title: Characterization of host response to Cryptococcus neoformans through quantitative proteomic analysis of cryptococcal meningitis co-infected with HIV.
abstract: Cryptococcal meningitis is the most common opportunistic fungal infection causing morbidity and mortality (>60%) in HIV-associated immunocompromised individuals caused by Cryptococcus neoformans. Molecular mechanisms of cryptococcal infection in brain have been studied using experimental animal models and cell lines. There are limited studies for the molecular understanding of cryptococcal meningitis in human brain. The proteins involved in the process of invasion and infection in human brain still remains obscure. To this end we carried out mass spectrometry-based quantitative proteomics of frontal lobe brain tissues from cryptococcal meningitis patients and controls to identify host proteins that are associated with the pathogenesis of cryptococcal meningitis. We identified 317 proteins to be differentially expressed (≥2-fold) from a total of 3423 human proteins. We found proteins involved in immune response and signal transduction to be differentially expressed in response to cryptococcal infection in human brain. Immune response proteins including complement factors, major histocompatibility proteins, proteins previously known to be involved in fungal invasion to brain such as caveolin 1 and actin were identified to be differentially expressed in cryptococcal meningitis brain tissues co-infected with HIV. We also validated the expression status of 5 proteins using immunohistochemistry. Overexpression of major histocompatibility complexes, class I, B (HLA-B), actin alpha 2 smooth muscle aorta (ACTA2) and caveolin 1 (CAV1) and downregulation of peripheral myelin protein 2 (PMP2) and alpha crystallin B chain (CRYAB) in cryptococcal meningitis were confirmed by IHC-based validation experiments. This study provides the brain proteome profile of cryptococcal meningitis co-infected with HIV for a better understanding of the host response associated with the disease.
authors.affiliation: Institute of Bioinformatics, International Technology Park, Bangalore 560066, India. keshav@ibioinformatics.org.
authors.forename: Lakshmi Dhevi N
authors.initials: LD
authors.lastname: Selvan
authors.forename: Sreelakshmi K
authors.initials: SK
authors.lastname: Sreenivasamurthy
authors.forename: Satwant
authors.initials: S
authors.lastname: Kumar
authors.forename: Soujanya D
authors.initials: SD
authors.lastname: Yelamanchi
authors.forename: Anil K
authors.initials: AK
authors.lastname: Madugundu
authors.forename: Abhijith K
authors.initials: AK
authors.lastname: Anil
authors.forename: Santosh
authors.initials: S
authors.lastname: Renuse
authors.forename: Bipin G
authors.initials: BG
authors.lastname: Nair
authors.forename: Harsha
authors.initials: H
authors.lastname: Gowda
authors.forename: Premendu P
authors.initials: PP
authors.lastname: Mathur
authors.forename: Parthasarathy
authors.initials: P
authors.lastname: Satishchandra
authors.forename: S K
authors.initials: SK
authors.lastname: Shankar
authors.forename: Anita
authors.initials: A
authors.lastname: Mahadevan
authors.forename: T S
authors.initials: TS
authors.lastname: Keshava Prasad
mesh_terms: D060085:Coinfection; D019295:Computational Biology / Q000379:methods; D003455:Cryptococcus neoformans / Q000502:physiology*; D015658:HIV Infections / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D007150:Immunohistochemistry; D016919:Meningitis, Cryptococcal / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D058977:Molecular Sequence Annotation; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D020543:Proteome; D040901:Proteomics / Q000379:methods; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry
chemical_list: D020543:Proteome