Pneumocystis pneumonia (PCP) remains a major cause of morbidity and mortality within immunocompromised patients. In this study, we examined the potential role of macrophage-inducible C-type lectin (Mincle) for host defense against... more
Pneumocystis pneumonia (PCP) remains a major cause of morbidity and mortality within immunocompromised patients. In this study, we examined the potential role of macrophage-inducible C-type lectin (Mincle) for host defense against Pneumocystis Binding assays implementing soluble Mincle carbohydrate recognition domain fusion proteins demonstrated binding to intact Pneumocystis carinii as well as to organism homogenates, and they purified major surface glycoprotein/glycoprotein A derived from the organism. Additional experiments showed that rats with PCP expressed increased Mincle mRNA levels. Mouse macrophages overexpressing Mincle displayed increased binding to P. carinii life forms and enhanced protein tyrosine phosphorylation. The binding of P. carinii to Mincle resulted in activation of FcRγ-mediated cell signaling. RNA silencing of Mincle in mouse macrophages resulted in decreased activation of Syk kinase after P. carinii challenge, critical in downstream inflammatory signaling....
Research Interests:
Research Interests:
Since its initial misidentification as a trypanosome some 100 years ago, Pneumocystis has remained recalcitrant to study. Although we have learned much, we still do not have definitive answers to such basic questions as, where is the... more
Since its initial misidentification as a trypanosome some 100 years ago, Pneumocystis has remained recalcitrant to study. Although we have learned much, we still do not have definitive answers to such basic questions as, where is the reservoir of infection, how does Pneumocystis reproduce, what is the mechanism of infection, and are there true species of Pneumocystis? The goal of this review is to provide the reader the most up to date information available about the biology of Pneumocystis and the disease it produces.
Research Interests:
Research Interests:
Research Interests:
ABSTRACT Phosphorylated ERK2 has an increased capacity to form homodimers relative to unphosphorylated ERK2. We have characterized the nature of the ERK2 dimer and have mutated residues in the crystal dimer interface to examine the impact... more
ABSTRACT Phosphorylated ERK2 has an increased capacity to form homodimers relative to unphosphorylated ERK2. We have characterized the nature of the ERK2 dimer and have mutated residues in the crystal dimer interface to examine the impact of dimerization on ERK2 activity. Analysis of the mutants by gel filtration indicates that at least five residues must be mutated simultaneously to produce an ERK2 mutant that is predominantly monomeric. Mutants, whether monomers or dimers, have specific protein kinase activities under fixed assay conditions that are roughly equivalent to wild-type ERK2. The ratio of dimers to monomers is increased as the salt concentration increases, consistent with a strong hydrophobic contribution to the energy of dimer formation. ERK2 dimerization also requires divalent cations. Sedimentation analysis indicates that the related c-Jun N-terminal kinase SAPKalphaI/JNK2 also forms dimers, but dimerization displays no dependence on phosphorylation; the unphosphorylated and phosphorylated forms of the kinase behave similarly, with low micromolar dimer dissociation constants.
Research Interests:
Research Interests:
Research Interests: Algorithms, Sleep Medicine, Public Health, Medicine, Humans, and 15 moreObstructive sleep apnea, Clarity, Fluconazole, Patient Compliance, Phenotype, Executive Summary, Intensive Care Medicine, Multidisciplinary Approach, Medicine and Health Sciences, Beryllium, Leak, Cryptococcosis, Continuous Positive Airway Pressure, Medical and Health Sciences, and Apnea hypopnea index
Research Interests:
Pirfenidone recently received FDA approval as one of the first two drugs designed to treat idiopathic pulmonary fibrosis. While the clinical data continues to support the efficacy of pirfenidone, the specific molecular mechanism of action... more
Pirfenidone recently received FDA approval as one of the first two drugs designed to treat idiopathic pulmonary fibrosis. While the clinical data continues to support the efficacy of pirfenidone, the specific molecular mechanism of action of this drug has not been fully defined. From a chemical perspective the comparatively simple and lipophilic structure of pirfenidone combined with its administration at high doses, both experimentally and clinically, complicates some of the basic tenants of drug action and drug design. Our objective here was to identify a commercially available structural mimic of pirfenidone which retains key aspects of its physical chemical properties but does not display any of its antifibrotic effects. We tested these molecules using lung fibroblasts derived from patients with idiopathic pulmonary fibrosis and found phenylpyrrolidine based analogs of pirfenidone that were non-toxic and lacked antifibrotic activity even when applied at millimolar concentrations...
