Michail Lionakis, M.D., Sc.D.

Michail S. Lionakis, M.D., Sc.D.

Chief, Fungal Pathogenesis Section

Major Areas of Research

  • Role of chemotactic factors in host defense against invasive candidiasis
  • Role of specific resident and recruited innate immune cells in antifungal host defense against mucosal and systemic fungal challenge
  • Genetic susceptibility to infection in mice and patients with candidiasis and aspergillosis
  • Organ-specific immunity in invasive candidiasis
  • Immunological mechanisms of susceptibility to systemic fungal infections in patients with CARD9 deficiency
  • Immunological mechanisms of susceptibility to chronic mucocutaneous candidiasis (CMC) in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome
  • Mechanism-based therapeutic interventions for autoimmunity in APECED patients
  • Identification of novel genetic defects in patients with inherited susceptibility to Candida, Aspergillus, and other mold infections

Program Description

Since the 1990s, fungal infections have emerged as a major cause of morbidity and mortality in immunosuppressed and critically ill patients. The yeast Candida is the most common human fungal pathogen and is responsible for both invasive and mucosal infections. Neutrophils and monocytes/macrophages are critical for host defense against invasive candidiasis, the most common deep-seated human mycosis and the fourth-leading cause of nosocomial bloodstream infection in the United States. Despite administration of antifungal therapy, mortality of patients who develop invasive Candida infection exceeds 40 percent. In stark contrast to the requirement of phagocytes for defense against invasive infection, mucosal candidiasis develops 1) in patients with impaired cellular immunity such as those with AIDS (more than 90 percent of whom develop oral thrush) or inborn errors of immunity leading to chronic mucocutaneous candidiasis (CMC) and 2) in the majority of healthy women, often associated with antibiotic use (vaginal candidiasis). Invasive aspergillosis, most often caused by the ubiquitous inhaled mold Aspergillus fumigatus, is a leading cause of infection-related mortality in cancer or hematopoietic stem cell transplant (HSCT) patients (mortality, >25-50%) and in patients with chronic granulomatous disease (CGD), who have a defective phagocyte oxidative burst. In all of these conditions, detailed knowledge of immunopathogenesis at the molecular and cellular levels is lacking and could inspire new treatment and prevention approaches.

Our laboratory research focuses on 1) cellular and molecular factors that regulate the immune response against mucosal and invasive candidiasis and invasive aspergillosis in clinically relevant animal models and on 2) better understanding the genetic and immune defects that underlie enhanced susceptibility to mucocutaneous and invasive fungal infections in humans. Our goal is to develop a detailed mechanistic understanding of the molecular and cellular basis of innate and adaptive immune responses against Candida and Aspergillus with an aim to devise novel strategies to improve the diagnosis and augment or supplement the current antifungal drug treatment against candidiasis. To this end, we utilize in vitro cell culture systems and clinically relevant mouse models of mucosal and systemic Candida and Aspergillus infections to study host-fungal interactions by using a variety of immunological, biological, and imaging approaches.

The first step in mounting any immune response is the effective recruitment and activation of immune cells at the site of infection. Yet, the molecular factors that mediate these processes in the setting of candidiasis are poorly defined. Hence, a major focus of the laboratory is to investigate the role of specific members of the chemoattractant system in mediating trafficking and effector function of specific resident and recruited immune cells in anti-Candida host defense in vivo. Characterization of the role of candidate chemotactic factors in antifungal host defense in mice is then followed by human immunogenomics studies, in which genetic polymorphisms in the identified chemotactic factor genes are tested for correlating effects on biological function and for associations with candidiasis in patients.

Further, an important event that determines the outcome of candidiasis is germination of Candida yeast into hyphae. Hence, Candida mutant strains that are unable to germinate are avirulent in vivo. We have previously demonstrated that in disseminated candidiasis, the innate antifungal immune response is highly idiosyncratic for each infected organ, associated with organ-specific differential ability of Candida to filament in these tissues. Thus, our laboratory is interested in delineating the host factors that govern antifungal resistance versus susceptibility at different anatomical sites. To that end, a major focus of our laboratory is the study of the immunological mechanisms that account for central nervous system (CNS)-targeted susceptibility to systemic candidiasis and other systemic fungal infections in patients with CARD9 mutations. Hence, via an investigational review board (IRB)-approved clinical protocol, our lab is recruiting patients with biallelic CARD9 mutations to NIH to study them immunologically. In parallel, the cellular and molecular basis of enhanced susceptibility to CNS-targeted system fungal diseases in CARD9 deficiency is investigated in Card9-/- mice.

