Pavel Svoboda

Veterinary Research Institute

Olga Stuchlik

Centers for Disease Control and Prevention

V. Kostka

University of Giessen

Miroslav Baudyš

Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry

Suryaprakash Sambhara

National Center for Immunization and Respiratory Diseases

Dean P. Jones

Emory University

William M. Shafer

Emory University

H. Anne Pereira

University of Oklahoma Health Sciences Center

Shivaprakash Gangappa

Centers for Disease Control and Prevention

Cooperative Institutions

Emory University

267

Centers for Disease Control and Prevention

199

National Center for Emerging and Zoonotic Infectious Diseases

University of Georgia

National Center for Immunization and Respiratory Diseases

National Institutes of Health

Division of Parasitic Diseases and Malaria

Georgia Institute of Technology

The University of Texas at Austin

National Center for Infectious Diseases

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Carbon Nanoparticles Inhibit the Antimicrobial Activities of the Human Cathelicidin LL-37 through Structural Alteration

The Journal of Immunology (2017)

Fern Findlay-Greene Jan Pohl Pavel Svoboda Priyanka Shakamuri Kevin McLean

Abstract Host defense peptides, also known as antimicrobial peptides, are key elements of innate host defense. One host defense peptide with well-characterized antimicrobial activity is the human cathelicidin, LL-37. LL-37 has been shown to be upregulated at sites of infection and inflammation and is regarded as one of the primary innate defense molecules against bacterial and viral infection. Human exposure to combustion-derived or engineered nanoparticles is of increasing concern, and the implications of nanomaterial exposure on the human immune response is poorly understood. However, it is widely acknowledged that nanoparticles can interact strongly with several immune proteins of biological significance, with these interactions resulting in structural and functional changes of the proteins involved. This study investigated whether the potent antibacterial and antiviral functions of LL-37 were inhibited by exposure to, and interaction with, carbon nanoparticles, together with characterizing the nature of the interaction. LL-37 was exposed to carbon black nanoparticles in vitro, and the antibacterial and antiviral functions of the peptide were subsequently assessed. We demonstrate a substantial loss of antimicrobial function when the peptide was exposed to low concentrations of nanomaterials, and we further show that the nanomaterial-peptide interaction resulted in a significant change in the structure of the peptide. The human health implications of these findings are significant, as, to our knowledge, this is the first evidence that nanoparticles can alter host defense peptide structure and function, indicating a new role for nanoparticle exposure in increased disease susceptibility.

Cathelicidin

Beta defensin

Carbon Nanoparticles

Nanomaterials

10.4049/jimmunol.1700706

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Citations (27)

CAP 37, A 37 kD human neutrophil granule cationic protein shares homology with inflammatory proteinases

Life Sciences (1990)

H. Anne Pereira John K. Spitznagel Jan Pohl Douglas E. Wilson John G. Morgan

Cathepsin G

Azurophilic granule

Neutrophil elastase

Proteinase 3

Pancreatic elastase

Monocyte

Serine Proteinase Inhibitors

Homology

10.1016/0024-3205(90)90104-y

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Citations (37)

Targeting tissue factor-expressing tumor angiogenesis and tumors with EF24 conjugated to factor VIIa

Journal of drug targeting (2008)

Mamoru Shoji Aiming Sun Walter Kisiel Yang Lu Hyunsuk Shim

Tissue factor (TF) is aberrantly expressed on tumor vascular endothelial cells (VECs) and on cancer cells in many malignant tumors, but not on normal VECs, making it a promising target for cancer therapy. As a transmembrane receptor for coagulation factor VIIa (fVIIa), TF forms a high-affinity complex with its cognate ligand, which is subsequently internalized through receptor-mediated endocytosis. Accordingly, we developed a method for selectively delivering EF24, a potent synthetic curcumin analog, to TF-expressing tumor vasculature and tumors using fVIIa as a drug carrier. EF24 was chemically conjugated to fVIIa through a tripeptide-chloromethyl ketone. After binding to TF-expressing targets by fVIIa, EF24 will be endocytosed along with the drug carrier and will exert its cytotoxicity. Our results showed that the conjugate inhibits vascular endothelial growth factor-induced angiogenesis in a rabbit cornea model and in a Matrigel model in athymic nude mice. The conjugate-induced apoptosis in tumor cells and significantly reduced tumor size in human breast cancer xenografts in athymic nude mice as compared with the unconjugated EF24. By conjugating potent drugs to fVIIa, this targeted drug delivery system has the potential to enhance therapeutic efficacy, while reducing toxic side effects. It may also prove to be useful for treating drug-resistant tumors and micro-metastases in addition to primary tumors.

