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PubMed | National Institute of Allergy and Infectious Diseases, Laboratory of Immunoregulation and Laboratory of Clinical Infectious Diseases
Type: Journal Article | Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | Year: 2016

Interferon-gamma (IFN) neutralizing autoantibodies are associated with disseminated nontuberculous mycobacterial infections. We report a previously healthy Thai woman with disseminated tuberculosis and high-titer IFN-neutralizing autoantibodies, who developed a severe inflammatory reaction during anti-tuberculosis treatment. IFN contributes to host control of tuberculosis but appears inessential for tuberculosis paradoxical reactions.


Greenberg D.E.,Laboratory of Clinical Infectious Diseases | Marshall-Batty K.R.,Laboratory of Clinical Infectious Diseases | Brinster L.R.,U.S. National Institutes of Health | Zarember K.A.,Laboratory of Host Defenses | And 5 more authors.
Journal of Infectious Diseases | Year: 2010

Background. Members of the Burkholderia cepacia complex (Bcc) cause considerable morbidity and mortality in patients with chronic granulomatous disease and cystic fibrosis. Many Bcc strains are antibiotic resistant, which requires the exploration of novel antimicrobial approaches, including antisense technologies such as phosphorodiamidate morpholino oligomers (PMOs). Methods. Peptide-conjugated PMOs (PPMOs) were developed to target acpP, which encodes an acyl carrier protein (AcpP) that is thought to be essential for growth. Their antimicrobial activities were tested against different strains of Bcc in vitro and in infection models. Results. PPMOs targeting acpP were bactericidal against clinical isolates of Bcc (>4 log reduction), whereas a PPMO with a scrambled base sequence (scrambled PPMO) had no effect on growth. Human neutrophils were infected with Burkholderia multivorans and treated with AcpP PPMO. AcpP PPMO augmented killing, compared with neutrophils alone and compared with neutrophils alone plus scrambled PPMO. Mice with chronic granulomatous disease that were infected with B. multivorans were treated with AcpP PPMO, scrambled PPMO, or water at 0, 3, and 6 h after infection. Compared with water-treated control mice, the AcpP PPMO-treated mice showed an ∼80% reduction in the risk of dying by day 30 of the experiment and relatively little pathology. Conclusion. AcpP PPMO is active against Bcc infections in vitro and in vivo. © 2010 by the Infectious Diseases Society ot America. All right reserved.


Cohen J.I.,Laboratory of Clinical Infectious Diseases | Hohman P.,Clinical Studies Unit | Fulton R.,Clinical Studies Unit | Turk S.-P.,Clinical Studies Unit | And 3 more authors.
Journal of Infectious Diseases | Year: 2010

Background. The smallpox vaccine is associated with more serious adverse events than any other live attenuated vaccine in use today. Although studies have examined serum cytokine levels in primary vaccine recipients at 1 and 3-5 weeks after vaccination with the smallpox vaccine, serial measurements have not been performed, and studies in revaccinated subjects have not been conducted. Methods. We analyzed cytokine responses in both primary vaccine recipients and revaccinated subjects every other day for 2 weeks after vaccination. Results. Primary vaccine recipients had maximal levels of granulocyte-colony-stimulating factor on days 6-7 after vaccination; peak levels of tumor necrosis factor (TNF)-α, soluble TNF receptor 1, interferon (IFN)-γ, IFNinducible protein-10 (IP-10), interleukin (IL)-6, and tissue inhibitor of metalloproteinases-1 on days 8-9 after vaccination; peak levels of soluble TNF receptor 2 and monokine induced by IFN-γ (MIG) on days 10-11 after vaccination; and peak levels of granulocyte-macrophage-colony-stimulating factor on days 12-13 after vaccination. Primary vaccine recipients were significantly more likely to have higher peak levels of IFN-γ], IP-10, and MIG after vaccination than were revaccinated subjects. Primary vaccine recipients were significantly more likely to have fatigue, lymphadenopathy, and headache, as well as a longer duration of these symptoms and more hours missed from work, compared with revaccinated subjects. Conclusions. The increased frequency and duration of symptoms observed in primary vaccine recipients, compared with revaccinated subjects, paralleled the increases in serum cytokine levels in these individuals. Trial registration. Clinicaltrials.gov identifier NCT00325975.


