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Role of Single Nucleotide Polymorphisms (SNPs) in PTPN2/22 and Mycobacterium avium subspecies paratuberculosis (MAP) in Rheumatoid Arthritis and Crohn's Disease
Title
Role of Single Nucleotide Polymorphisms (SNPs) in PTPN2/22 and Mycobacterium avium subspecies paratuberculosis (MAP) in Rheumatoid Arthritis and Crohn's Disease.
Creator
Sharp, Robert, Naser, Saleh, Parks, Griffith, Roy, Herve, Singla, Dinender, University of Central Florida
Abstract / Description
Both genetic pre-disposition and potential environmental triggers are shared between Rheumatoid arthritis (RA) and Crohn's disease (CD). We hypothesized that single nucleotide polymorphisms (SNPs) in the negative T-cell regulators Protein Tyrosine Phosphatase Non-receptor type 2 and 22 (PTPN2/22) lead to a dysregulated immune response as seen in RA and CD. To test the hypothesis, peripheral leukocytes samples from 204 consented subjects were TaqMan genotyped for 9 SNPs in PTPN2/22. The SNPs...
Show moreBoth genetic pre-disposition and potential environmental triggers are shared between Rheumatoid arthritis (RA) and Crohn's disease (CD). We hypothesized that single nucleotide polymorphisms (SNPs) in the negative T-cell regulators Protein Tyrosine Phosphatase Non-receptor type 2 and 22 (PTPN2/22) lead to a dysregulated immune response as seen in RA and CD. To test the hypothesis, peripheral leukocytes samples from 204 consented subjects were TaqMan genotyped for 9 SNPs in PTPN2/22. The SNPs effect on PTPN2/22 and IFN-y expression was determined using RT-PCR. Blood samples were analyzed for the Mycobacterium avium subspecies paratuberculosis (MAP) IS900 gene by nPCR. T-cell proliferation and response to phytohematoagglutonin (PHA) mitogen and MAP cell lysate were determined by BrdU proliferation assay. Out of 9 SNPs, SNP alleles of PTPN2:rs478582 occurred in 79% RA compared to 60% control (p-values ? 0.05). SNP alleles of PTPN22:rs2476601 occurred in 29% RA compared to 6% control (p-values ? 0.05). For the haplotype combination of PTPN2:rs478582/PTPN22rs2476601, 21.4% RA had both SNPs (C-A) compared to 2.4% control (p-values ? 0.05). PTPN2/22 expression in RA was decreased by an average of 1.2 fold. PTPN2:rs478582 upregulated IFN-y in RA by an average of 1.5 fold. Combined PTPN2:rs478582/PTPN22:rs2476601 increased T-cell proliferation by an average of 2.7 fold when treated with PHA. MAP DNA was detected in 34% RA compared to 8% controls (p-values ? 0.05), where samples with PTPN2:rs478582 and/or PTPN22:rs2476601 were more MAP positive. PTPN2:rs478582/PTPN22:rs2476601 together with MAP infection significantly increased T-cell response and IFN-y expression in RA samples. The same experimental approach was followed on blood samples from CD patients. Both PTPN2:rs478582/PTPN22:rs2476601 affected PTPN2/22 and IFN-y expression along with T-cell proliferation significantly more than in RA. MAP DNA was detected in 64% of CD. This is the first study to report the correlation between SNPs in PTPN2/22, IFN-y expression and MAP in autoimmune disease.
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Date Issued
2018
Identifier
CFE0007371, ucf:52094
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0007371
Zika virus-induced lysis of cervical cancer cells
Title
Zika virus-induced lysis of cervical cancer cells.
Creator
Krishnapura, Harini, Alexander, Kenneth, Parks, Griffith, Jewett, Mollie, University of Central Florida
Abstract / Description
Cervical cancer is the fourth most frequent cancer in women with an estimated 570,000 new cases globally in 2018. Treatment of advanced cervical cancer is often unsuccessful leading to high cancer-related mortality rates, especially in under-resourced countries. Recently, a possible role for the cell surface glycoprotein CD24 in host cell specificity of Zika virus was reported. As an extension of this work, Zika viruses have been proposed as oncolytic therapy for the treatment of...