Targeted drug delivery

10.1080/10611860801890093

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Citations (45)

A study of the peptidyldipeptidase activity of bovine spleen cathepsin B using synthetic substrates

De Gruyter eBooks (1986)

Jan Pohl Silvia Davinic Ivo Bláha P. Štrop V. Kostka

10.1515/9783110846836-012

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Human β-Defensin-1, a Potential Chromosome 8p Tumor Suppressor: Control of Transcription and Induction of Apoptosis in Renal Cell Carcinoma

Cancer Research (2006)

Carrie Sun Rebecca S. Arnold Carina Fernandez-Golarz Amanda B. Parrish Tara L. Almekinder

Human beta-defensin-1 (hBD-1) is a candidate tumor suppressor gene located on chromosome 8p23. Previously, we showed that cancer-specific loss of hBD-1 was found in 90% of renal clear cell carcinomas and in 82% of prostate cancers. To investigate the possible mechanisms of decreased gene expression and determine the function of hBD-1 protein in urological cancers, we sequenced hBD-1 gene coding regions in prostatic and renal cancer samples. We then analyzed the frequency distribution of promoter polymorphisms and determined the effect of these base changes on transcriptional activity of the hBD-1 promoter. A polymorphism at -688 bases upstream of the ATG start codon affects hBD-1 promoter activity, leading to a rate of reporter gene transcription that is 40% to 50% lower than the wild-type sequence when tested in either DU145 or TSU-Pr1 cell lines. In addition, a polymorphism at -44 bases was shown to enhance transcription up to 2.3 times more than the wild-type sequence in the same cell lines. In addition, three novel hBD-1 promoter mutations were found in renal and prostate cancer clinical samples. An iso-5-aza-2'-deoxycytidine treatment was effective in transcription up-regulation in DU145, suggesting a possible upstream methylation-dependent effect. Synthetic hBD-1 peptide inhibited bladder cancer cell TSU-Pr1 proliferation. Overexpression of the hBD-1 gene in renal cancer cells SW156 resulted in caspase-3-mediated apoptosis. These data support the hypothesis that hBD-1 is a potential tumor suppressor gene for urological cancers. Promoter point mutations may be responsible for cancer-specific loss of hDB-1 expression.

DU145

E2F1

10.1158/0008-5472.can-06-0294

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Development of a Multiplex Bead Assay To Detect Immunoglobulin G Antibodies to Babesia duncani in Human Serum

Journal of Clinical Microbiology (2021)

Yong Wang TaLesa Aderohunmu Henry Bishop Isabel McAuliffe Hilda N. Rivera

Babesia duncani is the causative agent of babesiosis in the western United States. The indirect fluorescent antibody (IFA) assay is the diagnostic test of choice for detection of B. duncani-specific antibodies. However, this test requires parasitized red blood cells harvested from infected hamsters, and test results are often difficult to interpret. To simplify serological testing for B. duncani, a proteomics approach was employed to identify candidate immunodiagnostic antigens. Several proteins were identified by electrospray ionization mass spectrometric analysis, and four recombinant protein constructs were expressed and used in a multiplex bead assay (MBA) to detect B. duncani-specific antibodies. Two antigens, AAY83295.1 and AAY83296.1, performed well with high sensitivities and specificities. AAY83295.1 had a higher sensitivity (100%) but lower specificity (89%) than AAY83296.1, which had a sensitivity of 90% and a specificity of 96%. Combining these two antigens did not improve the performance of the assay. This MBA could be useful for diagnosis, serosurveillance, and blood donor screening for B. duncani infection.

