This proposal on the pathogenesis of leptospirosis is based on the following findings in our models of acute lethal infection in the guinea pig, and chronic renal carriage in the rat: 1.) Pulmonary hemorrhage in guinea pigs parallels deposition of immunoglobulins and C3 along alveolar septae. 2.) Host-tissue Leptospira (HTL) disseminated in guinea pig tissues lack the O antigen (Oag) of in vitro cultivated Leptospira (IVCL), but HTL causing chronic infection restricted to rat renal tubules express Oag; 3.) guinea pig liver-derived and rat urine derived HTL protein composition differs from that of IVCL.
Three specific aims build on these findings. 1. Pathogenic mechanisms in acute hemorrhagic leptospirosis in guinea pigs and humans. The strain specificity of the pulmonary immunopathology will be determined. The time when an inflammatory cell infiltrate appears within alveolar septae will be related to the presence of leptospiral antigens, to the deposition of antibodies and C3, and to endothelial and epithelial damage. The target of antibodies along alveolar septae will be identified. 2. Role of down-regulation of O antigen synthesis (Oag-loss) in acute lethal infection; role of Oag in rat renal tubular colonization. We will assess whether Oag-loss loss during infection is a general property of pathogenic Leptospira, and when Oag-loss occurs in different guinea pig tissues. We will search for the signal that induces Oag-loss. Basic structural information about this form of LPS will be obtained. The hypotheses that Oag-loss promotes disseminated lethal infection, and that Oag promotes adherence to rat renal tubular epithelium will be tested. 3. Proteomics and cell surface structure of host-tissue leptospires. We will determine the protein composition of HTL derived from different tissues in temporal relation to the host immune response. The surface antigenic structure and biological properties of HTL and IVCL will be compared.
| Nally, Jarlath E; Whitelegge, Julian P; Bassilian, Sara et al. (2007) Characterization of the outer membrane proteome of Leptospira interrogans expressed during acute lethal infection. Infect Immun 75:766-73 |
| Nally, Jarlath E; Fishbein, Michael C; Blanco, David R et al. (2005) Lethal infection of C3H/HeJ and C3H/SCID mice with an isolate of Leptospira interrogans serovar copenhageni. Infect Immun 73:7014-7 |