– On track to report Phase 2 topline data for MAT2203 in the first half of 2017 – BEDMINSTER, N.J., Nov. 21, 2016 (GLOBE NEWSWIRE) -- Matinas BioPharma Holdings, Inc. (OTCQB:MTNB), a clinical-stage biopharmaceutical company focused on identifying and developing safe and effective broad spectrum therapeutics for the treatment of serious and life-threatening infections, announced today that it has initiated enrollment and the first group of patients have been dosed in its Phase 2 clinical study of lead anti-infective product candidate MAT2203 in patients with vulvovaginal candidiasis (VVC). MAT2203 is Matinas BioPharma’s orally-administered, encochleated formulation of the broad spectrum fungicidal medication amphotericin B. The Company’s proprietary lipid-crystal nano-particle formulation of amphotericin B has a novel mechanism of absorption and distribution to infected tissues and has the potential to transform the way this potent fungicidal agent is administered and used in clinical practice. This Phase 2 study is a randomized, multicenter, evaluator-blinded study of oral MAT2203 compared to oral fluconazole in adult female patients. Approximately 75 patients with a diagnosis of moderate to severe VVC will be enrolled and randomized into three treatment cohorts of 25 patients each. The first cohort will receive treatment with 200 mg of oral MAT2203 while a second cohort will receive 400 mg of oral MAT2203. The third cohort will be treated with oral fluconazole. The study will assess the efficacy, safety and tolerability of MAT2203. “The start of patient dosing in our second Phase 2 study of MAT2203 is an important step forward in the advancement of the clinical development strategy for our proprietary cochleate formulation of amphotericin B,” said Roelof Rongen, Chief Executive Officer. “We anticipate that this study, along with the Phase 2 of MAT2203 study ongoing at the NIH in severely immunocompromised patients suffering from mucocutaneous candidiasis, will provide further clinical evidence of MAT2203’s activity against candida infections.  We believe this will place us in a favorable position to move into Phase 3 registration trials with an intended first indication of prophylaxis, or prevention, of invasive fungal infections in patients on immunosuppressive therapy.  We are excited to see MAT2203 progressing quickly into the clinic and look forward to reporting topline results from both of these studies in the first half of 2017,” added Mr. Rongen. Matinas is also currently evaluating MAT2203 in a Phase 2a open-label, dose-titration study being conducted at the National Institutes of Health Clinical Center in Bethesda, MD, under the direction of Principal Investigator Alexandra Freeman, M.D., of the National Institute of Allergy and Infectious Diseases (NIAID) Laboratory of Clinical Infectious Diseases for the treatment of mucocutaneous candidiasis. The study is designed to assess the efficacy, safety, tolerability and pharmacokinetics of MAT2203 in predominantly hereditary immunodeficient patients with a recurrent or chronic mucocutaneous candidiasis infection (esophageal, oropharyngeal, vaginal) who are refractory or intolerant to standard non-intravenous therapies. The U.S. Food and Drug Administration (FDA) has designated MAT2203 as a QIDP with Fast Track status for the treatment of invasive candidiasis, aspergillus and prophylaxis (prevention) of invasive fungal infections in patients on immunosuppressive therapy. MAT2203 is also being explored for treatment of additional infections, including cryptococcal meningoencephalitis, and is being developed to be eligible for Orphan Drug Designations in various indications. Vulvovaginal candidiasis (VVC), more commonly known as a “yeast infection” is usually caused by Candida albicans, the most common cause of fungal infections worldwide. An estimated 75% of women will have at least one episode of VVC during their lifetime and 40-45% will have two or more. Current treatments for VVC include topical antifungals and the use of prescription oral antifungals such as fluconazole.  According to the CDC, certain species of Candida are becoming increasingly resistant to existing antifungal medications. This emerging resistance intensifies the need for new antifungal agents. MAT2203 is an orally-administered, encochleated formulation of amphotericin B (a broad spectrum fungicidal agent). Little to no clinical resistance has been reported to date with amphotericin B as compared to the rapidly emerging drug resistance seen in other antifungal therapies. Currently, IV-only administered amphotericin B is the only broad spectrum fungicidal available but its IV-delivery results in significant treatment-limiting side effects, including nephrotoxicity. The ability to provide amphotericin B via MAT2203’s proprietary and novel oral formulation may offer a new and promising alternative for patients and doctors. In a