Pulmonary & Critical Care Fellowship Program
MGH BIDMC Harvard Medical School

Michael B Feldman, MD

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Michael B. Feldman, MD, PhD

Instructor in Medicine

Areas of Expertise: Investigation

Academic Interests

As a pulmonary physician-scientist, my research and clinical interests are aligned on improving clinical outcomes for patients with either chronic or acute fungal lung disease. My specific research interests focus on host-pathogen interactions between human airway epithelium and fungal pathogens. Under the mentorship of Dr. Jatin Vyas and with support from Drs. Hongmei Mou, Jay Rajagopal, Michael Mansour, and Bryan Hurley, I have developed techniques to utilize advanced human airway stem cell culture techniques to generate novel models of infection with Aspergillus fumigatus on primary human airway epithelium ex vivo. I work closely with the Massachusetts General Hospital (MGH) Lung Transplant Program with regards to patient care, research, and patient sample acquisition. By housing my research in the Division of Infectious Diseases and my clinical care in the Division of Pulmonary and Critical Care Medicine, I am uniquely positioned to build a translational research program that addresses difficult-to-treat fungal lung infections.

Awards and Recognition

2005 Honors in Chemistry, Colby College

2006 Henry Adelman Fund for Medical Student Education in Geriatrics Scholarship, Weill Cornell Medical College

2007 Best Paper: Organ Specific Disease and Biology of Aging, American Geriatric Society

2009 Patrick Clark Memorial Scholarship, National Outdoor Leadership School

2013 The George G. Reader Prize in Public Health, Weill Cornell Medical College

2013 The Dr. Ida S. Scudder Foundation International Fellowship, Dr. Ida S. Scudder Foundation

2019 Fund for Medical Discovery (FMD) Fellowship, Executive Committee on Research, Massachusetts General Hospital

2019 Pathways Consult Service Patient-Derived Research Program Fellowship, Massachusetts General Hospital

A full list of Dr. Feldman’s published work can be found on My Bibliography.

More information can be found on Dr. Feldman’s Harvard Catalyst Profile.

Current Projects

+Fungal Pathogenesis and Mucosal Immunology

Fungal diseases cause a tremendous burden of morbidity and mortality in humans. Invasive fungal infections account for more than one million deaths annually, and more than half of the deaths in patients with HIV/AIDS. The burden of fungal infections has been increasing as immunomodulatory therapies are increasingly used in the treatment of cancer, rheumatologic disease, solid organ transplant, and bone marrow transplant. Invasive fungal infections, such as invasive aspergillosis, are being increasingly reported in otherwise normal hosts following primary Influenza A or Influenza B infections. Furthermore, fungal infections are being recognized as driving significant morbidity through non-invasive infections and chronic colonization. Aspergillus fumigatus is a ubiquitous saprophytic fungus capable of causing a wide range of human pulmonary diseases including invasive aspergillosis, chronic aspergillosis, and allergic bronchopulmonary aspergillosis (ABPA). In patients with abnormal airways, Aspergillus can lead to the decline of lung function decline and death. This problem is particularly common in cystic fibrosis (CF) patients, in whom almost 50% are affected by Aspergillus colonization or infection. The determinants contributing to the development of different clinical presentations in response to Aspergillus infection remains poorly understood.

The innate immune system plays a critical role in controlling fungal infections through early recognition of fungal epitopes leading to pathogen phagocytosis, immune recruitment, and pathogen clearance. To better understand how phagocytic trafficking contributes to the response to fungal diseases, we developed a fluorescent method to tracking division of Candida glabrata yeast in macrophages (Front Immunology, 2018). C. glabrata causes invasive blood stream infections in both immunosuppressed and acutely ill human hosts. We applied this carboxyfluorescein succinimidyl ester (CFSE) labeling strategy to identify the role of spleen tyrosine kinase (Syk) phosphorylation in C. glabrata control by macrophages. For patients who develop invasive fungal infections, therapeutic options are limited and resistance to the available antibiotics has emerged. While much of our research is focused on discovering immunomodulatory strategies to combat or prevent infection, we are also trying to identify compounds that are either new antifungal agents or may potentiate known antibiotics. We reported that the widely used biguanide medication, metformin, potentiates the activity of antifungal agents against C. glabrata (Virulence, 2018)