Research Interests:
Rationale: Diagnosis of latent TB infection (LTBI) remains challenging. The combination of QuantiFERON-TB Gold In-Tube (QFT) and flow cytometric (FC) detection of T-cell co-expression of CD25 (IL-2α receptor) and CD134 (OX40) after ex... more
Rationale: Diagnosis of latent TB infection (LTBI) remains challenging. The combination of QuantiFERON-TB Gold In-Tube (QFT) and flow cytometric (FC) detection of T-cell co-expression of CD25 (IL-2α receptor) and CD134 (OX40) after ex vivo TB-antigen specific challenge can visualize distinct immune subsets between unexposed subjects, untreated LTBI patients, and treated LTBI patients, which correlates with distinct TB reactivation risk predictions. We hypothesize that this strategy would identify patients with prior incomplete LTBI therapy and predict risk of TB reactivation. Objective: To apply this combinatorial dual-immunoassay analysis to subjects who were excluded from the original study, and to compare predicted cumulative risk of TB reactivation. Methods: QFT was combined with a FC assay that detects T-cell CD25 + CD134 + co-expression after TB-antigen stimulations in peripheral blood mononuclear cells. Analysis was based on previously determined technical cut-offs, and 95% bivariate normal density ellipse prediction. A modified “Online TST/IGRA interpreter” predictive formula was used. Results: We studied 74 subjects. Three out of 8 patients with history of previously incomplete LTBI therapy were identified with a combination of QFT(+) and FC assay(+) for CD4 + T-cells. Subjects with this immunoreactivity profile had the highest risk of TB reactivation (3.62± 2.60%). Conclusion: These findings further support that the strategy of combinatorial multi-immunoassay analysis is capable of generating subset profiles that can distinguish infection and treatment status, and probably confer distinctive risk of TB reactivation potential.
Research Interests:
Research Interests:
Research Interests:
Pulmonary emphysema is a common comorbidity in lung cancer, but its role in tumor prognosis remains obscure. Our aim was to evaluate the impact of the regional emphysema score (RES) on patient's overall survival, quality of life... more
Pulmonary emphysema is a common comorbidity in lung cancer, but its role in tumor prognosis remains obscure. Our aim was to evaluate the impact of the regional emphysema score (RES) on patient's overall survival, quality of life (QOL), and pulmonary function recovery in stage I-II lung cancer. Between 1997 and 2009, 1,073 patients were identified and divided into two surgical groups (cancer in emphysematous [group 1, n=565] and non-emphysematous [group 2, n=435] region) and one non-surgical group (group 3, n=73). RES was derived from the emphysematous region and categorized into mild (≤5%), moderate (6-24%) and severe (25-60%). In group 1, patients with moderate and severe RES experienced slight decreases in postoperative FEV1, but increases in FEV1/FVC, compared to those with mild RES (p<0.01); however, this correlation was not observed in group 2. Post-treatment QOL was lower in patients with greater RES in all groups mainly due to dyspnea (p<0.05). Cox-regression analys...
Research Interests: Quality of life, Medicine, Comorbidity, Lung Cancer, Humans, and 15 moreInternal Medicine, Female, Male, Dyspnea, Clinical Sciences, Aged, Middle Aged, Proportional hazards model, Predictive value of tests, Postoperative Period, Pulmonary function testing, Neoplasm staging, Cardiovascular medicine and haematology, lung neoplasms, and Pneumonectomy
We explored differential polarization of macrophages during infection using a rat model of Pneumocystis pneumonia. We observed enhanced pulmonary M1 macrophage polarization in immunosuppressed (IS) hosts, but an M2 predominant response in... more
We explored differential polarization of macrophages during infection using a rat model of Pneumocystis pneumonia. We observed enhanced pulmonary M1 macrophage polarization in immunosuppressed (IS) hosts, but an M2 predominant response in immunocompetent (IC) hosts following Pneumocystis carinii challenge. Increased inflammation and inducible nitric oxide synthase (iNOS) levels characterized the M1 response. However, macrophage ability to produce nitric oxide was defective. In contrast, the lungs of IC animals revealed a prominent M2 gene signature, and these macrophages effectively elicited an oxidative burst associated with clearance of Pneumocystis . In addition, during P. carinii infection the expression of Dectin-1, a critical receptor for recognition and clearance of P. carinii , was upregulated in macrophages of IC animals but suppressed in IS animals. In the absence of an appropriate cytokine milieu for M2 differentiation, Pneumocystis induced an M1 response both in vitro an...