clinical Phase 1a single-dose, double-blind, dose-escalating, pharmacokinetic study of 48 healthy volunteers, oral MAT2203 demonstrated a positive safety and tolerability profile with no serious adverse events reported, including little or no nephrotoxicity as compared to placebo. Enrollment is currently underway for the Phase 2a NIH/NIAID-funded clinical study with MAT2203 in patients with refractory mucocutaneous candidiasis. The FDA has designated MAT2203 as a Qualified Infectious Disease Product for the treatment of invasive candidiasis, aspergillosis and prevention of invasive fungal infections due to immunosuppressive therapy. MAT2203 is also being explored for treatment of additional anti-fungal indications and may have the potential for Orphan Drug Designation in certain of these indications. Matinas BioPharma is a clinical-stage biopharmaceutical company focused on identifying and developing safe and effective broad spectrum therapeutics for the treatment of serious and life-threatening infections. The Company's proprietary, disruptive technology utilizes lipid-crystal nano-particle cochleates to nano-encapsulate existing drugs, making them safer, more tolerable, less toxic and orally bioavailable. The Company's lead drug candidate is MAT2203, an orally-administered, encochleated formulation of amphotericin B (a broad spectrum fungicidal agent). The Company has an open Investigational New Drug (IND) application for MAT2501, which is an orally-administered, encochleated formulation of amikacin (a broad spectrum aminoglycoside antibiotic agent) for acute bacterial infections, including non-tuberculous mycobacterium (NTM) and multi-drug resistant gram negative bacterial infections. The Company's lead anti-infective product candidates, MAT2203 and MAT2501, position Matinas BioPharma to become a leader in the safe and effective delivery of anti-infective therapies utilizing its proprietary lipid-crystal nano-particle cochleate formulation technology. For more information, please visit www.matinasbiopharma.com and connect with the Company on Twitter, LinkedIn, Facebook, and Google+. Forward Looking Statements: This release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including those relating to the Company's strategic focus and the future development of its product candidates, including MAT2203 and MAT2501, the anticipated timing of regulatory submissions, the anticipated timing of clinical studies, the Company’s ability to identify and pursue development and partnership opportunities for its products or platform delivery technology on favorable terms, if at all, and the ability to obtain required regulatory approval and other statements that are predictive in nature, that depend upon or refer to future events or conditions. All statements other than statements of historical fact are statements that could be forward-looking statements. Forward-looking statements include words such as "expects," "anticipates," "intends," "plans," "could," "believes," "estimates" and similar expressions. These statements involve known and unknown risks, uncertainties and other factors which may cause actual results to be materially different from any future results expressed or implied by the forward-looking statements. Forward-looking statements are subject to a number of risks and uncertainties, including, but not limited to, our ability to obtain additional capital to meet our liquidity needs on acceptable terms, or at all, including the additional capital which will be necessary to complete the clinical trials of our product candidates; our ability to successfully complete research and further development and commercialization of our product candidates; the uncertainties inherent in clinical testing; the timing, cost and uncertainty of obtaining regulatory approvals; our ability to maintain and derive benefit from the Qualified Infectious Disease Product (QIDP), Orphan and/or Fast Track designations for MAT2203 and MAT2501, which does not change the standards for regulatory approval or guarantee regulatory approval on an expedited basis, or at all; our ability to protect the Company's intellectual property; the loss of any executive officers or key personnel or consultants; competition; changes in the regulatory landscape or the imposition of regulations that affect the Company's products; and the other factors listed under "Risk Factors" in our filings with the SEC, including Forms 10-K, 10-Q and 8-K. Investors are cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date of this release. Except as may be required by law, the Company does not undertake any obligation to release publicly any revisions to such forward-looking statements to reflect events or circumstances after the date hereof or to reflect the occurrence of unanticipated events. Matinas BioPharma's product candidates are all in a development stage and are not available for sale or use.


