Publications by authors named "Lanette Christensen"

5 Publications

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MEF2D sustains activation of effector Foxp3+ Tregs during transplant survival and anticancer immunity.

J Clin Invest 2020 12;130(12):6242-6260

Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

The transcription factor MEF2D is important in the regulation of differentiation and adaptive responses in many cell types. We found that among T cells, MEF2D gained new functions in Foxp3+ T regulatory (Treg) cells due to its interactions with the transcription factor Foxp3 and its release from canonical partners, like histone/protein deacetylases. Though not necessary for the generation and maintenance of Tregs, MEF2D was required for the expression of IL-10, CTLA4, and Icos, and for the acquisition of an effector Treg phenotype. At these loci, MEF2D acted both synergistically and additively to Foxp3, and downstream of Blimp1. Mice with the conditional deletion in Tregs of the gene encoding MEF2D were unable to maintain long-term allograft survival despite costimulation blockade, had enhanced antitumor immunity in syngeneic models, but displayed only minor evidence of autoimmunity when maintained under normal conditions. The role played by MEF2D in sustaining effector Foxp3+ Treg functions without abrogating their basal actions suggests its suitability for drug discovery efforts in cancer therapy.
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http://dx.doi.org/10.1172/JCI135486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685736PMC
December 2020

Legionnaires' Disease Mortality in Guinea Pigs Involves the p45 Mobile Genomic Element.

J Infect Dis 2019 10;220(10):1700-1710

Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University Health Science Center, Bryan.

Background: Legionella can cause Legionnaires' disease, a potentially fatal form of pneumonia that occurs as sporadic epidemics. Not all strains display the same propensity to cause disease in humans. Because Legionella pneumophila serogroup 1 is responsible for >85% of infections, the majority of studies have examined this serogroup, but there are 3 commonly used laboratory strains: L pneumophila serogroup 1 Philadelphia (Phil-1)-derived strains JR32 and Lp01 and 130b-derived strain AA100.

Methods: We evaluated the ability of Phil-1, JR32, Lp01, and AA100 to cause disease in guinea pigs.

Results: We found that, although Phil-1, JR32, and AA100 cause an acute pneumonia and death by 4 days postinfection (100%), strain Lp01 does not cause mortality (0%). We also noted that Lp01 lacks a mobile element, designated p45, whose presence correlates with virulence. Transfer of p45 into Lp01 results in recovery of the ability of this strain to cause mortality, leads to more pronounced disease, and correlates with increased interferon-γ levels in the lungs and spleens before death.

Conclusions: These observations suggest a mechanism of Legionnaires' disease pathogenesis due to the presence of type IVA secretion systems that cause higher mortality due to overinduction of a proinflammatory response in the host.
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http://dx.doi.org/10.1093/infdis/jiz340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6782102PMC
October 2019

Legionella pneumophila p45 element influences host cell entry and sensitivity to sodium.

PLoS One 2019 27;14(6):e0218941. Epub 2019 Jun 27.

Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas, United States of America.

Legionella pneumophila are environmental bacteria found ubiquitously in both natural and man-made water reservoirs, sometimes as constituents of biofilm communities, but mostly intracellularly within protozoal hosts. In the event that Legionella become aerosolized in water droplets and inhaled by humans, they can cause a potentially fatal form of pneumonia called Legionnaires' disease. Strains of L. pneumophila have highly plastic genomes that harbor numerous inter- and intra-genomic elements, enhancing their ability to live under diverse environmental conditions. One such mobile genomic element, p45 carries ~45 kbp of genes, including the Lvh (Legionella Vir homolog) type IVa secretion system. This element was evaluated for its contribution to L. pneumophila environmental resilience and virulence-related characteristics by comparing clinically isolated strain Philadelphia-1 that carries p45, Lp01 that lacks p45, and Lp01 with p45 reintroduced, Lp01+p45. We found that the p45 element impacts host cell entry and resistance to sodium, both virulence-related characteristics in Legionella species.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218941PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597080PMC
February 2020

Regulation of virulence gene expression resulting from Streptococcus pneumoniae and nontypeable Haemophilus influenzae interactions in chronic disease.

PLoS One 2011 5;6(12):e28523. Epub 2011 Dec 5.

Department of Biological Sciences, Northern Arizona University, Flagstaff, Arizona, United States of America.

Chronic rhinosinusitis (CRS) is a common inflammatory disease of the sinonasal cavity mediated, in part, by polymicrobial communities of bacteria. Recent molecular studies have confirmed the importance of Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi) in CRS. Here, we hypothesize that interaction between S. pneumoniae and NTHi mixed-species communities cause a change in bacterial virulence gene expression. We examined CRS as a model human disease to validate these polymicrobial interactions. Clinical strains of S. pneumoniae and NTHi were grown in mono- and co-culture in a standard biofilm assay. Reverse transcriptase real-time PCR (RTqPCR) was used to measure gene expression of key virulence factors. To validate these results, we investigated the presence of the bacterial RNA transcripts in excised human tissue from patients with CRS. Consequences of physical or chemical interactions between microbes were also investigated. Transcription of NTHi type IV pili was only expressed in co-culture in vitro, and expression could be detected ex vivo in diseased tissue. S. pneumoniae pyruvate oxidase was up-regulated in co-culture, while pneumolysin and pneumococcal adherence factor A were down-regulated. These results were confirmed in excised human CRS tissue. Gene expression was differentially regulated by physical contact and secreted factors. Overall, these data suggest that interactions between H. influenzae and S. pneumoniae involve physical and chemical mechanisms that influence virulence gene expression of mixed-species biofilm communities present in chronically diseased human tissue. These results extend previous studies of population-level virulence and provide novel insight into the importance of S. pneumoniae and NTHi in CRS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028523PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3230614PMC
July 2012

In vitro antimicrobial studies of silver carbene complexes: activity of free and nanoparticle carbene formulations against clinical isolates of pathogenic bacteria.

J Antimicrob Chemother 2012 Jan 3;67(1):138-48. Epub 2011 Oct 3.

Department of Biological Sciences, Northern Arizona University, PO Box 5640, Building 21, Flagstaff, AZ 86011, USA.

Objectives: Silver carbenes may represent novel, broad-spectrum antimicrobial agents that have low toxicity while providing varying chemistry for targeted applications. Here, the bactericidal activity of four silver carbene complexes (SCCs) with different formulations, including nanoparticles (NPs) and micelles, was tested against a panel of clinical strains of bacteria and fungi that are the causative agents of many skin and soft tissue, respiratory, wound, blood, and nosocomial infections.

Methods: MIC, MBC and multidose experiments were conducted against a broad range of bacteria and fungi. Time-release and cytotoxicity studies of the compounds were also carried out. Free SCCs and SCC NPs were tested against a panel of medically important pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Acinetobacter baumannii (MRAB), Pseudomonas aeruginosa, Burkholderia cepacia and Klebsiella pneumoniae.

Results: All four SCCs demonstrated strong efficacy in concentration ranges of 0.5-90 mg/L. Clinical bacterial isolates with high inherent resistance to purified compounds were more effectively treated either with an NP formulation of these compounds or by repeated dosing. Overall, the compounds were active against highly resistant bacterial strains, such as MRSA and MRAB, and were active against the biodefence pathogens Bacillus anthracis and Yersinia pestis. All of the medically important bacterial strains tested play a role in many different infectious diseases.

Conclusions: The four SCCs described here, including their development as NP therapies, show great promise for treating a wide variety of bacterial and fungal pathogens that are not easily killed by routine antimicrobial agents.
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http://dx.doi.org/10.1093/jac/dkr408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236053PMC
January 2012