With regard to mucosal candidiasis, the laboratory investigates the mechanisms of Candida susceptibility in inherited immunodeficiencies that lead to CMC and in healthy subjects following antibiotic use. Hence, the laboratory aims to define the immunological mechanisms that account for universal susceptibility to CMC in patients with the autosomal-recessive autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome. APECED, caused by mutations in autoimmune regulator (AIRE), is the only primary immunodeficiency in which CMC develops in >90 percent of patients and is the only consistent infectious disease phenotype. Hence, our laboratory, via an investigational review board (IRB)-approved clinical protocol, has recruited >120 APECED patients to the National Institutes of Health to study them immunologically. In parallel, the cellular and molecular basis of enhanced susceptibility to mucosal candidiasis in APECED is investigated in Aire-/- mice. In addition to investigating mechanisms of Aire-dependent mucosal antifungal host defense, our laboratory is interested in developing a better understanding of the clinical presentation, diagnostic criteria, genetics, and mechanisms of autoimmunity in AIRE deficiency with a goal to devise mechanism-based preventative and treatment strategies for affected patients, which are tested in clinical trials at the NIH Clinical Center. Beyond AIRE deficiency, the laboratory actively investigates the mechanisms of susceptibility to CMC in STAT1 gain-of-function mutations and DOCK8 deficiency using human and mouse studies.

With regard to invasive aspergillosis, the laboratory studies novel genetic defects that cause susceptibility to pulmonary and/or extrapulmonary infection beyond CGD and investigates the mechanisms of Aspergillus susceptibility in the setting of iatrogenic inhibition of BTK (Bruton’s tyrosine kinase) in Btk-/- and Btk conditional knockout mice and in patients that are treated with the BTK inhibitors ibrutinib and acalabrutinib. Last, our lab is working with the NIAID Clinical Genomics Program with a goal to identify novel genetic variants that result in inherited susceptibility to fungal infections by Candida, Aspergillus, and other molds.

Biography

Dr. Lionakis obtained his M.D. and Sc.D. from the University of Crete in Greece. In 2002, he came to the United States and worked as a research fellow at the University of Texas MD Anderson Cancer Center (MDACC) under the mentorship of Dimitrios Kontoyiannis. At MDACC, Dr. Lionakis did clinical research on risk factors, diagnosis, and management of opportunistic fungal infections in cancer patients and bench research focusing on pharmacology and microbial factors in mouse and Drosophila models of invasive aspergillosis, fusariosis, and candidiasis.

After completing his clinical training in Internal Medicine at Baylor College of Medicine and Infectious Diseases at NIAID, Dr. Lionakis joined the Laboratory of Molecular Immunology (LMI) in 2008 and began to work on fungal immunology under the mentorship of Philip Murphy. At LMI, Dr. Lionakis did bench research on how chemotactic factors regulate the innate immune response in invasive candidiasis. In 2010, he was recruited as an Assistant Clinical Investigator in the NIAID Transition Program in Clinical Research and established the Clinical Mycology Unit within LMI. In 2012, Dr. Lionakis was recruited as a tenure-track investigator in the NIAID intramural research program and established the Fungal Pathogenesis Unit within the Laboratory of Clinical Infectious Diseases. He received tenure in 2017 and now heads the Fungal Pathogenesis Section within the Laboratory of Clinical Immunology and Microbiology.

Awards/Honors

Fellow, American Academy of Microbiology (AAM) (2019); NIH Director’s Award (2019); NIAID Merit Award (2018); Fellow, European Confederation of Medical Mycology (FECMM); Young Investigator Award, International Immunocompromised Host Society (ICHS) (2018); American College of Physicians (ACP) Walter J. McDonald Award for Early Career Physicians (2017); Fellow of Infectious Diseases Society of America (FIDSA) (2016);  IDWeek Investigator Award (2015); BeHEARD Science Prize Winner, Rare Genomics Institute (2015);​ 50th ICAAC George McCracken Infectious Disease Fellow Award (2010); 49th ICAAC Infectious Disease Fellows Grant Program Award (2009); Henry McIntosh Award for Outstanding Resident in Medicine (2007); Offered Chief Resident position, Baylor College of Medicine (2006); Certificate of Merit, MD Anderson Cancer Center (2004); 1st place Bristol-Myers Squibb Award in Clinical/Translational Research, Trainee Recognition Day, MD Anderson Cancer Center (2004); 43rd ICAAC Program Committee Award for Outstanding Research in the Pathogenesis of Microbial Diseases (2003); Giorgos Gennimatas Scholarship Award (2002); GlaxoWellcome Scholarship Award (2000); Lilian Voudouri Foundation Scholarship Award (2000); The Hellenic National Scholarships' Foundation Scholarship Award (2000); Dretakis Foundation Scholarship Award (2000)