Sugui J.A.,Laboratory of Clinical Infectious Diseases | Peterson S.W.,U.S. Department of Agriculture | Clark L.P.,Laboratory of Clinical Infectious Diseases | Nardone G.,U.S. National Institutes of Health | And 8 more authors.
Journal of Clinical Microbiology | Year: 2012

The most common cause of invasive aspergillosis (IA) in patients with chronic granulomatous disease (CGD) is Aspergillus fumigatus followed by A. nidulans; other aspergilli rarely cause the disease. Here we review two clinical cases of fatal IA in CGD patients and describe a new etiologic agent of IA refractory to antifungal therapy. Unlike typical IA caused by A. fumigatus, the disease caused by the new species was chronic and spread from the lung to multiple adjacent organs. Mycological characteristics and the phylogenetic relationship with other aspergilli based on the sequence analysis of Mcm7, RPB2, and Tsr1 indicated that the new species, which we named as A. tanneri, belongs to Aspergillus section Circumdati. The species has a higher amphotericin B, voriconazole, and itraconazole MIC and causes more chronic infection in CGD mice than A. fumigatus. This is the first report documenting IA in CGD patients caused by a species belonging to the Aspergillus section Circumdati that is inherently resistant to azoles and amphotericin B. Unlike the results seen with many members of Aspergillus section Circumdati, ochratoxin was not detected in filtrates of cultures grown in various media. Our phenotypic and genetic characterization of the new species and the case reports will assist future diagnosis of infection caused by A. tanneri and lead to more appropriate patient management. Copyright © 2012, American Society for Microbiology. All Rights Reserved.


Kutty G.,U.S. National Institutes of Health | Achaz G.,University Pierre and Marie Curie | Maldarelli F.,U.S. National Cancer Institute | Varma A.,Laboratory of Clinical Infectious Diseases | And 4 more authors.
Journal of Infectious Diseases | Year: 2010

The life cycle of Pneumocystis, which causes life-threatening pneumonia in immunosuppressed patients, remains poorly defined. In the present study, we have identified and characterized an orthologue of dmc1, a gene specific for meiotic recombination in yeast, in 3 species of Pneumocystis. dmc1 is a single-copy gene that is transcribed as ∼1.2-kb messenger RNA, which encodes a protein of 336-337 amino acids. Pneumocystis Dmc1 was 61%-70% identical to those from yeast. Confocal microscopy results indicated that the expression of Dmc1 is primarily confined to the cyst form of Pneumocystis. By sequence analysis of 2 single-copy regions of the human Pneumocystis jirovecii genome, we can infer multiple recombination events, which are consistent with meiotic recombination in this primarily haploid organism. Taken together, these studies support the occurrence of a sexual phase in the life cycle of Pneumocystis. © 2010 by the Infectious Diseases Society of America. All rights reserved.


Huang Y.-L.,Laboratory of Clinical Infectious Diseases | Morales-Rosado J.,Laboratory of Clinical Infectious Diseases | Ray J.,Laboratory of Clinical Infectious Diseases | Myers T.G.,U.S. National Institutes of Health | And 4 more authors.
Journal of Biological Chemistry | Year: 2014

Macrophages in infected tissues may sense microbial molecules that significantly alter their metabolism. In a seeming paradox, these critical host defense cells often respond by increasing glucose catabolism while simultaneously storing fatty acids (FA) as triglycerides (TAG) in lipid droplets. We used a loadchase strategy to study the mechanisms that promote long term retention of TAG in murine and human macrophages. Toll-like receptor (TLR)1/2, TLR3, and TLR4 agonists all induced the cells to retain TAG for ≥3 days. Prolonged TAG retention was accompanied by the following: (a) enhanced FA uptake and FA incorporation into TAG, with long lasting increases in acyl-CoA synthetase long 1 (ACSL1) and diacylglycerol acyltransferase-2(DGAT2), and (b) decreases in lipolysis and FA β-oxidation that paralleled a prolonged drop in adipose triglyceride lipase (ATGL). TLR agonist-induced TAG storage is a multifaceted process that persists long after most early pro-inflammatory responses have subsided and may contribute to the formation of "lipid-laden" macrophages in infected tissues. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.