Research Interests:
A 19-year-old male with a history of idiopathic panuveitis, currently taking methotrexate and infliximab, presented to our institution with 6 weeks of cough, dyspnoea and fevers. He had failed outpatient antimicrobial therapy.... more
A 19-year-old male with a history of idiopathic panuveitis, currently taking methotrexate and infliximab, presented to our institution with 6 weeks of cough, dyspnoea and fevers. He had failed outpatient antimicrobial therapy. Computerised tomography (CT) of the chest revealed the presence of a lobar pneumonia and he was treated with broad spectrum antibiotics, which did not improve his symptoms. Bronchoalveolar lavage was performed with a transbronchial lung biopsy because of the diagnostic uncertainty of the patient's presentation. Pathology revealed non-budding yeasts, consistent with Pneumocystis Serological and urine studies were positive for both Histoplasma and Blastomyces The diagnosis of Histoplasma pneumonia was made because of the presentation being inconsistent with Pneumocystis pneumonia, and serology, urine and pathology testing being more consistent with Histoplasma The patient was treated with oral itraconazole and was doing well at follow-up 12 weeks after hospi...
Research Interests:
Use of immunosuppressants and inflammatory bowel disease (IBD) may increase the risk of pneumonia caused by Pneumocystis jirovecii (PJP). We assessed the risk of PJP in a population-based cohort of patients with IBD treated with... more
Use of immunosuppressants and inflammatory bowel disease (IBD) may increase the risk of pneumonia caused by Pneumocystis jirovecii (PJP). We assessed the risk of PJP in a population-based cohort of patients with IBD treated with corticosteroids, immune-suppressive medications, and biologics. We performed a population-based cohort study of residents of Olmsted County, Minnesota, diagnosed with Crohn's disease (n=427) or ulcerative colitis (n=510) from 1970 through 2011. Records of patients were reviewed to identify all episodes of immunosuppressive therapies and concomitant PJP prophylaxis through February 2016. We reviewed charts to identify cases of PJP, cross-referenced with the Rochester Epidemiology Project database (using diagnostic codes for PJP) and the Mayo Clinic and Olmsted Medical Center databases. The primary outcome was risk of PJP and associated with use corticosteroids, immune-suppressive medications, and biologics by patients with IBD. Our analysis included 937 p...
Research Interests:
Introduction.Pneumocystispneumonia (PCP) is rising in the non-HIV population and associates with higher morbidity and mortality. The aggressive immunosuppressive regimens, as well as the lack of stablished guidelines for chemoprophylaxis,... more
Introduction.Pneumocystispneumonia (PCP) is rising in the non-HIV population and associates with higher morbidity and mortality. The aggressive immunosuppressive regimens, as well as the lack of stablished guidelines for chemoprophylaxis, are likely contributors to this increased incidence. Herein, we have explored the underlying conditions, immunosuppressive therapies, and clinical outcomes of PCP in HIV-negative patients.Methods. Retrospective analysis of PCP in HIV-negative patients at Mayo Clinic from 2006–2010. The underlying condition, immunosuppressive therapies, coinfection, and clinical course were determined. PCP diagnosis required symptoms of pneumonia and identification of the organisms by visualization or by a real-time polymerase chain reaction.Results. A total of 128 cases of PCP were identified during the study period. Hematological malignancies were the predisposing condition for 50% of the patients. While 87% had received corticosteroids or other immunosuppressive ...
