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  1. AU="Files, Megan"
  2. AU="Pietrzykowski, Łukasz"
  3. AU="Karimi, Poorya"
  4. AU="Mannava, Yamini"
  5. AU="Sangiovanni, Giuseppe"
  6. AU="Duff, John H."
  7. AU="Jin, Peng"
  8. AU="Bursill, Christina A"
  9. AU="Huchzermeyer, Cord"
  10. AU="Di Caprio, Simone"
  11. AU="Firl, Christina E M"
  12. AU="Davies, Jane" AU="Davies, Jane"
  13. AU="Srinivasan, Karpagam"
  14. AU="Pritam Banerjee"
  15. AU="Fried, Miriam"
  16. AU="Andita P. Newton"
  17. AU="Larsen, B. B."
  18. AU="McPheeters, D"

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  1. Artikel: Nanomaterials-based vaccines to target intracellular bacterial pathogens.

    Files, Megan A / Kristjansson, Kadin M / Rudra, Jai S / Endsley, Janice J

    Frontiers in microbiology

    2022  Band 13, Seite(n) 1040105

    Abstract: Development of novel immunization approaches to combat a growing list of emerging and ancient infectious agents is a global health priority. Intensive efforts over the last several decades have identified alternative approaches to improve upon ... ...

    Abstract Development of novel immunization approaches to combat a growing list of emerging and ancient infectious agents is a global health priority. Intensive efforts over the last several decades have identified alternative approaches to improve upon traditional vaccines that are based on live, attenuated agents, or formulations of inactivated agents with adjuvants. Rapid advances in RNA-based and other delivery systems for immunization have recently revolutionized the potential to protect populations from viral pathogens, such as SARS-CoV-2. Similar efforts to combat bacterial pathogens, especially species with an intracellular niche, have lagged significantly. In the past decade, advances in nanotechnology have yielded a variety of new antigen/adjuvant carrier systems for use in vaccine development against infectious viruses and bacteria. The tunable properties of nanomaterial-based vaccines allow for balancing immunogenicity and safety which is a key hurdle in traditional antigen and adjuvant formulations. In this review, we discuss several novel nanoparticle-based vaccine platforms that show promise for use against intracellular bacteria as demonstrated by the feasibility of construction, enhanced antigen presentation, induction of cell mediated and humoral immune responses, and improved survival outcomes in
    Sprache Englisch
    Erscheinungsdatum 2022-11-18
    Erscheinungsland Switzerland
    Dokumenttyp Journal Article ; Review
    ZDB-ID 2587354-4
    ISSN 1664-302X
    ISSN 1664-302X
    DOI 10.3389/fmicb.2022.1040105
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Peptide-based supramolecular vaccine systems.

    O'Neill, Conor L / Shrimali, Paresh C / Clapacs, Zoe E / Files, Megan A / Rudra, Jai S

    Acta biomaterialia

    2021  Band 133, Seite(n) 153–167

    Abstract: Currently approved replication-competent and inactivated vaccines are limited by excessive reactogenicity and poor safety profiles, while subunit vaccines are often insufficiently immunogenic without co-administering exogenous adjuvants. Self-assembling ... ...

