Increasing evidence points to a critical role of microbial microevolution during chronic C. neoformans infection as a mechanism, which allows C. neoformans to escape host response and persist during chronic infection. We recently demonstrated that C. neoformans can switch from a smooth (SM) to a mucoid (MC) colony variant during chronic infection and showed that this switch is associated with lethal outcome. Simultaneously we showed that the newly generated MC switch variant produces a viscous capsular polysaccharide, which leads to dysfunctional phagocytosis by macrophages. The inflammatory response in the lung of MC infected mice is characterized by intense macrophage infiltration and lung destruction, whereas lungs of SM infected mice exhibit an effective lymphocyte dominated inflammatory response. Analysis of differentially expressed genes between the switch variants demonstrated that an immunogenic epitope is downregulated in the MC switch variant. Consistent with these findings we find a lack of effective T-cell response and evidence for inadequate phagocytosis and overstimulation of alveolar macrophages. Here we will examine the effects of phenotypic switching on the inflammatory immune response and survival. We propose three specific Aims to test our central hypothesis: 1.) To explore mechanisms by which phenotypic switching affects interactions of alveolar macrophages with C. neoformans.
Aim 2.) To determine if down regulation of an immunogenic epitope in the pathogen affects T-cell response and Aim 3.) To examine the effects of macrophage function in the host and epitope expression in the pathogen on outcome of C. neoformans infection in mice. If our hypothesis is correct, the work proposed here will have broad significance in the long-term, because it will establish insight into the dynamics of host-pathogen interaction in chronic cryptococcosis. This should in the long-term enable us to develop novel, selective lung-protective therapies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BM-2 (02))
Program Officer
Duncan, Rory A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Albert Einstein College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Bahr, Nathan C; Panackal, Anil A; Durkin, Michelle M et al. (2018) Cryptococcal meningitis is a cause for cross-reactivity in cerebrospinal fluid assays for anti-Histoplasma, anti-Coccidioides and anti-Blastomyces antibodies. Mycoses :
Diago-Navarro, Elizabeth; Calatayud-Baselga, Isabel; Sun, Donglei et al. (2017) Antibody-Based Immunotherapy To Treat and Prevent Infection with Hypervirulent Klebsiella pneumoniae. Clin Vaccine Immunol 24:
Bouklas, Tejas; Jain, Neena; Fries, Bettina C (2017) Modulation of Replicative Lifespan in Cryptococcus neoformans: Implications for Virulence. Front Microbiol 8:98
Jain, Neena; Bouklas, Tejas; Gupta, Anjali et al. (2016) ALL2, a Homologue of ALL1, Has a Distinct Role in Regulating pH Homeostasis in the Pathogen Cryptococcus neoformans. Infect Immun 84:439-51
Mihu, Mircea Radu; Roman-Sosa, Jessica; Varshney, Avanish K et al. (2015) Methamphetamine Alters the Antimicrobial Efficacy of Phagocytic Cells during Methicillin-Resistant Staphylococcus aureus Skin Infection. MBio 6:e01622-15
Bouklas, Tejas; Diago-Navarro, Elizabeth; Wang, Xiaobo et al. (2015) Characterization of the virulence of Cryptococcus neoformans strains in an insect model. Virulence 6:809-13
Tassieri, Manlio; Del Giudice, Francesco; Robertson, Emma J et al. (2015) Microrheology with optical tweezers: measuring the relative viscosity of solutions 'at a glance'. Sci Rep 5:8831
Bouklas, Tejas; Fries, Bettina C (2015) Aging: an emergent phenotypic trait that contributes to the virulence of Cryptococcus neoformans. Future Microbiol 10:191-7
Bouklas, Tejas; Fries, Bettina C (2015) Aging as an emergent factor that contributes to phenotypic variation in Cryptococcus neoformans. Fungal Genet Biol 78:59-64
Robertson, Emma J; Najjuka, Grace; Rolfes, Melissa A et al. (2014) Cryptococcus neoformans ex vivo capsule size is associated with intracranial pressure and host immune response in HIV-associated cryptococcal meningitis. J Infect Dis 209:74-82

Showing the most recent 10 out of 41 publications