Research Interests: Incidence Geometry, Medicine, Population, Humans, Female, and 14 morePneumonia, Male, Young Adult, Minnesota, Intensive Care Unit, Aged, Middle Aged, Anti-Bacterial Agents, Adult, Mechanical Ventilation, Retrospective Studies, Immunosuppressive Agents, Adrenal cortex hormones, and Pneumocystis pneumonia
Research Interests:
Research Interests:
An important precursor to lung cancer development is chronic obstructive pulmonary disease (COPD), independent of exposure to tobacco smoke. Both diseases are associated with increased host susceptibility, inflammation, and genomic... more
An important precursor to lung cancer development is chronic obstructive pulmonary disease (COPD), independent of exposure to tobacco smoke. Both diseases are associated with increased host susceptibility, inflammation, and genomic instability. However, validation of the candidate genes and functional confirmation to test shared genetic contribution and cellular mechanisms to the development of lung cancer in patients with COPD remains underexplored. Here, we show that loss of PARK2 (encoding Parkin) increases the expression of proinflammation factors as well as nuclear NF-κB localization, suggesting a role of PARK2 loss in inflammation. Additional exploration showed that PARK2 deficiency promotes genomic instability and cell transformation. This role of PARK2 in inflammation and chromosome instability provides a potential link among Parkin, COPD and lung cancer. A further comprehensive validation of 114 informative single nucleotide polymorphism (SNP) variants of PARK2, in 2,484 ca...
Research Interests:
Despite shared environmental exposures, IPF and COPD are usually studied in isolation and the presence of shared molecular mechanisms is unknown. We applied an integrative genomic approach to identify convergent transcriptomic pathways in... more
Despite shared environmental exposures, IPF and COPD are usually studied in isolation and the presence of shared molecular mechanisms is unknown. We applied an integrative genomic approach to identify convergent transcriptomic pathways in emphysema and idiopathic pulmonary fibrosis (IPF). We defined the transcriptional repertoire of COPD, IPF or normal histology lungs using RNA-seq (n=87). Genes increased in both emphysema and IPF relative to control were enriched for the p53/hypoxia pathway, a finding confirmed in an independent cohort using both gene expression arrays and the nCounter Analysis System (n=193). Immunohistochemistry confirmed over-expression of HIF1A, MDM2, and NFKBIB, members of this pathway in tissues from patients with emphysema or IPF. Using reads aligned across splice junctions, we determined that alternative splicing of p53/Hypoxia pathway associated molecules NUMB and PDGFA occurred more frequently in IPF or emphysema compared to control and validated these fi...
Research Interests:
Research Interests:
Effective treatments for idiopathic pulmonary fibrosis (IPF) are not yet available. Current concepts indicate that multi-agent synergistic drug regimens will be needed to control this lethal condition. The available animal models for lung... more
Effective treatments for idiopathic pulmonary fibrosis (IPF) are not yet available. Current concepts indicate that multi-agent synergistic drug regimens will be needed to control this lethal condition. The available animal models for lung fibrosis are laborious, variably reproducible, and do not faithfully represent the histopathologic features of IPF. To address this, we developed a new in vitro assay to screen potential drugs for synergistic activity against lung fibrosis. Our group was among the first to implicate transforming growth factor-b1 (TGF-b1) as a principal growth factor in mediating IPF. Additional data indicate roles for platelet-derived growth factor (PDGF) and tumor necrosis factor-a (TNF-a) in the fibrotic process. Accordingly, we cultured IMR90 human lung fibroblasts in the presence of cytokines, such as TGF-b1 (5 ng/ml). The generation of extracellular matrix fibronectin and collagen 1 was quantified by real-time PCR using the iCycler system (Bio-Rad, Hercules, CA), and confirmed with enzyme-linked immunosorbent assay. With this approach we undertook studies of oral agents with activity against cytokinedriven fibrosis. Addition of pentoxifylline (an anti–TNF-a agent) and pirfenidone (an agent with activity against TGF-b1 and PDGF), each individually significantly reduced collagen and fibronectin expression. However, together the combination yielded nearly complete suppression of cytokine-stimulated matrix expression. This synergistic regimen also displayed no abnormal toxicity on the cultured Institute for Medical Research (IMR) lung fibroblasts. Currently, we are testing another drug combination that includes the PPAR-g agonist, Rosiglitazone, along with pentoxifylline, and have shown similar synergistic effects to that of pirfenidone and pentoxifylline. Finally, for both drug combinations Western blotting with a-smooth muscle actin was conducted to determine if these two drug combinations prevented fibroblast to myofibroblast differentiation phenotype. Results from these experiments showed no effect on a-smooth muscle protein levels, suggesting that these drug combinations are acting downstream and independently of SMADs. In conclusion, we believe that this rapid screening approach will be useful to efficiently identify drug combinations with greater activity against fibrosis. Selected combinations can be subsequently tested in available animal models, and ultimately recommended for clinical trials in humans.