    Abstract Currently approved replication-competent and inactivated vaccines are limited by excessive reactogenicity and poor safety profiles, while subunit vaccines are often insufficiently immunogenic without co-administering exogenous adjuvants. Self-assembling peptide-, peptidomimetic-, and protein-based biomaterials offer a means to overcome these challenges through their inherent modularity, multivalency, and biocompatibility. As these scaffolds are biologically derived and present antigenic arrays reminiscent of natural viruses, they are prone to immune recognition and are uniquely capable of functioning as self-adjuvanting vaccine delivery vehicles that improve humoral and cellular responses. Beyond this intrinsic immunological advantage, the wide range of available amino acids allows for facile de novo design or straightforward modifications to existing sequences. This has permitted the development of vaccines and immunotherapies tailored to specific disease models, as well as generalizable platforms that have been successfully applied to prevent or treat numerous infectious and non-infectious diseases. In this review, we briefly introduce the immune system, discuss the structural determinants of coiled coils, β-sheets, peptide amphiphiles, and protein subunit nanoparticles, and highlight the utility of these materials using notable examples of their innate and adaptive immunomodulatory capacity. STATEMENT OF SIGNIFICANCE: Subunit vaccines have recently gained considerable attention due to their favorable safety profiles relative to traditional whole-cell vaccines; however, their reduced efficacy requires co-administration of reactogenic adjuvants to boost immune responses. This has led to collaborative efforts between engineers and immunologists to develop nanomaterial-based vaccination platforms that can elicit protection without deleterious side effects. Self-assembling peptidic biomaterials are a particularly attractive approach to this problem, as their structure and function can be controlled through primary sequence design and their capacity for multivalent presentation of antigens grants them intrinsic self-adjuvanticity. This review introduces the various architectures adopted by self-assembling peptides and discusses their application as modulators of innate and adaptive immunity.
    Mesh-Begriff(e) Adaptive Immunity ; Adjuvants, Immunologic/pharmacology ; Antigens ; Peptides ; Vaccines, Subunit
    Chemische Substanzen Adjuvants, Immunologic ; Antigens ; Peptides ; Vaccines, Subunit
    Sprache Englisch
    Erscheinungsdatum 2021-05-16
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2173841-5
    ISSN 1878-7568 ; 1742-7061
    ISSN (online) 1878-7568
    ISSN 1742-7061
    DOI 10.1016/j.actbio.2021.05.003
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Coiled Coil Crosslinked Alginate Hydrogels Dampen Macrophage-Driven Inflammation.

    Clapacs, Zoe / ONeill, Conor L / Shrimali, Paresh / Lokhande, Giriraj / Files, Megan / Kim, Darren D / Gaharwar, Akhilesh K / Rudra, Jai S

    Biomacromolecules

    2022  Band 23, Heft 3, Seite(n) 1183–1194

    Abstract: Alginate hydrogels are widely used for tissue engineering and regenerative medicine due to their excellent biocompatibility. A facile and commonly used strategy to crosslink alginate is the addition of ... ...

    Abstract Alginate hydrogels are widely used for tissue engineering and regenerative medicine due to their excellent biocompatibility. A facile and commonly used strategy to crosslink alginate is the addition of Ca
    Mesh-Begriff(e) Alginates/chemistry ; Animals ; Hydrogels/chemistry ; Hydrogels/pharmacology ; Inflammation/pathology ; Macrophages/pathology ; Mice ; Tissue Engineering/methods
    Chemische Substanzen Alginates ; Hydrogels
    Sprache Englisch
    Erscheinungsdatum 2022-02-16
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1526-4602
    ISSN (online) 1526-4602
    DOI 10.1021/acs.biomac.1c01462
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Baseline mapping of Oropouche virology, epidemiology, therapeutics, and vaccine research and development.

    Files, Megan A / Hansen, Clairissa A / Herrera, Vanessa C / Schindewolf, Craig / Barrett, Alan D T / Beasley, David W C / Bourne, Nigel / Milligan, Gregg N

    NPJ vaccines

    2022  Band 7, Heft 1, Seite(n) 38

    Abstract: Oropouche virus (OROV) is an arthropod-borne orthobunyavirus found in South America and causes Oropouche fever, a febrile infection similar to dengue. It is the second most prevalent arthropod-borne viral disease in South America after dengue. Over 500, ... ...

    Abstract Oropouche virus (OROV) is an arthropod-borne orthobunyavirus found in South America and causes Oropouche fever, a febrile infection similar to dengue. It is the second most prevalent arthropod-borne viral disease in South America after dengue. Over 500,000 cases have been diagnosed since the virus was first discovered in 1955; however, this is likely a significant underestimate given the limited availability of diagnostics. No fatalities have been reported to date, however, up to 60% of cases have a recurrent phase of disease within one month of recovery from the primary disease course. The main arthropod vector is the biting midge Culicoides paraensis, which has a geographic range as far north as the United States and demonstrates the potential for OROV to geographically expand. The transmission cycle is incompletely understood and vertebrate hosts include both non-human primates and birds further supporting the potential ability of the virus to spread. A number of candidate antivirals have been evaluated against OROV in vitro but none showed antiviral activity. Surprisingly, there is only one report in the literature on candidate vaccines. We suggest that OROV is an undervalued pathogen much like chikungunya, Schmallenberg, and Zika viruses were before they emerged. Overall, OROV is an important emerging disease that has been under-investigated and has the potential to cause large epidemics in the future. Further research, in particular candidate vaccines, is needed for this important pathogen.
    Sprache Englisch
    Erscheinungsdatum 2022-03-17
    Erscheinungsland England
    Dokumenttyp Journal Article ; Review
    ISSN 2059-0105
    ISSN (online) 2059-0105
    DOI 10.1038/s41541-022-00456-2
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Self-adjuvanting nanovaccines boost lung-resident CD4

