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William Goldman, PhD

Professor
6204 Marsico Hall

Research

Molecular basis of microbial pathogenesis

Successful respiratory pathogens must be able to respond swiftly to a wide array of sophisticated defense mechanisms in the mammalian lung.  In histoplasmosis, macrophages – a first line of defense in the lower respiratory tract – are effectively parasitized by Histoplasma.  This process depends on virulence factors produced as this “dimorphic” fungus undergoes a temperature-triggered conversion from a saprophytic mold form to a parasitic yeast form.  We discovered a calcium-binding protein (CBP) that is secreted preferentially by the yeast form and is essential for Histoplasma virulence.  We also proved that that α-(1,3)-glucan, a yeast phase-specific cell wall polysaccharide, is involved in masking recognition of Histoplasma by the innate immune response.

This work has relied heavily on molecular genetic tools that we developed for Histoplasma, including the first genetically marked strains, the first DNA transformation protocols, the first plasmid vector systems, the first reporter genes, and the first gene disruption strategy. We also were the first to adapt RNAi as an alternative system for reverse genetics and optimized an Agrobacterium-mediated transformation system to perform the first forward genetics study by insertional mutagenesis.  Our recent work has used genome-wide population genetics to re-define species boundaries in the Histoplasma genus, and we have characterized how these newly defined species are distinct in various aspects of biology, virulence, and host response.

We are also continuing studies of one of the virulence factors of Bordetella pertussis:  tracheal cytotoxin (TCT) is a released fragment of peptidoglycan that causes pulmonary inflammation in pertussis (whooping cough).  TCT and endotoxin synergistically trigger respiratory epithelial production of nitric oxide, causing ciliated cell damage that corresponds to the well-known airway cytopathology of pertussis.  A variety of host receptor systems have been shown to recognize and respond to peptidoglycan fragments, and some are evolutionarily conserved from flies to mammals.  Depending on the relationship between bacteria and host, the results of exposure to TCT can be beneficial or pathological.  Our current work is aimed at understanding host responses to TCT that include host defense, cytopathology, and remodeling.

Selected Publications (last 12 years)

Bourret, R.B., E.N. Kennedy, C.A. Foster, V.E. Sepúlveda, and W.E. Goldman.  2021.  A radical reimagining of fungal two-component regulatory systems.  Trends in Microbiology S0966-842X(21)00064-0.

Rappleye, C.A., and W.E. Goldman.  2008.  Fungal stealth technology.  Trends in Immunology 29:18-24.

Beck, M.R., G.T. DeKoster, D.M. Hambly, M.L. Gross, D.P. Cistola, and W.E. Goldman.  Structural features responsible for biological stability of Histoplasma’s virulence factor CBP.  2008.  Biochemistry 47:4427-4438.

Beck, M.R., G.T. DeKoster, D.P. Cistola, and W.E. Goldman.  2009.  NMR structure of a fungal virulence factor reveals structural homology with mammalian saposin B.  Molecular Microbiology 72:344-353.

Price, P.A., J. Jin, and W.E. Goldman.  2012.  Pulmonary infection by Yersinia pestis rapidly establishes a permissive environment for microbial proliferation.  Proceedings of the National Academy of Sciences U.S.A. 109:3083-3088.

Pechous, R.D., V. Sivaraman, P.A. Price, N.M. Stasulli, and W.E. Goldman.  2013.  Early host cell targets of Yersinia pestis during primary pneumonic plague.  PLOS Pathogens 9:e1003679.

Sepúlveda, V.E., C.L. Williams, and W.E. Goldman.  2014.  Comparison of Histoplasma capsulatum isolates from phylogenetically distinct lineages reveals evolutionary divergence in virulence strategies.  mBio 5:e01376-14.

Sivaraman, V., R.D. Pechous, N.M. Stasulli, K.R. Eichelberger, E.A. Miao, and W.E. Goldman.  2015.  Yersinia pestis activates both IL-1β and IL-1 receptor antagonist to modulate lung inflammation during pneumonic plague.  PLOS Pathogens 11:e1004688.

Pechous, R.D., C.A. Broberg, N.M. Stasulli, V.L. Miller, and W.E. Goldman.  2015.  In vivo transcriptional profiling of Yersinia pestis reveals a novel bacterial mediator of pulmonary inflammation.  mBio 6:e02302-14.