Research Interests:
While rheumatoid arthritis (RA) associated ILD (UIP pattern) is clinically very similar to idiopathic UIP (idiopathic pulmonary fibrosis or IPF), limited information exists regarding genomic signatures of RA-ILD compared with IPF. To... more
While rheumatoid arthritis (RA) associated ILD (UIP pattern) is clinically very similar to idiopathic UIP (idiopathic pulmonary fibrosis or IPF), limited information exists regarding genomic signatures of RA-ILD compared with IPF. To study this, we obtained frozen lung biopsy specimens from the National Institutes of Health Lung Tissue Research Consortium project, and extracted RNA from 20 control lung specimens, 20 IPF samples, and 5 RA-lung biopsies from patients with diffuse lung involvement. Samples were submitted for mRNA sequencing using the Illumina TruSeq mRNA approach for Next Generation Sequencing analysis. Samples were processed using the Mayo analysis pipeline, MAP-RSeq, and differentially expressed genes were obtained using edgeR. Expression for tumor necrosis factor (TNF), granulocyte macrophage colony stimulating factor (GM-CSF), interleukin-1 (IL-1), and interferon-gamma (IFNγ), RANTES, CCR5, CD40L, and interleukin-6 receptor (IL-6R) were upregulated in RA vs IPF tissues. Conversely, mRNA expression for matrix genes (collagen-1 and -3) and matrix metalloproteinases (MMP1, 2, 9, 13) were upregulated in IPF compared to RA lung specimens. These preliminary findings outline key differences in immune and tissue remodeling genes between RA-associated and idiopathic UIP, and provide insight into molecular mechanisms of fibrotic lung disease development in RA. Supported by a Rheumatology Research Foundation grant to RV.
Research Interests:
Pneumocystis carinii pneumonia has emerged as a significant cause of morbidity and mortality in immunocompromised patients with and without AIDS. To determine differences in P. carinii pneumonia in patients with and without AIDS, the P.... more
Pneumocystis carinii pneumonia has emerged as a significant cause of morbidity and mortality in immunocompromised patients with and without AIDS. To determine differences in P. carinii pneumonia in patients with and without AIDS, the P. carinii parasite numbers, lung inflammatory cell populations, gas exchange, and survival were assessed in a series of 75 consecutive patients with P. carinii pneumonia. Bronchoalveolar lavage was used to quantify the parasite and inflammatory cell numbers in these patients. The data from this study indicate: (1) patients with P. carinii pneumonia and AIDS have significantly greater numbers of P. carinii per ml of lavage compared to other immunocompromised patients with P. carinii pneumonia (p less than 0.0001); (2) patients with P. carinii pneumonia and AIDS also have significantly fewer neutrophils recovered in the lavage compared to other immunocompromised patients with P. carinii pneumonia (p = 0.0001); (3) patients with AIDS and P. carinii pneumonia have higher arterial oxygen tensions than those patients with P. carinii pneumonia in conditions other than AIDS (p = 0.008); and (4) increased lavage neutrophils (rather than parasite number) correlate with poorer oxygenation and poorer patient survival (p = 0.01). This investigation demonstrates substantial differences in lung inflammation and parasite number during P. carinii pneumonia in patients with and without AIDS. The data further suggest that lung inflammation contributes substantially to respiratory impairment in patients with P. carinii pneumonia.
Research Interests:
Research Interests:
B lymphocytes play an essential regulatory role in the adaptive immune response through Ab production during infection. A less known function of B lymphocytes is their ability to respond directly to infectious Ags through stimulation of... more
B lymphocytes play an essential regulatory role in the adaptive immune response through Ab production during infection. A less known function of B lymphocytes is their ability to respond directly to infectious Ags through stimulation of pattern recognition receptors expressed on their surfaces. β-Glucans are carbohydrates present in the cell wall of many pathogenic fungi that can be detected in the peripheral blood of patients during infection. They have been shown to participate in the innate inflammatory response, as they can directly activate peripheral macrophages and dendritic cells. However, their effect as direct stimulators of B lymphocytes has not been yet fully elucidated. The aim of this study was to examine the molecular mechanisms and cytokine profiles generated following β-glucan stimulation of B lymphocytes, compared with the well-established TLR-9 agonist CpG oligodeoxynucleotide (CpG), and study the participation of β-glucan-stimulated B cells in the innate immune r...