    Files, Megan A / Naqvi, Kubra F / Saito, Tais B / Clover, Tara M / Rudra, Jai S / Endsley, Janice J

    NPJ vaccines

    2022  Band 7, Heft 1, Seite(n) 48

    Abstract: Heterologous vaccine regimens could extend waning protection in the global population immunized with Mycobacterium bovis Bacille Calmette-Guerin (BCG). We demonstrate that pulmonary delivery of peptide nanofibers (PNFs) bearing an Ag85B ... ...

    Abstract Heterologous vaccine regimens could extend waning protection in the global population immunized with Mycobacterium bovis Bacille Calmette-Guerin (BCG). We demonstrate that pulmonary delivery of peptide nanofibers (PNFs) bearing an Ag85B CD4
    Sprache Englisch
    Erscheinungsdatum 2022-04-26
    Erscheinungsland England
    Dokumenttyp Journal Article
    ISSN 2059-0105
    ISSN (online) 2059-0105
    DOI 10.1038/s41541-022-00466-0
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel: Coiled Coil Crosslinked Alginate Hydrogels Dampen Macrophage-Driven Inflammation

    Clapacs, Zain / ONeill, Conor L. / Shrimali, Paresh / Lokhande, Giriraj / Files, Megan / Kim, Darren D. / Gaharwar, Akhilesh K. / Rudra, Jai S.

    Biomacromolecules. 2022 Feb. 16, v. 23, no. 3

    2022  

    Abstract: Alginate hydrogels are widely used for tissue engineering and regenerative medicine due to their excellent biocompatibility. A facile and commonly used strategy to crosslink alginate is the addition of Ca²⁺ that leads to hydrogelation. However, ... ...

    Abstract Alginate hydrogels are widely used for tissue engineering and regenerative medicine due to their excellent biocompatibility. A facile and commonly used strategy to crosslink alginate is the addition of Ca²⁺ that leads to hydrogelation. However, extracellular Ca²⁺ is a secondary messenger in activating inflammasome pathways following physical injury or pathogenic insult, which carries the risk of persistent inflammation and scaffold rejection. Here, we present graft copolymers of charge complementary heterodimeric coiled coil (CC) peptides and alginate that undergo supramolecular self-assembly to form Ca²⁺ free alginate hydrogels. The formation of heterodimeric CCs was confirmed using circular dichroism spectroscopy, and scanning electron microscopy revealed a significant difference in crosslink density and homogeneity between Ca²⁺ and CC crosslinked gels. The resulting hydrogels were self-supporting and display shear-thinning and shear-recovery properties. In response to lipopolysaccharide (LPS) stimulation, peritoneal macrophages and bone marrow-derived dendritic cells cultured in the CC crosslinked gels exhibited a 10-fold reduction in secretion of the proinflammatory cytokine IL-1β compared to Ca²⁺ crosslinked gels. A similar response was also observed in vivo upon peritoneal delivery of Ca²⁺ or CC crosslinked gels. Analysis of peritoneal lavage showed that macrophages in mice injected with Ca²⁺ crosslinked gels display a more inflammatory phenotype compared to macrophages from mice injected with CC crosslinked gels. These results suggest that CC peptides by virtue of their tunable sequence–structure–function relationship and mild gelation conditions are promising alternative crosslinkers for alginate and other biopolymer scaffolds used in tissue engineering.
    Schlagwörter alginates ; biocompatibility ; biopolymers ; calcium ; circular dichroism spectroscopy ; composite polymers ; crosslinking ; gelation ; hydrogels ; inflammasomes ; inflammation ; lipopolysaccharides ; macrophages ; medicine ; phenotype ; risk ; second messengers ; secretion
    Sprache Englisch
    Erscheinungsverlauf 2022-0216
    Umfang p. 1183-1194.
    Erscheinungsort American Chemical Society
    Dokumenttyp Artikel
    ISSN 1526-4602
    DOI 10.1021/acs.biomac.1c01462
    Datenquelle NAL Katalog (AGRICOLA)

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  7. Artikel ; Online: A class of hydrazones are active against non-replicating Mycobacterium tuberculosis.