Heimall J.,Laboratory of Clinical Infectious Diseases | Davis J.,U.S. National Institutes of Health | Shaw P.A.,U.S. National Institutes of Health | Hsu A.P.,Laboratory of Clinical Infectious Diseases | And 4 more authors.
Clinical Immunology | Year: 2011

Autosomal dominant HIES (AD-HIES) is a primary immunodeficiency caused by dominant negative mutations in STAT3 clustered in the DNA binding and SH2 domains. Although in vitro differences in mutational constructs are observed, clinical phenotypic correlates of these genetic changes have not been described. We reviewed the charts of 65 AD-HIES patients (DNA binding n = 35; SH2 n = 30), recorded the components of the NIH HIES clinical scoring system as well as brain and coronary artery abnormalities and analyzed data by mutation region in adults and children. Patients with SH2 domain mutations had increased frequency of high palate, broad inter-alar distance, upper respiratory tract infections and, in the pediatric sub-group, significant scoliosis. There was suggestion of increased mortality for patients with DNA binding mutations. Although subtle differences in phenotype were observed to depend on the STAT3 genotype, overall the clinical phenotypes were similar between individuals with DNA binding and SH2 domain mutations. © 2011.


Chang Y.C.,Laboratory of Clinical Infectious Diseases | Lamichhane A.K.,Laboratory of Clinical Infectious Diseases | Bradley J.,Laboratory of Clinical Infectious Diseases | Rodgers L.,Laboratory of Clinical Infectious Diseases | And 2 more authors.
PLoS ONE | Year: 2015

The ability to grow on media containing certain D-amino acids as a sole nitrogen source is widely utilized to differentiate Cryptococcus gattii from C. neoformans. We used the C. neoformans H99 and C. gattii R265 strains to dissect the mechanisms of D-amino acids utilization. We identified three putative D-amino acid oxidase (DAO) genes in both strains and showed that each DAO gene plays different roles in D-amino acid utilization in each strain. Deletion of DAO2 retarded growth of R265 on eleven D-amino acids suggesting its prominent role on D-amino acid assimilation in R265. All three R265 DAO genes contributed to growth on D-Asn and D-Asp. DAO3 was required for growth and detoxification of D-Glu by both R265 and H99. Although growth of H99 on most D-amino acids was poor, deletion of DAO1 or DAO3 further exacerbated it on four D-amino acids. Overexpression of DAO2 or DAO3 enabled H99 to grow robustly on several D-amino acids suggesting that expression levels of the native DAO genes in H99 were insufficient for growth on D-amino acids. Replacing the H99 DAO2 gene with a single copy of the R265 DAO2 gene also enabled its utilization of several D-amino acids. Results of gene and promoter swaps of the DAO2 genes suggested that enzymatic activity of Dao2 in H99 might be lower compared to the R265 strain. A reduction in virulence was only observed when all DAO genes were deleted in R265 but not in H99 indicating a pathobiologically exclusive role of the DAO genes in R265. These results suggest that C. neoformans and C. gattii divergently evolved in D-amino acid utilization influenced by their major ecological niches. © 2015, Public Library of Science. All rights reserved. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.


PubMed | Laboratory of Clinical Infectious Diseases
Type: Journal Article | Journal: The Journal of biological chemistry | Year: 2014

Macrophages in infected tissues may sense microbial molecules that significantly alter their metabolism. In a seeming paradox, these critical host defense cells often respond by increasing glucose catabolism while simultaneously storing fatty acids (FA) as triglycerides (TAG) in lipid droplets. We used a load-chase strategy to study the mechanisms that promote long term retention of TAG in murine and human macrophages. Toll-like receptor (TLR)1/2, TLR3, and TLR4 agonists all induced the cells to retain TAG for 3 days. Prolonged TAG retention was accompanied by the following: (a) enhanced FA uptake and FA incorporation into TAG, with long lasting increases in acyl-CoA synthetase long 1 (ACSL1) and diacylglycerol acyltransferase-2 (DGAT2), and (b) decreases in lipolysis and FA -oxidation that paralleled a prolonged drop in adipose triglyceride lipase (ATGL). TLR agonist-induced TAG storage is a multifaceted process that persists long after most early pro-inflammatory responses have subsided and may contribute to the formation of lipid-laden macrophages in infected tissues.

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