Research Specialties: Fungal genetics, fungal cell biology, marine mycology, and human fungal; pathogens.
Ph.D., 2017, Duke University, Durham, NC
Our lab has a deep and sustained interest in cell morphogenesis and fungal cell regulate their shape. Our research interests are shaped by the critical roles that fungal morphology and cell wall play in disease progression and antifungal drug targeting. In the last decade, there has been a notable increase in the incidence of invasive mycosis, partly due to a rise in the immunocompromised patient population. Additionally, the range of geographically restricted endemic fungal diseases is expanding, which increases the size of the human populations at risk. In order to tackle this challenge, our research program aims to provide a mechanistic understanding of how fungal pathogens respond to anti-cell wall drugs and how fungi regulate their morphology. The cell wall is an attractive therapeutic target since mammalian cells lack this structure, and it provides the fungal cells with mechanical force to withstand the changing environment inside the host. This research program will provide key insight into fungal cell biology, leading to the development of effective strategies to treat invasive mycoses. For these reasons our research program aims to provide insights into the following questions:
1) Does the septin cytoskeleton contribute to fungal host-pathogen interactions?
A. fumigatus infections have multiple manifestations, depending on the host’s immune status. Invasive aspergillosis is the most severe type of Aspergillus-related infection, targeting severely immunocompromised patients. The Infectious Diseases Society of America issued a statement that emphasized A. fumigatus as one of six pathogens for which new treatments are critically needed due to the increased incidence of invasive aspergillosis, its excessive mortality rate (35-95%), and the lack of effective treatments. Septins are important cytoskeletal complexes that regulate cellular processes and morphogenesis events in A. fumigatus. His studies elucidated non-overlapping roles for individual septin genes in conidiation, septation, and cell wall stress resistance. Ultrastructural studies implicated the core septin complex in the formation and/or maintenance of the conidial cell wall. Interestingly, the septin deletion strains exhibited hypervirulence in an invertebrate model of invasive aspergillosis, as well as increased TNF-alpha production in bone marrow-derived macrophages. Taken together, these results point to the importance of A. fumigatus septins as modulators of host-microbe interactions. In a second project conducted by Dr. Vargas-Muñiz, he examined how cells control where septins assemble in space and time. He evaluated how septins might be regulated by mutating a series of septin associated kinases and phosphatases. Loss of one of these kinases, Gin4, resulted in an increase in virulence of A. fumigatus in both the invertebrate and murine models due to uncontrolled fungal growth. These results highlight the importance of septin regulators in A. fumigatus development.
2) How the septin cytoskeleton contributes to anti-cell wall drug response?
The anti-cell wall drug caspofungin is guideline-recommended as second-line therapy for invasive aspergillosis after the azoles treatment, which targets the cell membrane components. However, the increasing emergence of azole resistance amongst A. fumigatus isolates is causing an increase in the use of caspofungin to treat invasive aspergillosis. Therefore, it is critical to understand the fungal response to this antifungal agent. Caspofungin targets beta-1,3-D-glucan synthase, which synthesizes a major component of the A. fumigatus cell wall. Caspofungin is fungistatic against A. fumigatus, yet the mechanism behind the A. fumigatus response to this commonly used antifungal is not fully understood. Deletion of septin genes increased the susceptibility to caspofungin in Candida albicans and A. fumigatus, suggesting a broader role of septin-mediated caspofungin response in pathogenic fungi. Nonetheless, the mechanism behind the septin-mediated response to caspofungin remains unclear.
3) What are the molecular mechanisms that marine fungi use to alter their morphology and adapt to stress?
