Project description:To predict the outcomes of disseminated fungal disease, a deeper understanding of host-pathogen interactions at the site of infection is needed to identify targets for clinical intervention and diagnostic development. Cryptococcus neoformans is the causative agent of cryptococcosis, the largest infectious killer of individuals living with HIV. Cryptococcal infection begins in the lungs, with loss of immunological control leading to disseminated central nervous system disease and death. Using advanced mass spectrometry-based proteomic techniques, in vivo infection models, and patient-derived clinical strains, we explored the proteomic profiles of C. neoformans infections related to differences in strain virulence. Our findings reveal the non-lethal latent infection produces a proteomic response that drastically differs from those caused by lethal infections, and that the proteomic profiles of typical and hypervirulent infections are surprisingly similar despite differences in time-to-death.
Project description:Prenatal Human Cytomegalovirus (HCMV) infection often causes CNS maldevelopment. In a murine model, we detect Murine Cytomegalovirus (MCMV) in brain following intra-peritoneal inoculation at birth. Infected mice show impaired cerebellar development and impaired neurologic function on a beam balance test as adults. Among developmental genes differentially regulated, hindbrain expression of the homeodomain transcription factor HOXa5 was reduced with infection, and fewer HOXa5 expressing neurons were found in vestibular nuclei. Based on the hypothesis that immune activation connects focal viral infection and global CNS maldevelopment, we defined the components of CNS immune response. Flow cytometry showed a large increase in both number and activation of CNS monocytes. Monocytes were found in close association with infected cells by immunohistochemistry (IHC). Oligonucleotide microarrays contained herein identified many differentially expressed genes related to innate immune response. Chemokines, cytokines, cell surface receptors, and proteases are some of the many immunological genes shown to be differentially regulated by MCMV infection. These results together show that MCMV infection induces a complex immune response associated with changes in developmental gene expression and lasting neurologic defecit. Keywords: disease state comparison (virus infection) and competetive hybridization for expression analysis
Project description:Toxoplasma gondii (T. gondii) is an opportunistic parasite that can infect the central nervous system, causing severe toxoplasmosis and behavioral cognitive impairment. Mortality is high in immunocompromised individuals with toxoplasmosis, most commonly due to reactivation of infection in the central nervous system (CNS). There are still no effective vaccines and drugs for the prevention and treatment of toxoplasmosis. There are five developmental stages for T. gondii to complete life cycle, of which the tachyzoite and bradyzoite stages are the key to the acute and chronic infection. In this study, to better understanding of how T. gondii interacts with the host central nervous system at different stages of infection, we constructed acute and chronic infection models of T. gondii in astrocytes, and used lab-free proteomics to detect the proteome changes before and after infection, respectively.