    Bonnett, Shilah A / Dennison, Devon / Files, Megan / Bajpai, Anumita / Parish, Tanya

    PloS one

    2018  Band 13, Heft 10, Seite(n) e0198059

    Abstract: There is an urgent need for the development of shorter, simpler and more tolerable drugs to treat antibiotic tolerant populations of Mycobacterium tuberculosis. We previously identified a series of hydrazones active against M. tuberculosis. We selected ... ...

    Abstract There is an urgent need for the development of shorter, simpler and more tolerable drugs to treat antibiotic tolerant populations of Mycobacterium tuberculosis. We previously identified a series of hydrazones active against M. tuberculosis. We selected five representative compounds for further analysis. All compounds were active against non-replicating M. tuberculosis, with two compounds demonstrating greater activity under hypoxic conditions than aerobic culture. Compounds had bactericidal activity with MBC/MIC of < 4 and demonstrated an inoculum-dependent effect against aerobically replicating bacteria. Bacterial kill kinetics demonstrated a faster rate of kill against non-replicating bacilli generated by nutrient starvation. Compounds had limited activity against other bacterial species. In conclusion, we have demonstrated that hydrazones have some attractive properties in terms of their anti-tubercular activity.
    Mesh-Begriff(e) Antitubercular Agents/chemistry ; Antitubercular Agents/pharmacology ; Humans ; Hydrazones/chemistry ; Hydrazones/pharmacology ; Microbial Sensitivity Tests ; Microbial Viability/drug effects ; Mycobacterium tuberculosis/cytology ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/metabolism ; Oxygen/metabolism ; Tuberculosis/drug therapy ; Tuberculosis/microbiology
    Chemische Substanzen Antitubercular Agents ; Hydrazones ; Oxygen (S88TT14065)
    Sprache Englisch
    Erscheinungsdatum 2018-10-17
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0198059
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel ; Online: Novel chemical entities inhibiting Mycobacterium tuberculosis growth identified by phenotypic high-throughput screening.

    Kumar, Anuradha / Chettiar, Somsundaram / Brown, Brian S / Early, Julie / Ollinger, Juliane / Files, Megan / Bailey, Mai A / Korkegian, Aaron / Dennison, Devon / McNeil, Matthew / Metz, James / Osuma, Augustine / Curtin, Michael / Kunzer, Aaron / Freiberg, Gail / Bruncko, Milan / Kempf, Dale / Parish, Tanya

    Scientific reports

    2022  Band 12, Heft 1, Seite(n) 14879

    Abstract: We performed a high-throughput phenotypic whole cell screen of Mycobacterium tuberculosis against a diverse chemical library of approximately 100,000 compounds from the AbbVie corporate collection and identified 24 chemotypes with anti-tubercular ... ...

    Abstract We performed a high-throughput phenotypic whole cell screen of Mycobacterium tuberculosis against a diverse chemical library of approximately 100,000 compounds from the AbbVie corporate collection and identified 24 chemotypes with anti-tubercular activity. We selected two series for further exploration and conducted structure-activity relationship studies with new analogs for the 4-phenyl piperidines (4PP) and phenylcyclobutane carboxamides (PCB). Strains with mutations in MmpL3 demonstrated resistance to both compound series. We isolated resistant mutants for the two series and found mutations in MmpL3. These data suggest that MmpL3 is the target, or mechanism of resistance for both series.
    Mesh-Begriff(e) Antitubercular Agents/chemistry ; Antitubercular Agents/pharmacology ; Bacterial Proteins/metabolism ; High-Throughput Screening Assays ; Membrane Transport Proteins/genetics ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis/metabolism
    Chemische Substanzen Antitubercular Agents ; Bacterial Proteins ; Membrane Transport Proteins
    Sprache Englisch
    Erscheinungsdatum 2022-09-01
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-19192-7
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  9. Artikel ; Online: Dual activity of niclosamide to suppress replication of integrated HIV-1 and Mycobacterium tuberculosis (Beijing).

    Fan, XiuZhen / Xu, Jimin / Files, Megan / Cirillo, Jeffrey D / Endsley, Janice J / Zhou, Jia / Endsley, Mark A

    Tuberculosis (Edinburgh, Scotland)

    2019  Band 116S, Seite(n) S28–S33

    Abstract: The human immunodeficiency virus (HIV) pandemic is driving the re-emergence of tuberculosis (TB) as a global health threat, both by increasing the susceptibility of HIV-infected people to infection with Mycobacterium tuberculosis (Mtb), and increasing ... ...