Memberships

  • European Confederation of Medical Mycology
  • American College of Physicians
  • American Society of Microbiology
  • Infectious Diseases Society of America
  • Mycoses Study Group
  • International Immunocompromised Host Society
  • International Society for Human and Animal Mycology
  • American Association of Immunologists
  • Clinical Immunology Society
  • American Association for the Advancement of Science

Editorial Boards

  • JCI Insight
  • Journal of Infectious Diseases
  • Infection & Immunity
  • Frontiers in Cellular & Infection Microbiology
  • Virulence
  • Journal of Visualized Experiments
  • F1000 Research (Immunology/Immunity to Infections)

Research Group

Michael Abers, M.D.

Michael Abers, M.D.

Credit
NIAID

Michael Abers, M.D. Michael obtained his B.A. in biological sciences with a concentration in biochemistry from Northwestern University and his M.D. from Baylor College of Medicine. He then completed internal medicine residency at Massachusetts General Hospital. After his first year of clinical fellowship in infectious diseases at Harvard Medical School, he transferred to NIH to join FPS for his research fellowship. Michael's work at FPS will focus on gaining an understanding of immunopathogenesis of invasive fungal infections using clinically relevant mouse models and patient cohorts.

Gregory Constantine, M.D.

Gregory Constantine, M.D.

Credit
NIAID

Gregory Constantine, M.D. Gregory obtained his M.D. from the University of Texas Health Science Center, San Antonio. He then completed his internal medicine residency and chief residency at Baylor College of Medicine in Houston, Texas. He matriculated into NIAID to continue subspecialty training in allergy and immunology. His clinical and research interests include gaining a better understanding of the pathogenesis and potential therapeutic applications for immune dysregulation disorders. In joining the FPS, his work will focus on better understanding the genetics and molecular mechanisms that underlie autoimmunity in patients with APECED.

Jigar Desai, M.S., Ph.D.

Jigar Desai, M.S., Ph.D.

Credit
NIAID

Jigar Desai, M.S., Ph.D. Jigar obtained his bachelor's degree and master's degree in pharmacy from the Maharaja Sayajirao University of Baroda in India and Virginia Commonwealth University in Richmond, respectively. He did his Ph.D. at Carnegie Mellon University in Pittsburgh, where he studied the genetic factors that control Candida biofilm formation and the biophysical mechanisms of hyphal invasion. After that, he joined the FPS, where his research focuses on characterizing theCandida and host molecular factors that affect organ-specific fungal virulence.

Elise Ferré, PA-C, M.P.H.

Elise Ferré, PA-C, M.P.H. 

Credit
NIAID

Elise Ferré, PA-C, M.P.H. Elise obtained a Master of Science in health sciences for physician assistant studies from George Washington University, as well as a Master of Public Health with a concentration in community-oriented primary care. At FPS, Elise focuses her work on clinical care and clinical research in patients with inherited (e.g., APECED, CARD9 deficiency) and acquired (e.g., antibiotic-induced vaginal candidiasis) susceptibility to fungal disease.

Yannis Hadjiyannis, B.Sc.

Yannis Hadjiyannis, B.Sc.

Credit
NIAID

Yannis Hadjiyannis obtained his B.Sc. in Molecular Genetics with Research Distinction in Molecular Genetics from The Ohio State University. He is a rising third-year medical student from The Ohio State University College of Medicine joining the lab through the NIH Medical Research Scholars Program (MRSP). Through this 12-month program designed to immerse professional students in the full continuum of biomedical research conducted at the NIH, he will work on elucidating the histologic aberrations occurring in the gut and other affected tissues of APECED patients.  

Ahnika Kline, M.D., Ph.D.

Ahnika Kline, M.D., Ph.D.