Show moreCervical cancer is the fourth most frequent cancer in women with an estimated 570,000 new cases globally in 2018. Treatment of advanced cervical cancer is often unsuccessful leading to high cancer-related mortality rates, especially in under-resourced countries. Recently, a possible role for the cell surface glycoprotein CD24 in host cell specificity of Zika virus was reported. As an extension of this work, Zika viruses have been proposed as oncolytic therapy for the treatment of neuroblastoma and other CD24 positive tumors. To determine the permissiveness of cervical cancer cells to Zika virus infection and its association with CD24, we assessed cytopathic effect (CPE) induced by Zika virus in cervical cancer cell lines (HeLa, SiHa and CaSki) by light microscopy and by cytotoxicity assay. Cervical cancer cells were susceptible to Zika virus-induced apoptosis. Upon infection, the morphology of cervical cancer cells changed, exhibiting Zika virus-induced CPE. Cervical cancer cell expression of viral non-structural protein 1 (NS1) after infection demonstrated viral protein translation. Quantitative plaque assays demonstrated the production of competent virions. Because CD24 expression was found to be important for Zika virus infection in neuroblastoma cells, CD24 expression was assessed in cervical cancer cells. Cervical cancer cells expressed low but measurable levels of CD24 mRNA and protein. siRNA-mediated knockdown of CD24 resulted in reduced NS1 expression and reduced levels of virus-induced apoptosis. Taken together our data suggest a possible role for CD24 in Zika virus-induced apoptosis in cervical cancer cells. Zika virus-induced apoptosis of cultured cervical cancer cells presents the possibility for the use of Zika virus as a potential oncolytic therapy for cervical cancer.
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Date Issued
2019
Identifier
CFE0007480, ucf:52682
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0007480
A Cytoplasmic-Replicating RNA Virus Sensitizes Cancer Cells to DNA Modifying Agents
Title
A Cytoplasmic-Replicating RNA Virus Sensitizes Cancer Cells to DNA Modifying Agents.
Creator
Fox, Candace, Parks, Griffith, Copik, Alicja, Khaled, Annette, Zervos, Antonis, University of Central Florida
Abstract / Description
The Parainfluenza virus 5 (PIV5) mutant P/V-CPI- is restricted for spread in normal cells but not in cancer cells in vitro and is effective at reducing tumor burden in mouse model systems. Here we show that P/V-CPI- infection of human laryngeal cancer HEp-2 cells resulted in the majority of the cells dying, but unexpectedly, a population of cells emerged as P/V-CPI- persistently infected (PI) cells. P/V-CPI- PI cells had elevated levels of basal caspase activation, and viability was highly...
Show moreThe Parainfluenza virus 5 (PIV5) mutant P/V-CPI- is restricted for spread in normal cells but not in cancer cells in vitro and is effective at reducing tumor burden in mouse model systems. Here we show that P/V-CPI- infection of human laryngeal cancer HEp-2 cells resulted in the majority of the cells dying, but unexpectedly, a population of cells emerged as P/V-CPI- persistently infected (PI) cells. P/V-CPI- PI cells had elevated levels of basal caspase activation, and viability was highly dependent on activity of cellular inhibitors of apoptosis, such as Survivin. In challenge experiments with external inducers of apoptosis, the PI cells were highly sensitive to cisplatin-induced DNA damage and cell death. This increased cisplatin sensitivity correlated with defects in the phosphorylation cascade controlling DNA damage signaling pathways, as well as translocation of damage-specific DNA binding protein 1 (DDB1) to the nucleus. Similar sensitivity to cisplatin was seen with cells during acute infection with P/V-CPI-, as well as acute infections with WT PIV5. Based on this finding, we tested the hypothesis that histone deacetylase (HDAC) inhibitors would also act with P/V-CPI- infection to enhance cancer cell killing. Using human lung and laryngeal cancer cell lines, 10 HDAC inhibitors were tested for their effect on viability of P/V-CPI- infected cells. HDAC inhibitors such as scriptaid enhanced caspase-3/7, -8 and -9 activity induced by P/V-CPI- and overall cell toxicity. Scriptaid treatment also enhanced the spread of P/V-CPI- through a population of cancer cells and suppressed interferon-beta induction through blocking phosphorylation and nuclear translocation of Interferon Regulatory Factor 3 (IRF-3). These results support a therapeutic approach of combining parainfluenza infection and chemotherapy, but also raise questions on the mechanism by which a cytoplasmic-replicating RNA virus can alter cellular DNA damage responses.
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Date Issued
2019
Identifier
CFE0007803, ucf:52355
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0007803
The Role of Type-I Interferon in Limiting Spread and Killing of an Oncolytic RNA Virus in Prostate Cells
Title
The Role of Type-I Interferon in Limiting Spread and Killing of an Oncolytic RNA Virus in Prostate Cells.
Creator
Kedarinath, Kritika, Parks, Griffith, Chakrabarti, Ratna, Altomare, Deborah, University of Central Florida
Abstract / Description
Prostate cancer is the second most prevalent cancer amongst men and there is an urgent need to address viable therapeutic options for its treatment. Development of viruses which target and kill cancer cells has gained momentum due to the first FDA approved oncolytic virus for treating human cancer patients. Our previous work with the RNA virus, Parainfluenza Virus 5 (PIV5), has led to the generation of mutants that are potential candidates for oncolytic viruses: 1) the hyperfusogenic (P/V/F)...