    Abstract The human immunodeficiency virus (HIV) pandemic is driving the re-emergence of tuberculosis (TB) as a global health threat, both by increasing the susceptibility of HIV-infected people to infection with Mycobacterium tuberculosis (Mtb), and increasing the rate of emergence of drug-resistant Mtb. There are several other clinical challenges for treatment of co-infected patients including: expense, pill burden, toxicity, and malabsorption that further necessitate the search for new drugs that may be effective against both pathogens simultaneously. The anti-helminthic niclosamide has been shown to have activity against a laboratory strain of Mtb in liquid culture while bacteriostatic activity against non-replicating M. abscessus was also recently described. Here we extend these findings to further demonstrate that niclosamide inhibits mycobacterial growth in infected human macrophages and mediates potent bacteriostatic activity against the virulent Mtb Beijing strain. Importantly, we provide the first evidence that niclosamide inhibits HIV replication in human macrophages and Jurkat T cells through post-integration effects on pro-virus transcription. The dual antiviral and anti-mycobacterial activity was further observed in an in vitro model of HIV and Mtb co-infection using human primary monocyte-derived macrophages. These results support further investigation of niclosamide and derivatives as anti-retroviral/anti-mycobacterial agents that may reduce clinical challenges associated with multi-drug regimens and drug resistance.
    Mesh-Begriff(e) Humans ; Anti-HIV Agents/pharmacology ; Antitubercular Agents/pharmacology ; Coinfection ; HIV-1/drug effects ; HIV-1/growth & development ; Jurkat Cells ; Macrophages/drug effects ; Macrophages/microbiology ; Macrophages/virology ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/growth & development ; Mycobacterium tuberculosis/pathogenicity ; Niclosamide/pharmacology ; T-Lymphocytes/drug effects ; T-Lymphocytes/virology ; Virulence ; Virus Replication/drug effects ; Tuberculosis
    Chemische Substanzen Anti-HIV Agents ; Antitubercular Agents ; Niclosamide (8KK8CQ2K8G)
    Schlagwörter covid19
    Sprache Englisch
    Erscheinungsdatum 2019-04-25
    Erscheinungsland Scotland
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2046804-0
    ISSN 1873-281X ; 1472-9792
    ISSN (online) 1873-281X
    ISSN 1472-9792
    DOI 10.1016/j.tube.2019.04.008
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  10. Artikel ; Online: T-SPOT.TB Reactivity in Southern African Children With and Without in Utero Human Immunodeficiency Virus Exposure.

    Iwase, Saori C / Edlefsen, Paul T / Bhebhe, Lynnette / Motsumi, Kesego / Moyo, Sikhulile / Happel, Anna-Ursula / Shao, Danica / Mmasa, Nicholas / Schenkel, Sara / Gasper, Melanie A / Dubois, Melanie / Files, Megan A / Seshadri, Chetan / Duffy, Fergal / Aitchison, John / Netea, Mihai G / Jao, Jennifer / Cameron, Donald W / Gray, Clive M /
    Jaspan, Heather B / Powis, Kathleen M

    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

    2023  Band 77, Heft 8, Seite(n) 1133–1136

    Abstract: Infants who are human immunodeficiency virus (HIV)-exposed uninfected (iHEU) experience higher risk of infectious morbidity than infants HIV-unexposed uninfected (iHUU). We compared tuberculosis (TB) infection prevalence in 418 Bacillus Calmette-Guérin ... ...

    Abstract Infants who are human immunodeficiency virus (HIV)-exposed uninfected (iHEU) experience higher risk of infectious morbidity than infants HIV-unexposed uninfected (iHUU). We compared tuberculosis (TB) infection prevalence in 418 Bacillus Calmette-Guérin vaccinated sub-Saharan African iHEU and iHUU aged 9-18 months using T-SPOT.TB. Prevalence of TB infection was low and did not differ by HIV exposure status.
    Mesh-Begriff(e) Infant ; Humans ; Child ; HIV ; HIV Infections/epidemiology ; Tuberculosis/prevention & control ; Latent Tuberculosis ; Prevalence
    Sprache Englisch
    Erscheinungsdatum 2023-06-07
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 1099781-7
    ISSN 1537-6591 ; 1058-4838
    ISSN (online) 1537-6591
    ISSN 1058-4838
    DOI 10.1093/cid/ciad356
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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