Research Interests: Immunology, Biology, Immunology of the Gut, Innate immunity, Medicine, and 15 moreToll like receptor signaling, Humans, NF-kappa B, T lymphocytes, Neutrophils, Immune system, Beta-Glucans, Tumor necrosis factor-alpha, B Lymphocytes, Cell Proliferation, Interleukin, Innate Immune System, TLR, immunoglobulin M, and Protein tyrosine kinases
Research, clinical care, and education are the three cornerstones of academic health centers in the United States. The research climate has always been riddled with ebbs and flows, depending on funding availability. During a time of... more
Research, clinical care, and education are the three cornerstones of academic health centers in the United States. The research climate has always been riddled with ebbs and flows, depending on funding availability. During a time of reduced funding, the number and scope of research studies have been reduced, and in some instances, a field of study has been eliminated. Recent reductions in the research funding landscape have led institutions to explore new ways to continue supporting research. Mayo Clinic in Rochester, MN has developed a clinical trials unit within the Department of Medicine, which provides shared resources for many researchers and serves as a solution for training and mentoring new investigators and study teams. By building on existing infrastructure and providing supplemental resources to existing research, the Department of Medicine Clinical Trials Unit has evolved into an effective mechanism for conducting research. This article discusses the creation of a centra...
Research Interests:
Research Interests:
Research Interests:
Research Interests:
The majority of immunocompetent patients diagnosed with latent tuberculosis infection (LTBI) will not progress to tuberculosis (TB) reactivation. However, current diagnostic tools cannot reliably distinguish non-progressing from... more
The majority of immunocompetent patients diagnosed with latent tuberculosis infection (LTBI) will not progress to tuberculosis (TB) reactivation. However, current diagnostic tools cannot reliably distinguish non-progressing from progressing patients a priori, and thus LTBI therapy must be prescribed with suboptimal patient specificity. Despite this limitation, treatment for LTBI confers a clinical state of low-risk of TB reactivation. We hypothesized that LTBI diagnostics could be improved by generating immunomarker profiles capable of categorizing distinct patient subsets by a combinatorial immunoassay approach. A combinatorial immunoassay analysis was applied to identify potential immunomarker combinations that distinguish among unexposed subjects, untreated LTBI, and treated LTBI patients, and differentiate risk of reactivation. Interferon-gamma release assay (IGRA) was combined with a flow cytometric assay that detects induction of CD25+CD134+ co-expression on TB-antigen-stimula...
Research Interests:
Page 1. / Poster C24 PNEUMOCYSTIS AND OTHER FUNGAL PNEUMONIAS: PATHOGENESIS AND CLINICAL CONSEQUENCES Discussion Session / Tuesday, May 17/8:15 AM-10:45 AM / Room 601 (Street Level), Colorado Convention Center ...
Research Interests:
Research Interests:
Page 1. / Thematic Poster Session / Sunday, May 15/8:15 AM-4:30 PM / Area F, Hall B (Upper Level), A69 LIPID-MEDIATED SIGNALING Colorado Convention Center Glycosphingolipids Modulate Tgf-Beta Fibrotic Signaling In Human Lung Fibroblasts ...
Research Interests:
Inflammation is a major cause of respiratory impairment during Pneumocystis pneumonia. Studies support a significant role for cell wall β-glucans in stimulating inflammatory responses. Fungal β-glucans are comprised of d -glucose... more
Inflammation is a major cause of respiratory impairment during Pneumocystis pneumonia. Studies support a significant role for cell wall β-glucans in stimulating inflammatory responses. Fungal β-glucans are comprised of d -glucose homopolymers containing β-1,3-linked glucose backbones with β-1,6-linked glucose side chains. Prior studies in Pneumocystis carinii have characterized β-1,3 glucan components of the organism. However, recent investigations in other organisms support important roles for β-1,6 glucans, predominantly in mediating host cellular activation. Accordingly, we sought to characterize β-1,6 glucans in the cell wall of Pneumocystis and to establish their activity in lung cell inflammation. Immune staining revealed specific β-1,6 localization in P. carinii cyst walls. Homology-based cloning facilitated characterization of a functional P. carinii kre6 ( Pckre6 ) β-1,6 glucan synthase in Pneumocystis that, when expressed in kre6 -deficient Saccharomyces cerevisiae , resto...