Show moreProstate cancer is the second most prevalent cancer amongst men and there is an urgent need to address viable therapeutic options for its treatment. Development of viruses which target and kill cancer cells has gained momentum due to the first FDA approved oncolytic virus for treating human cancer patients. Our previous work with the RNA virus, Parainfluenza Virus 5 (PIV5), has led to the generation of mutants that are potential candidates for oncolytic viruses: 1) the hyperfusogenic (P/V/F) mutant has a mutated P/V and fusion gene which activates anti-viral responses and causes massive cell-cell fusion respectively, and 2) the Leader mutant has a mutated viral genomic promoter which kills cells due to overactive viral gene expression. The P/V/F mutant has shown effectiveness in reducing prostate tumor burden in a mouse model system, however, the specificity of these viruses is unclear, i.e. targeting cancerous prostate cells while leaving uninvolved cells unaffected. In this study, we addressed how these PIV5 mutants replicate in and killed tumor versus benign human prostate cells. Flow cytometry demonstrated that the mutants are able to infect and replicate in prostate tumor cells (22Rv1), resulting in effective cell killing. However, these mutants showed highly restricted spread in benign prostatic hyperplasia cells (BPH-1). Upon further exploration, it was determined that the restriction observed in the BPH-1 cells is due to the induction and signaling of type-I Interferon (IFN). This was confirmed upon treatment with an IFN-? neutralizing antibody, which relieved restricted spread of mutants in benign cells. BPH-1 cells infected with the mutants also showed upregulation of key anti-viral, IFN-induced genes such as TLR3, IFIT1, and OAS2. Upon characterization of the mutant viruses in an additional metastatic prostate cancer cell line (C4-2B), a restriction in viral spread was observed. The restricted spread did not correlate with production of high levels of type-I IFN, suggesting that other cytokines or intracellular factors can limit replication in tumor cells. Therefore, these studies lay the groundwork for further improving the specificity of oncolytic PIV5 mutants by exploiting type-I IFN pathways as well as other anti-viral factors.
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Date Issued
2016
Identifier
CFE0006468, ucf:51445
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0006468
Knowledge and Attitudes Regarding the Recent Zika Outbreak Among a Sample of South Florida Residents
Title
Knowledge and Attitudes Regarding the Recent Zika Outbreak Among a Sample of South Florida Residents.
Creator
Elakkari, Mohamed, Naser, Saleh, Parks, Griffith, Samsam, Mohtashem, University of Central Florida
Abstract / Description
South Florida has had the largest number of U.S. Zika infection cases during the recent outbreak. This study aimed at assessing South Floridians' basic knowledge, perceptions of the seriousness and susceptibility to Zika infection, their information sources and needs, as well as their attitudes towards the protective measures proposed by the CDC. We also wanted to assess whether any of those factors have affected the frequency of participants' undertaking of the protective behaviors. To this...
Show moreSouth Florida has had the largest number of U.S. Zika infection cases during the recent outbreak. This study aimed at assessing South Floridians' basic knowledge, perceptions of the seriousness and susceptibility to Zika infection, their information sources and needs, as well as their attitudes towards the protective measures proposed by the CDC. We also wanted to assess whether any of those factors have affected the frequency of participants' undertaking of the protective behaviors. To this end, we designed an online questionnaire and surveyed the responses of five hundred South Floridians (Age=18-78 years). We found significant gaps in participants' knowledge about the risk groups, routes of transmission, treatment, and complications of Zika infection. Older age and college education were associated with significantly higher knowledge scores, while the presence of pregnant women in the household was associated with lower scores. About half of the participants perceived Zika to be a profoundly severe health problem, but less than one-third believed that their susceptibility to the infection is high.Most participants agreed that undertaking the measures that limit exposure to mosquito bites would be effective in preventing infections and that they would be able to carry-out these measures if recommended by the CDC, but a significantly lower proportion had similar responses to the items regarding protection against sexual transmission.There was a significant association between the frequency of protective behavior undertaking and respondents' beliefs about the seriousness and personal susceptibility to the infection, as well as their beliefs regarding the efficacy of the protective behaviors.Finally, most participants reported media platforms as their sources of information about Zika, while a minority of them received their information directly from healthcare professionals.These findings suggest that more targeted risk communication efforts are needed to increase South Floridians' awareness about Zika's public health threat.
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Date Issued
2018
Identifier
CFE0006998, ucf:51622
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0006998