When infectious fungal spores are inhaled, the airway epithelium becomes the first point of contact in the host lungs. Increasingly, the airway epithelium is being recognized as an immunologically active tissue that contributes to cytokine production, innate immune cell recruitment, and possibly pathogen phagocytosis and sequestration. Epithelial derangements in patients with CF contribute to the establishment of chronic infections, while also leading to neutrophilic mucus production and airway destruction. In the case of Aspergillus spp, it has been proposed that phagocytosis of inhaled spores by airway epithelial cells may protect the fungus from clearance by macrophages and neutrophils, thereby promoting infection. I recently reviewed the role of professional phagocytes, as well as non-professional phagocytes, including the airway epithelium, in response to fungal infections (Sem Cell Dev Biol, 2018).

+Airway Stem Cell Biology

Goblet cell hyperplasia and overproduction of mucus features in many human respiratory diseases including CF, ABPA and infections, chronic obstructive pulmonary disease and asthma. The overproduction of mucous impairs mucociliary clearance, causing retention of pathogens, allergens, and toxic particles. Inflammatory mediators released from goblet cells may act in an autocrine and paracrine manner, further enhancing inflammation in diseases and complex repair processes leading to persist airway remodeling. Indeed, the progression of airway diseases and decline in lung function is positively associated with the accumulation of inflammatory mucous and airflow obstruction. Several signaling pathways have been identified as important regulators of goblet cell differentiation such as the NOTCH signaling pathway and the epidermal growth factor (EGF) cascade. Recent studies have also linked the relevance of the GABAergic system to asthma and mucous production. In this context, c-aminobutyric acid (GABA) is secreted from pulmonary neuroendocrine cells (PNECs) in the lung and act on airway epithelial cells through the subtype A GABA receptor (GABAAR). The action of this autocrine-paracrine GABAergic system in the airway epithelial cells is essential to induce goblet cell hyperplasia in allergen-challenged mice and humans affected with asthma. In my first-author publication in the American Journal of Respiratory Cell and Molecular Biology, we identify transforming growth factor (TGF)-β superfamily canonical SMAD signaling as a critical pathway controlling goblet cell differentiation. BMP/TGF-β/SMAD signaling is exceptionally versatile and has been implicated in orchestrating multiple biological functions including organ development, tissue homeostasis, and injury repair. Previously, we reported that BMP and TGF-β signaling balances stem cell proliferation and differentiation in airway epithelium and in epithelia at large. We observed that the degree of SMAD signaling activation is associated with epithelial maturity. Suppression of BMP and TGF-β signaling activity is essential for maintaining p63+ basal cell stemness by impeding epithelial differentiation. Dual SMAD signaling inhibition can be deployed in cell culture in vitro to achieve prolonged expansion of murine and human cells, while maintaining their ability to differentiate into functional tissues. We demonstrate that although mucin-secreting goblet cells are post-mitotic differentiated cells, the SMAD signaling activity is largely suppressed. SMAD signaling inhibition markedly amplifies goblet cell hyperplasia induced by inflammatory mediators, whereas its activation restricts its production and facilitates its resolution. Furthermore, the inhibitory effects on goblet cell generation imposed by GABAergic system inhibitors can be overcome by SMAD signaling inhibition suggesting a functional relationship of these two pathways that are critical for goblet cell differentiation and regulation. Our data not only demonstrate the essential role of SMAD signaling pathway in regulating goblet cell fate determination, but also may lead to new therapeutic strategies for the management of allergic diseases.