Credit
NIAID

Ahnika Kline, M.D., Ph.D. Ahnika obtained her B.S. in biology and B.A. in mathematics from Johns Hopkins University in Baltimore, Maryland. She then obtained her M.D and Ph.D. from the University of California in San Francisco, where she studied the role of integrins in developmental and tumor angiogenesis. She then completed a residency in internal medicine at the University of California in San Diego, followed by a chief resident year in quality and safety at the Veterans Affairs Hospital in San Diego, before becoming an NIAID fellow in infectious diseases. Her research at FPS focuses on the pathogenicity of rare mold infections, aiming to understand virulence factors in these molds, as well as identifying host antimicrobial peptides with anti-mold activity.

Hongfang Liu, M.D., Ph.D.

Hongfang Liu, M.D., Ph.D.

Credit
NIAID

Hongfang Liu, M.D., Ph.D. Hongfang obtained her M.D. and Ph.D. from Zhongshan School of Medicine, Sun Yat-sen University in Guangzhou, China. She is a practicing dermatologist and a researcher with a strong interest in severe subcutaneous fungal skin infections. In joining the FPS on a sabbatical, her work will focus on studying the genetics and immunology of chromoblastomysosis in human and mouse systems.

Vasileios Oikonomou, Ph.D

Vasileios Oikonomou, Ph.D

Credit
NIAID

Vasileios Oikonomou, Ph.D. Vasileios obtained his bachelor’s degree in biology and his Ph.D. in biology and molecular biotechnology, both at University of Perugia in Italy. His graduate work focused on deciphering the molecular pathways underlying the detrimental effects of excessive inflammation in murine and human fungal infections, with a special focus on inflammasomes and their interception with the autophagy machinery. At FPS, Vasileios focuses his work on investigating the AIRE-dependent mechanisms of antifungal immunity and protection from autoimmunity in mouse models of AIRE deficiency and in APECED patients. His goal is to develop novel mechanism-based strategies to treat fungal disease and autoimmunity in APECED patients.

Whitney Osborne, M.P.H.

Whitney Osborne, M.P.H.

Credit
NIAID

 

Whitney Osborne, M.P.H. Whitney obtained her B.S. in Chemistry from Norfolk State University and her M.P.H. with a concentration in Epidemiology from George Washington University. She previously worked as a study coordinator on several clinical research studies addressing type 1 diabetes, adult congenial heart disease and dyslipidemia. She joins FPS to manage and coordinate our natural history and interventional studies on human fungal infections and autoimmunity.

Monica Schmitt, C.R.N.P.

Monica Schmitt, C.R.N.P.

Credit
NIAID

Monica Schmitt, C.R.N.P. Monica obtained her Master of Science in Nursing from George Mason University as well as her Family Nurse Practitioner Certificate from George Washington University. She comes to FPS with a strong clinical and clinical research background working at NHLBI with patients with hematological disorders and transplant recipients. Monica’s work at FPS will focus on the clinical care of our patients with inherited and acquired susceptibilities to fungal disease and designing and implementing the current and future treatments of their conditions and comorbidities.

Muthulekha Swamydas, Ph.D.

Muthulekha Swamydas, Ph.D.

Credit
NIAID

Muthulekha Swamydas, Ph.D. Muthulekha obtained her bachelor of medicine and bachelor of surgery from India and her Ph.D. in anatomy and cell biology from Wayne State University in Detroit. Her work at FPS focuses on understanding the in vivo role of phagocyte-targeted chemoattractant receptors in host defense against invasive candidiasis in mice.

Marissa Zarakas, D.D.S., M.D.

Marissa Zarakas, D.D.S., M.D. 

Credit
NIAID

Marissa Zarakas, D.D.S., M.D., obtained her D.D.S. and M.D. both from the National and Kapodistrian University of Athens, Greece. She joined the FPS after being granted a scholarship from the World Hellenic Biomedical Association in collaboration with the Stavros Niarchos Foundation. Her research in the FPS focuses on understanding the mechanistic role of complement and Btk signaling in systemic antifungal host defenses in mouse models and patients with fungal disease.