Pechous, R.D., and W.E. Goldman.  2015.  Illuminating targets of bacterial secretion.  PLOS Pathogens 11:e1004981.

Stasulli, N.M., P.A. Price, K.R. Eichelberger, R.D. Pechous, S.A. Montgomery, J.S. Parker, and W.E. Goldman.  2015.  Spatially distinct neutrophil responses within the inflammatory lesions of pneumonic plague.  mBio 6:e01530-15.

Pechous, R.D., V. Sivaraman, N.M. Stasulli, and W.E. Goldman.  2016.  Pneumonic plague:  The darker side of Yersinia pestisTrends in Microbiology 24:190-197.

Sepúlveda, V.E., R. Márquez, D.A. Turissini, W.E. Goldman, and D.R. Matute.  2017.  Genome sequences reveal cryptic speciation in the human pathogen Histoplasma capsulatummBio 8:e01339-17.

Maxwell, C.S., V.E. Sepúlveda, D.A. Durissini, W.E. Goldman, and D.R. Matute.  2018.  Recent admixture between species of the fungal pathogen Histoplasma.  Evolution Letters 2:210-220.

Eichelberger, K.R., and W.E. Goldman.  2019.  Human neutrophil isolation and degranulation responses to Yersinia pestis infection.  Methods in Molecular Biology 2010:197-209.

Eichelberger, K.R., G.S. Jones, and W.E. Goldman.  2019.  Inhibition of neutrophil primary granule release during Yersinia pestis pulmonary infection.  mBio 10:e02759-19.

Eichelberger, K.R., V.E. Sepúlveda, J. Ford, S.R. Selitsky, P.A. Mieczkowski, J.S. Parker, and W.E. Goldman.  2020.  Tn-Seq analysis identifies genes important for Yersinia pestis adherence during primary pneumonic plague.  mSphere 5:e00715-20.

Jones, G.S., V.E. Sepúlveda, and W.E. Goldman.  2020.  Biodiverse Histoplasma species elicit distinct patterns of pulmonary inflammation following sublethal infection.  mSphere 5:e00742-20.

Eichelberger, K.R., and W.E. Goldman.  2020.  Manipulating neutrophil degranulation as a bacterial virulence strategy.  PLOS Pathogens 16:e1009054.

Link to My Bibliography

Accomplishments

Honors and Leadership Activities

1999 ASM Division D (Bacteria of Medical Importance) Lecturer
2000 Chair of FASEB Research Conference on Microbial Pathogenesis
1996-2001 Burroughs Wellcome Fund Scholar Award in Molecular Pathogenic Mycology
2002 Chair of Gordon Research Conference on Microbial Toxins and Pathogenicity
1998-2007 Director, Washington University Graduate Program in Molecular Microbiology
2010 ASM Division F (Medical Mycology) Lecturer
2008-2018 Chair, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill
2017-2018 President, Association of Medical School Microbiology and Immunology Chairs
2002-present Fellow of the American Academy of Microbiology (AAM)
2012-present Fellow of the American Association for the Advancement of Science (AAAS)

Other Professional Activities

1990-1994 Member, NIH Biological Sciences Study Section, Subcommittee 3
1998 Ad hoc member, NIAID Board of Scientific Counselors
1987-2001 Editorial Board, Infection & Immunity
1991-2002 Ad hoc reviewer, NIH Bacteriology and Mycology Study Section, Subcommittees 1 & 2
2003-2004 AAM Colloquia on new directions/issues in microbiology and genomics
2005 ASM-NIH Workshop on Basic Bacterial Research
2001-2008 Editor, Molecular Microbiology
2001, 2009 ASM General Meeting Colloquium Advisory Committee
2007-2009 Program Committee, ASM Biodefense and Emerging Diseases Research Meeting
2005-2012 Advisory Committee, Burroughs Wellcome Fund
2004-2014 ASM Conference Committee (Chair 2012-2014)
2001-2018 “Faculty of 1000” Section Co-Head (Cellular Microbiology and Pathogenesis)
2011-2018 “Pearls” Editor, PLoS Pathogens
1984-present 85 lectures at international conferences; 140 invited seminars at research institutes
1997-present Editorial Boards: Current Opinion in Microbiology, Trends in Microbiology
2018-present Chair, Biomedical Subcommittee of the ASM Public and Scientific Affairs Committee