Research Interests:
Pneumocystis is an opportunistic fungal pathogen that causes an often-lethal pneumonia in immunocompromised hosts. Although the organism was discovered in the early 1900s, the first cases of Pneumocystis pneumonia in humans were initially... more
Pneumocystis is an opportunistic fungal pathogen that causes an often-lethal pneumonia in immunocompromised hosts. Although the organism was discovered in the early 1900s, the first cases of Pneumocystis pneumonia in humans were initially recognized in Central Europe after the Second World War in premature and malnourished infants. This unusual lung infection was known as plasma cellular interstitial pneumonitis of the newborn, and was characterized by severe respiratory distress and cyanosis with little or no fever and no pathognomic physical signs. At that time, only anecdotal cases were reported in adults and usually these patients had a baseline malignancy that led to a malnourished state. In the 1960-1970s additional cases were described in adults and children with hematological malignancies, but Pneumocystis pneumonia was still considered a rare disease. However, in the 1980s, with the onset of the HIV epidemic, Pneumocystis prevalence increased dramatically and became widely ...
Research Interests:
Nonspecific interstitial pneumonia (NSIP) has been identified as a distinct entity with a more favorable prognosis and better response to immunosuppressive therapies than usual interstitial pneumonia (UIP). However the inflammatory... more
Nonspecific interstitial pneumonia (NSIP) has been identified as a distinct entity with a more favorable prognosis and better response to immunosuppressive therapies than usual interstitial pneumonia (UIP). However the inflammatory profile of NSIP has not been characterized. Using immunohistochemistry techniques on open lung biopsy specimens, the infiltrate in NSIP was characterized in terms of T and B cells, and macrophages, and the T cell population further identified as either CD4 (helper) or CD8 (suppressor-cytotoxic) T cells. The extent of Th1 and Th2 cytokine producing cells was determined and compared to specimens from patients with UIP. In ten NSIP tissue samples 41.4 +/- 4% of mononuclear cells expressed CD3, 24.7 +/- 1.8% CD4, 19.1 +/- 2% CD8, 27.4 +/- 3.9% CD20, and 14.3 +/- 1.6% had CD68 expression. Mononuclear cells expressed INFgamma 21.9 +/- 1.9% of the time and IL-4 in 3.0 +/- 1%. In contrast, biopsies from eight patients with UIP demonstrated substantially less cell...
Research Interests:
Drug-induced lung disease frequently poses a diagnostic challenge. Knowledge of common radiological patterns of lung involvement and corresponding histopathologic diagnoses can facilitate management of individual patients. We outline a... more
Drug-induced lung disease frequently poses a diagnostic challenge. Knowledge of common radiological patterns of lung involvement and corresponding histopathologic diagnoses can facilitate management of individual patients. We outline a framework for understanding radiological and histologic patterns of drug-induced lung disease. Diffuse forms of drug-induced lung disease include processes that mimic acute respiratory distress syndrome (ARDS) and diffuse alveolar hemorrhage. These patterns of drug-induced lung disease are especially common in patients receiving cytotoxic chemotherapeutic agents. Chronic forms of drug-induced lung disease include many of the interstitial pneumonias seen more commonly in patients with idiopathic disease. Bronchiolitis obliterans organizing pneumonia and eosinophilic pneumonia are nonspecific patterns of drug-induced lung disease that are radiologically and histologically indistinguishable from their idiopathic counterparts. In some patients organizing ...
Research Interests:
Pneumocystis carinii causes severe pneumonia in immunocompromised hosts. Although this most commonly occurs in patients with the acquired immunodeficiency syndrome (AIDS), other groups of immunocompromised patients without AIDS are also... more
Pneumocystis carinii causes severe pneumonia in immunocompromised hosts. Although this most commonly occurs in patients with the acquired immunodeficiency syndrome (AIDS), other groups of immunocompromised patients without AIDS are also at risk for P. carinii pneumonia. These patients have solid or hematologic malignancies, organ transplantation, or inflammatory conditions requiring chronic immunosuppressive drugs, particularly corticosteroids. There are important differences in the clinical presentation of P. carinii pneumonia in patients with and without AIDS. P. carinii causes an acute fulminate pneumonia in patients without AIDS while patients with AIDS have more insidious involvement. The organism burden and lung inflammatory response are markedly different between these groups, contributing to substantial differences in clinical presentation, outcome, and mortality. The diagnosis of P. carinii pneumonia remains challenging for primary care physicians and specialists alike. The...