The black yeast Hortaea werneckii is the etiological agent of tinea nigra, a superficial skin infection commonly localized in the palms of the hands or the soles of the feet. Tinea nigra is common in the tropics, including the Caribbean, and it mostly affects immunocompromised patients. Additionally, H. werneckii strains have been isolated in challenging environments such as ocean water and marine salterns. H. werneckii displays a striking combination of division patterns, indicating that rules for the cell cycle established in conventional model systems may be broken by fungi growing in extreme environmental conditions. Cell size is highly variable suggesting that cell cycle regulation may have different mechanistic roots than the well-studied model yeasts. Specifically, these cells alternate between fission and budding from cell cycle to cell cycle which is highly distinct from the conventional model yeast systems. The cell division patterns and morphology of H. werneckii can be regulated by the concentration of NaCl. Morphology is also highly variable between different isolates of H. werneckii coming from diverse environments, making it a prime candidate for comparative genomics to identify the molecular mechanisms that control different cell morphologies.
- Mitchison-Field LM, Vargas-Muñiz JM, Stormo BM, Vogt EJ, Van Dierdonck S, Pelletier JF, Ehrlich C, Lew DJ, Field CM, Gladfelter AS. Unconventional cell division cycles from marine-derived yeasts. Current Biology. 2019 Oct 21;29(20):3439-56. Link
- Anthony Amend, Gaetan Burgaud, Michael Cunliffe, Virginia P. Edgcomb, Cassandra L. Ettinger, M. H. Gutiérrez, Joseph Heitman, Erik F. Y. Hom, Giuseppe Ianiri, Adam C. Jones, Maiko Kagami, Kathryn T. Picard, C. Alisha Quandt, Seshagiri Raghukumar, Mertixell Riquelme, Jason Stajich, José Vargas-Muñiz, Allison K. Walker, Oded Yarden, Amy S. Gladfelter. Fungi in the marine environment: Open questions and unsolved problems. MBio. 2019 Apr 30;10(2). Link
- Renshaw H, Vargas-Muñiz JM, Juvvadi PR, Richards AD, Waitt G, Soderblom EJ, Moseley MA, Steinbach WJ. The tail domain of the Aspergillus fumigatus class V myosin MyoE orchestrates septal localization and hyphal growth. Journal of cell science. 2018 Feb 1;131(3). Link
- Vargas-Muñiz JM, Renshaw H, Waitt G, Soderblom EJ, Moseley MA, Palmer JM, Juvvadi PR, Keller NP, Steinbach WJ. Caspofungin exposure alters the core septin AspB interactome of Aspergillus fumigatus. Biochemical and biophysical research communications. 2017 Apr 1;485(2):221-6. Link
- Vargas-Muñiz JM, Juvvadi PR, Steinbach WJ. Forging the ring: from fungal septins' divergent roles in morphology, septation and virulence to factors contributing to their assembly into higher order structures. Microbiology. 2016 Sep;162(9):1527. Link
- Vargas-Muñiz JM, Renshaw H, Richards AD, Waitt G, Soderblom EJ, Moseley M, Asfaw Y, Juvvadi PR, Steinbach WJ. Dephosphorylation of the core septin, AspB, in a protein phosphatase 2A-dependent manner impacts its localization and function in the fungal pathogen Aspergillus fumigatus. Frontiers in microbiology. 2016 Jun 22;7:997. Link
- Renshaw H, Vargas-Muñiz JM, Richards AD, Asfaw YG, Juvvadi PR, Steinbach WJ. Distinct roles of myosins in Aspergillus fumigatus hyphal growth and pathogenesis. Infection and immunity. 2016 May 1;84(5):1556-64. Link
- Falloon K, Juvvadi PR, Richards AD, Vargas-Muñiz JM, Renshaw H, Steinbach WJ. Characterization of the FKBP12-Encoding Genes in Aspergillus fumigatus. PloS one. 2015 Sep 14;10(9):e0137869. Link
- Vargas-Muñiz JM, Renshaw H, Richards AD, Lamoth F, Soderblom EJ, Moseley MA, Juvvadi PR, Steinbach WJ. The Aspergillus fumigatus septins play pleiotropic roles in septation, conidiation, and cell wall stress, but are dispensable for virulence. Fungal Genetics and Biology. 2015 Aug 1;81:41-51. Link