Multiplex

Immunofluorescence

10.1128/jcm.00458-21

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Citations (2)

Structural Comparison of Human Monoamine Oxidases A and B

Journal of Biological Chemistry (2003)

František Hubálek Jan Pohl Dale E. Edmondson

Monoamine oxidases (MAO) A and B are approximately 60-kDa outer mitochondrial membrane flavoenzymes catalyzing the degradation of neurotransmitters and xenobiotic arylalkyl amines. Despite 70% identity of their amino acid sequences, both enzymes exhibit strikingly different properties when exposed to thiol-modifying reagents. Human MAO A and MAO B each contain 9 cysteine residues (7 in conserved sequence locations). MAO A is inactivated by N-ethylmaleimide (NEM) much faster (tau(1/2) = approximately 3 min) than MAO B (tau(1/2) = approximately 8 h). These differences in thiol reactivities are also demonstrated by monitoring the NEM modification stoichiometries by electrospray mass spectrometry. Inactivation of either enzyme with acetylenic inhibitors results in alterations of their thiol reactivities. Cys5 and Cys266 were identified as the only residues modified by biotin-derivatized NEM in clorgyline-inactivated MAO A and pargyline-inactivated MAO B, respectively. The x-ray structure of MAO B (Binda, C., Newton-Vinson, P., Hubalek, F., Edmondson, D. E., and Mattevi, A. (2002) Nat. Struct. Biol. 9, 22-26) shows that Cys5 is located on the surface of the molecule opposite to the membrane-binding region. Cys266 in MAO A is predicted to be located in the same region of the molecule. These thiol residues are also modified by biotin-derivatized NEM in the mitochondrial membrane-bound MAO A and MAO B. This study shows that the MAO A structure is "more flexible" than that of MAO B and that clorgyline and pargyline inactivation of MAO A and B, respectively, increases the structural stability of both enzymes. No evidence is found for the presence of disulfide bonds in either enzyme, contrary to a previous suggestion.

Clorgyline

Pargyline

Monoamine oxidase B

Thiol

10.1074/jbc.m303712200

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Citations (42)

Proteomic identification of the wt-p53-regulated tumor cell secretome

Oncogene (2006)

Fatima W. Khwaja Pavel Svoboda Matthew S. Reed Jan Pohl Beata Pyrzyńska

Secretory protein

Tumor progression

10.1038/sj.onc.1209969

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Citations (68)

Interferon as an immunoadjuvant to enhance antibodies following influenza B infection and vaccination in ferrets

npj Vaccines (2024)

Thomas Rowe A. Fletcher Pavel Svoboda Jan Pohl Yasuko Hatta

Despite annual vaccination, influenza B viruses (IBV) continue to cause significant morbidity and mortality in humans. We have found that IBV infection resulted in a weaker innate and adaptive immune response than influenza A viruses (IAV) in ferrets. To understand and overcome the weak immune responses to IBV in ferrets, we administered type-I or type-III interferon (IFN) to ferrets following infection or vaccination and evaluated their effects on the immune response. IFN signaling following viral infection plays an important role in the initial innate immune response and affects subsequent adaptive immune responses. In the respiratory tract, IFN lambda (IFNL) has regulatory effects on adaptive immunity indirectly through thymic stromal lymphopoietin (TSLP), which then acts on immune cells to stimulate the adaptive response. Following IBV infection or vaccination, IFN treatment (IFN-Tx) upregulated gene expression of early inflammatory responses in the upper respiratory tract and robust IFN, TSLP, and inflammatory responses in peripheral blood cells. These responses were sustained following challenge or vaccination in IFN-Tx animals. Serum IFNL and TSLP levels were enhanced in IFN-Tx animals following challenge/rechallenge over mock-Tx; however, this difference was not observed following vaccination. Antibody responses in serum of IFN-Tx animals following IBV infection or vaccination increased more quickly and to higher titers and were sustained longer than mock-Tx animals over 3 months. Following rechallenge of infected animals 3 months post treatment, antibody levels remained higher than mock-Tx. However, IFN-Tx did not have an effect on antibody responses following challenge of vaccinated animals. A strong direct correlation was found between TSLP levels and antibody responses following challenge-rechallenge and vaccination-challenge indicating it as a useful tool for predicting adaptive immune responses following IBV infection or vaccination. The effects of IFN on strengthening both innate and adaptive responses to IBV may aid in development of more effective treatments following infection and improved influenza vaccines.

10.1038/s41541-024-00973-2

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Citations (1)

Purification and Characterization of an Interleukin-1β-converting Enzyme Family Protease That Activates Cysteine Protease P32 (CPP32)

Journal of Biological Chemistry (1996)

Xuesong Liu Caryn Naekyung Kim Jan Pohl Xiaodong Wang

Cysteine protease

10.1074/jbc.271.23.13371

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Citations (87)