Jennifer K. Lodge, Ph.D.

Professor
Molecular Microbiology

Molecular Microbiology and Microbial Pathogenesis Program
Molecular Genetics and Genomics Program
Molecular Cell Biology Program

  • 314-747-0515

  • 8106

  • 8250 McDonnell Pediatric Research Building

  • lodgejk@wustl.edu

  • Signal transduction, cell wall biosynthesis and resistance to oxidative and nitrosative stresses  in the pathogenic fungus, Cryptococcus neoformans

Research Abstract:

Cryptococcus neoformans is a significant fungal pathogen, particularly in immunocompromised patients, that causes pulmonary infections and meningoencephalitis. It has been estimated that over 1,000,000 new cases of Cryptococcus occur, with over 650,000 deaths per year. The majority of these cases are in parts of Africa. There is a tremendous need for new antifungal therapies and for vaccines against fungal diseases. Our laboratory is studying the cell wall of Cryptococcus to develop new targets for antifungal therapies and for vaccines.

The fungal cell wall is an essential organelle, vital for maintaining cell integrity against various chemical, physical and biological stressors. This complex structure, immediately adjacent to the plasma membrane, serves several biological functions. Its cohesive structure, linked by covalent and hydrogen bonding or other types of interactions, provides great strength and stability. In this way, the cell wall prevents bursting that would be caused by internal turgor pressure and protects against external mechanical injury. The cell wall is the primary determinant of cell morphogenesis, and is constantly being remodeled to allow for growth, cell division and transitioning from yeast to branching hyphal forms to structures of sporulation. Since it is present at the cell surface, the cell wall interacts with the environment. In the case of pathogenic fungi, host defense systems are often directed against cell wall components. The cell wall has long been recognized as an ideal target for antifungal therapies because it is essential for fungal cell viability and many of its components are absent from the mammalian host.

We have demonstrated that chitosan is an abundant component of Cryptococcus cell walls, both during vegetative growth and infection of mammalian lungs, and that it is a critical component of the wall during infection. We have created chitosan deficient strains of Cryptococcus that are avirulent and protective against subsequent challenge by virulent, wild type strains.

Three independent lines of mutants that have defects in chitosan production are all completely avirulent, and rapidly cleared from mammalian lungs. This data suggests that chitosan biosynthesis is a highly attractive anticryptococcal target. We have explored genes that contribute to chitosan production, and shown that only one (CHS3) of eight chitin synthases, and one (CSR2) of three putative chitin synthase regulators substantially impact chitosan levels. In addition, we have demonstrated that three of four potential polysaccharide deacetylases produce chitosan, and are currently investigating the role of each of these in chitosan production. Our current models of chitosan biosynthesis suggest that a complex of a specific chitin synthase, a regulator and a chitin deacetylase are located in a membrane and together, produce chitosan.

Multiple signal transduction pathways detect the environment and are used by fungi to respond to stresses. We have shown that the PKC1 pathway (aka the cell integrity pathway) has a role in response to antimicrobial defenses that are found in the human host, including oxidative and nitrosative stresses and chitinases. Our lab is exploring the role of upstream signaling molecules that detect and transmit these stresses, and determining mechanisms of how C. neoformans protects itself from these stresses.

Selected Publications:

Janbon G, Ormerod KL, Paulet D, Byrnes EJ, Chatterjee G, Yadav V, Hon CC, Billmyre RB, Brunel F, Bahn Y-S, Chen W, Chen Y, Chow EWL, Coppe J-Y, Floyd-Averette A, Gaillardin C, Gerik KJ, Goebels C, Goldberg J, Gonzalez-Hilarion S, Gujja S, Hamlin JL, Hsueh Y-P, Ianiri; Jones GS, Kodira CD, Lam W, Marra M, Mesner LD, Mieczkowski PA, Moyrand F, Nielsen K, Proux C, Rossignol T, Schein JE, Sun S, Wood IA, Zeng Q, Neuvglise C, Newlon CS, Perfect JR, Lodge JK, Idnurm A, Stajich JE, Kronstad JW, Sanyal K, Heitman J, Fraser JA, Cuomo CA, Dietrich FS (2014) The genome and transcriptome sequences of Cryptococcus neoformans var. grubii reveal complex mechanisms of RNA expression and virulence plasticity. PLoS Genetics 10(4):e1004261. PMID: 24743168

Upadhya R, Kim H, Jung K-W, Park G , Lam W, Lodge JK, and Bahn Y-S (2013) Sulfiredoxin plays peroxiredoxin-dependent and –independent roles via the HOG signaling pathway in Cryptococcus neoformans and contributes to fungal virulence. Mol. Micro. 90:630-48 PMID: 23998805

Upadhya R., Campbell, L.T., Donlin, M.J., Aurora, R., Lodge, J.K. (2013) Global transcriptome profile of Cryptococcus neoformans during exposure to hydrogen peroxide induced oxidative stress. PLoS One. 8 (1):e55110. PMID: 23383070. PMCID: PMC3557267

Lam, W.C., Gerik, K.J., and Lodge, J.K. (2013) Role of Cryptococcus neoformans Rho 1 GTPases in the PKC1 signaling pathway in response to thermal stress. Eukaryot Cell. 12(1): 118-31. PMID:23159519.

Gilbert NM, Baker LG, Specht, CA and Lodge JK. (2012) A glycosylphosphatidylinositol anchor is required for membrane localization but dispensable for cell wall association of chitin deacetylase 2 in Cryptococcus neoformans. mBio 3:7-12. PMID: 22354955

Baker LG, Specht CA and Lodge JK. Cell wall chitosan is necessary for virulence in the opportunistic pathogen Cryptococcus neoformans. Eukaryot Cell. 2011 10:1264-8.

Brown SM, Upadhya R, Shoemaker JD and Lodge JK. Isocitrate Dehydrogenase is Important for Nitrosative Stress Resistance in Cryptococcus nerformans, but Oxidative Stress Resistance in Not Dependant on Glucose-6-Phosphate Dehydrogenase. Eukaryotic Cell. 2010 Jun;9(6):971-80.

Gilbert NM, Donlin MJ, Gerik KJ, Specht CA, Djordjevic JT, Wilson CF, Sorrell TC, Lodge JK. (2010) KRE genes are required for beta-1,6-glucan synthesis, maintenance of capsule architecture and cell wall protein anchoring in Cryptococcus neoformans. Mol. Microb. 76(2):517-34. PMID 20384682.

Baker LG, Specht CA and Lodge JK. Chitinases are essential for sexual development but not vegetative growth in Cryptococcus neoformans. Eukaryotic Cell. 2009 8:1692-705.

Gerik KJ, Bhimireddy SR, Ryerse JS, Specht CA and Lodge JK. Protein Kinase C1 (PKC1) is essential for protection against both oxidative and nitrosative stress, cell integrity, and normal manifestation of virulence factors in the pathogenic fungus Cryptococcus neoformans. Eukaryotic Cell 2008 7:1685-98.



Last Updated: 6/10/2014 11:09:46 AM

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