Fungal Pathogenesis Section Alumni

  • Daisuke Yamanaka, PhD, Assistant Professor, Tokyo University of Pharmacy and Life Sciences, Japan.
  • Mukil Natarajan. Medical Officer, Office of Antimicrobial Products, Center for Drug Evaluation, U.S. Food and Drug Administration; Silver Spring, Maryland.
  • Timothy Break. Scientist I, Meso Scale Diagnostics; Rockville, Maryland.
  • Amanda Collar. MD-PhD Candidate, Department of Molecular Genetics and Microbiology; University of New Mexico School of Medicine, New Mexico.
  • Rebecca Drummond. Birmingham Fellow, Institute of Immunology & Immunotherapy / Institute of Microbiology & Infection, College of Medical and Dental Sciences; University of Birmingham, UK.
  • Stacey Rose. Assistant Professor, Department of Infectious Diseases; Associate Director, Internal Medicine Residency Program; Baylor College of Medicine, Houston, Texas.

Featured Research

Selected Publications

Ferré EMN, Break TJ, Burbelo PD, Allgäuer M, Kleiner DE, Jin D, Xu Z, Folio LR, Mollura DJ, Swamydas M, Gu W, Hunsberger S, Lee CR, Bondici A, Hoffman KW, Lim JK, Dobbs K, Niemela JE, Fleisher TA, Hsu AP, Snow LN, Darnell DN, Ojaimi S, Cooper MA, Bozzola M, Kleiner GI, Martinez JC, Deterding RR, Kuhns DB, Heller T, Winer KK, Rajan A, Holland SM, Notarangelo LD, Fennelly KP, Olivier KN, Lionakis MS. Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance. Sci Transl Med. 2019 Jun 5;11(495). pii: eaav5597.

Drummond RA, Swamydas M, Oikonomou V, Zhai B, Dambuza IM, Schaefer BC, Bohrer AC, Mayer-Barber KD, Lira SA, Iwakura Y, Filler SG, Brown GD, Hube B, Naglik JR, Hohl TM, Lionakis MS. CARD9+ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment. Nat Immunol. 2019 May;20(5):559-570.

Lionakis MS, Dunleavy K, Roschewski M, Widemann BC, Butman JA, Schmitz R, Yang Y, Cole DE, Melani C, Higham CS, Desai JV, Ceribelli M, Chen L, Thomas CJ, Little RF, Gea-Banacloche J, Bhaumik S, Stetler-Stevenson M, Pittaluga S, Jaffe ES, Heiss J, Lucas N, Steinberg SM, Staudt LM, Wilson WH. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell. 2017 Jun 12;31(6):833-843.e5.

Rieber N, Gazendam RP, Freeman AF, Hsu AP, Collar AL, Sugui JA, Drummond RA, Rongkavilit C, Hoffman K, Henderson C, Clark L, Mezger M, Swamydas M, Engelholm M, Schüle R, Neumayer B, Ebel F, Mikelis CM, Pittaluga S, Prasad VK, Singh A, Milner JD, Williams KW, Lim JK, Kwon-Chung KJ, Holland SM, Hartl D,  Kuijpers TW, Lionakis MS. Extrapulmonary aspergillus infection in patients with CARD9 deficiency. JCI Insight. 2016 Oct 20;1(17):e89890.

Swamydas M, Gao JL, Break TJ, Johnson MD, Jaeger M, Rodriguez CA, Lim JK, Green NM, Collar AL, Fischer BG, Lee CR, Perfect JR, Alexander BD, Kullberg BJ, Netea MG, Murphy PM, Lionakis MS. CXCR1-mediated neutrophil degranulation and fungal killing promotes Candida clearance and host survivalSci Transl Med. 2016. 2016 Jan 20;8(322):322ra10.

Lionakis MS, Swamydas M, Fischer B, Plantinga T, Johnson MD, Jaeger M, Masedunskas A, Weigert R, Mikelis C, Wan W, Richard Lee CC, Lim JK, Rivollier A, Yang J, Laird G, Wheeler RT, Alexander BD, Perfect J, Gao JL, Kullberg BJ, Netea MG, Murphy PM. CX3CR1-dependent renal macrophage survival promotes Candida control and host survival. J Clin Invest. 2013 Dec 2;123(12):5035-51.

Visit PubMed for a complete publication listing.

Protocols and Patents

Clinical research protocols

The Natural History and Pathogenesis of Human Fungal Infections, #11-I-0187

Research patent

Kontoyiannis DP, Arap W, Pasqualini R, Lionakis MS, Lahdenranta J, inventors; Board of Regents, The University of Texas System, assignee. Biopanning as an approach to study the pathogenesis of and produce novel treatment modalities for invasive Aspergillosis. United States patent application US 20050187161. 2005 Aug 25.

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