Research Interests:
Research Interests: Microbiology, Immunology, Biology, Inflammation, Medicine, and 15 moreMacrophage, Animals, Pneumonia, Steady state, Rats, Phagocytosis, Fibronectin, Tumor necrosis factor-alpha, Protein Binding, Pneumocystis, Alveolar Macrophage, Pneumocystis carinii pneumonia, Macrophage activation, In Vitro Techniques, and Pneumocystis carinii
Pneumocystis pneumonia remains the most prevalent opportunistic infection in patients with AIDS. It is also a common devastating infection in patients with other causes of altered immunity. Though scientific study of this fungal pathogen... more
Pneumocystis pneumonia remains the most prevalent opportunistic infection in patients with AIDS. It is also a common devastating infection in patients with other causes of altered immunity. Though scientific study of this fungal pathogen is challenging given the inability to propagate the organism outside of the host lung, studies utilizing advanced molecular techniques and genomic analysis have broadened our understanding of the epidemiology and pathogenesis of Pneumocystis and will be described herein. Results from advanced molecular techniques suggest that Pneumocystis organisms not only cause infection in patients with impaired immunity but also colonize mammals with normal immune systems. Advanced technology has also identified acquired Pneumocystis genetic mutations that confer resistance to currently utilized therapeutics. Though not yet widely utilized in clinical medicine, advanced polymerase chain reaction techniques improve the diagnostic yield of respiratory specimen ana...
Research Interests:
Intense lung inflammation characterizes respiratory failure associated with Pneumocystis pneumonia. Our laboratory has previously demonstrated that alveolar epithelial cells (AECs) elaborate inflammatory cytokines and chemokines in... more
Intense lung inflammation characterizes respiratory failure associated with Pneumocystis pneumonia. Our laboratory has previously demonstrated that alveolar epithelial cells (AECs) elaborate inflammatory cytokines and chemokines in response to the Pneumocystis carinii cell wall constituent β-(1→3)-glucan (PCBG), and that these responses require lactosylceramide, a prominent glycosphingolipid constituent of certain cell membrane microdomains. The relevance of membrane microdomains, also termed plasma membrane lipid rafts, in cell signaling and macromolecule handling has been increasingly recognized in many biologic systems, but their role in P. carinii-induced inflammation is unknown. To investigate the mechanisms of microdomain-dependent P. carinii-induced inflammation, we challenged primary rat AECs with PCBG with or without pre-incubation with inhibitors of microdomain function. Glycosphingolipid and cholesterol rich microdomain inhibition resulted in significant attenuation of P....
Research Interests:
Research Interests: Treatment Outcome, Risk assessment, Medicine, Critical Care, Clinical Practice, and 14 moreHumans, Female, Male, Antifungal, Clinical Sciences, Immunocompromised host, Prognosis, Chest, Antifungal Agents, Intensive Care Medicine, Risk Assessment, Disease Management, Critical Illness, and Opportunistic Infections
Research Interests:
Pneumocystis pneumonia (PcP) is a significant cause of morbidity and mortality in immunocompromised patients. In humans, PcP is caused by the opportunistic fungal species Pneumocystis jirovecii. Progress in Pneumocystis research has been... more
Pneumocystis pneumonia (PcP) is a significant cause of morbidity and mortality in immunocompromised patients. In humans, PcP is caused by the opportunistic fungal species Pneumocystis jirovecii. Progress in Pneumocystis research has been hampered by a lack of viable in vitro culture methods, which limits laboratory access to human-derived organisms for drug testing. Consequently, most basic drug discovery research for P. jirovecii is performed using related surrogate organisms such as Pneumocystis carinii, which is derived from immunosuppressed rodents. While these studies provide useful insights, important questions arise about interspecies variations and the relative utility of identified anti-Pneumocystis agents against human P. jirovecii. Our recent work has identified the histone acetyltransferase (HAT) Rtt109 in P. carinii (i.e., PcRtt109) as a potential therapeutic target for PcP, since Rtt109 HATs are widely conserved in fungi but are absent in humans. To further address the...