This application investigates a general problem in virulence of how pathogenic microbes adapt to and/or escape host defenses. Most infections are characterized by a complex relationship between the host and the pathogen referred to as pathoadaptation. The system under study is based on Cryptococcus neoformans, a human pathogenic fungus that is a major cause of mortality and morbidity in immunocompromised patients. C. neoformans undergoes phenotypic switching from a smooth (SM) to a mucoid (MC) colony switch variant during chronic infection. Prior work has associated this switch with virulence including high intracranial pressure and the ability to persist in the host. We have determined that the switch of the SM parent to the hypervirulent MC variant is associated with down-regulation of several genes, among them ALL1 and ALL2. These genes encode for highly homologous cytosolic proteins of unknown function. Deletion mutants of these proteins, namely all1(?and all2(, mimic the hypervirulent phenotype of the MC variant. Especially the all1(?mutant has a striking phenotype as it is more virulent than the SM parent in pulmonary infection and results in augmented intracranial pressure in a CNS infection model. Most interestingly, the all1(?exhibits enhanced stress resistance, manifests a prolonged life span and excretes an altered polysaccharide. Since capsular polysaccharide is implicated in high intracranial pressure we now have a mechanistic link between ALL1 and the changes in virulence. The all1(?exhibits impaired capsule induction, sheds a qualitative different polysaccharide and is more resistant to stress from oxygen radical. Here we propose to examine the function of ALL1. Our proposal is divided in three aims: I.) To investigate characteristics of the polysaccharide capsule in the all1(?mutant ii.) To explore the functional relationships of ALL1 iii.) To elucidate the regulatory pathway of ALL1.

Public Health Relevance

This grant proposal studies how a fungus that causes chronic infection in patients changes. Cryptococcus neoformans can change from a smooth a mucoid colony type. We are interested to study two genes that change when the fungus switches. We will investigate the function of these genes how they are regulated and how they specifically make the fungus more virulent.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059681-07
Application #
8298968
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2004-06-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$415,000
Indirect Cost
$165,000
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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
Helbig, S; Achkar, J M; Jain, N et al. (2013) Diagnosis and inflammatory response of patients with candiduria. Mycoses 56:61-9
Jain, Neena; Cordero, Radames J B; Casadevall, Arturo et al. (2013) Allergen1 regulates polysaccharide structure in Cryptococcus neoformans. Mol Microbiol 88:713-27
Bouklas, Tejas; Pechuan, Ximo; Goldman, David L et al. (2013) Old Cryptococcus neoformans cells contribute to virulence in chronic cryptococcosis. MBio 4:
Ormerod, Kate L; Morrow, Carl A; Chow, Eve W L et al. (2013) Comparative Genomics of Serial Isolates of Cryptococcus neoformans Reveals Gene Associated with Carbon Utilization and Virulence. G3 (Bethesda) :
Bouklas, Tejas; Fries, Bettina C (2013) Cryptococcus neoformans constitutes an ideal model organism to unravel the contribution of cellular aging to the virulence of chronic infections. Curr Opin Microbiol 16:391-7
Wang, Xiabo; Fries, Bettina C (2011) A murine model for catheter-associated candiduria. J Med Microbiol 60:1523-9
Guerrero, A; Jain, N; Wang, X et al. (2010) Cryptococcus neoformans variants generated by phenotypic switching differ in virulence through effects on macrophage activation. Infect Immun 78:1049-57
Achkar, Jacqueline M; Fries, Bettina C (2010) Candida infections of the genitourinary tract. Clin Microbiol Rev 23:253-73

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