 

Publications

+Selected Publications

  1. Tam JM, Reedy JL, Lukason DP, Kuna SG, Acharya M, Khan NS, Negoro PE, Xu S, Ward RA, Feldman MB, Dutko RA, Jeffery JB, Sokolovska A, Wivagg CN, Lassen KG, Le Naour F, Matzaraki V, Garner EC, Xavier RJ, Kumar V, van de Veerdonk FL, Netea MG, Miranti CK, Mansour MK, Vyas JM. Tetraspanin CD82 Organizes Dectin-1 into Signaling Domains to Mediate Cellular Responses to Candida albicans. J Immunol. 2019 Jun 01; 202(11):3256-3266. PMID: 31010852.
  2. Feldman MB, Wood M, Lapey A, Mou H. SMAD Signaling Restricts Mucous Cell Differentiation in Human Airway Epithelium. Am J Respir Cell Mol Biol. 2019 Mar 08. PMID: 30848657.
  3. Feldman MB, Vyas JM, Mansour MK. It Takes a Village: Phagocytes Play a Central Role in Fungal Immunity. Semin Cell Dev Biol. 2019 May; 89:16-23. PMID: 29727727.
  4. Dagher Z, Xu S, Negoro PE, Khan NS, Feldman MB, Reedy JL, Tam JM, Sykes DB, Mansour MK. Fluorescent Tracking of Yeast Division Clarifies the Essential Role of Spleen Tyrosine Kinase in the Intracellular Control of Candida glabrata in Macrophages. Front Immunol. 2018; 9:1058. PMID: 29868018.
  5. Xu S, Feliu M, Lord AK, Lukason DP, Negoro PE, Khan NS, Dagher Z, Feldman MB, Reedy JL, Steiger SN, Tam JM, Soukas AA, Sykes DB, Mansour MK. Biguanides enhance antifungal activity against Candida glabrata. Virulence. 2018; 9(1):1150-1162. PMID: 29962263.
  6. Wang L, Pulk A, Wasserman MR, Feldman MB, Altman RB, Cate JH, Blanchard SC. Allosteric Control of the Ribosome by Small-Molecule Antibiotics. Nat Struct Mol Biol. 2012 Sep; 19(9):957-63. PMID: 22902368.
  7. Wang L, Wasserman MR, Feldman MB, Altman RB, Blanchard SC. Mechanistic Insights into Antibiotic Action on the Ribosome Through Single-Molecule Fluorescence Imaging. Ann N Y Acad Sci. 2011 Dec; 1241:E1-16. PMID: 23419024.
  8. Dunkle JA, Wang L, Feldman MB, Pulk A, Chen VB, Kapral GJ, Noeske J, Richardson JS, Blanchard SC, Cate JH. Structures of the Bacterial Ribosome in Classical and Hybrid States of tRNA Binding. Science. 2011 May 20; 332(6032):981-4. PMID: 21596992.
  9. Geggier P, Dave R, Feldman MB, Terry DS, Altman RB, Munro JB, Blanchard SC. Conformational Sampling of Aminoacyl-tRNA During Selection on the Bacterial Ribosome. J Mol Biol. 2010 Jun 18; 399(4):576-95. PMID: 20434456.
  10. Feldman MB, Terry DS, Altman RB, Blanchard SC. Aminoglycoside Activity Observed on Single pre-translocation ribosome complexes. Nat Chem Biol. 2010 Jan; 6(1):54-62. PMID: 19946275.
  11. Katz JL, Feldman MB, Conry RR. Synthesis of Functionalized Oxacalix[4]arenes. Org Lett. 2005 Jan 06; 7(1):91-4. PMID: 15624985.
  12. Wines ME, Lee L, Katari MS, Zhang L, DeRossi C, Shi Y, Perkins S, Feldman M, McCombie WR, Holdener BC. Identification of Mesoderm Development (mesd) Candidate Genes by Comparative Mapping and Genome Sequence Analysis. Genomics. 2001 Feb 15; 72(1):88-98. PMID: 11247670.