Experimental yellow fever virus infection in the Golden Hamster (Mesocricetus auratus). I. Virologic, biochemical, and immunologic studies.

This report describes the clinical laboratory findings in golden hamsters experimentally infected with yellow fever (YF) virus. An accompanying paper describes the pathologic findings. Following intraperitoneal inoculation of a virulent strain of YF virus, hamsters developed a high-titered viremia (up to 109/mL) lasting 5--6 days and abnormal liver function tests. YF hemagglutination-inhibiting antibodies appeared 4 or 5 days after infection, often while viremia was still present. The mortality rate in YF-infected hamsters was variable, depending on the virus strain and the age of the animals. Clinical and pathologic changes in the infected hamsters were very similar to those described in experimentally infected macaques and in fatal human cases of YF, which indicates that the golden hamster may be an excellent alternative animal model, in place of nonhuman primates, for research on the pathogenesis and treatment of YF and other viscerotropic flavivirus diseases.

Comparative pathology, and immunohistology associated with clinical illness after Ehrlichia phagocytophila-group infections.

The Ehrlichia phagocytophila-group also includes E. equi and the human granulocytic ehrlichiosis (HGE) agent that are probably a single species. Disease is mild to severe illness in ruminants, horses, and humans, but the comparative pathology and ehrlichial distribution in tissues is poorly described. We compared pathology and ehrlichial distribution in humans with HGE, horses with E. equi infection, and a sheep with E. phagocytophila infection. Frequent findings included splenic lymphoid depletion, small macrophage aggregates and apoptoses in liver, and paracortical hyperplasia in lymph nodes. Bone marrow was normocellular or hypercellular. Only the spleen was frequently infected; other organs with infected cells included lung, liver, heart, and kidney, but lesions were present in lung and liver only. Most infected cells were neutrophils. Ehrlichia phagocytophila-group infections are associated with moderate tissue damage. While the pathogenesis of granulocytic ehrlichiosis is not clear, pathologic studies suggest that the process is initiated by ehrlichia-infected cells but may result from host-mediated injury and immunosuppression.

Pathology, immunohistology, and cytokine responses in early phases of human granulocytic ehrlichiosis in a murine model.

Human granulocytic ehrlichiosis (HGE) results in fever, pancytopenia, and mild liver injury. We used a mouse model to examine immunity in the pathogenesis of HGE. HGE agent-infected C3H/HeJ mice were necropsied over 21 days. Histologic, immunohistologic, and serologic analyses, blood culture, tissue and blood polymerase chain reaction (PCR), cell counts, serum chemistries, and plasma cytokine ELISAs were performed. No clinical signs were detected. Ehrlichiae were identified in neutrophils in hematopoietic tissues maximally on day 7. Interleukin (IL)-10 levels were high throughout, whereas interferon (IFN)-gamma levels peaked on days 7 and 10 and dropped thereafter. Hepatic lymphohistiocytic aggregates with apoptoses were maximal at day 14. HGE-agent infection of mice induces pathologic changes similar to those in infected humans, despite differences in cytokine profile. The IFN-gamma peak prior to maximal pathologic change, when ehrlichiae are absent in tissues, suggests a role for host immunity in the pathogenesis of HGE.

Detection of pathogenic Leptospira spp. infections among mammals captured in the Peruvian Amazon basin region.

To identify potential zoonotic reservoirs of pathogenic leptospires in the Peruvian Amazon basin, wild mammals were trapped from July 1997 to December 1998 near the city of Iquitos. After extraction of nucleic acids from animal kidneys, DNA of pathogenic leptospires was identified by polymerase chain reaction (PCR) assays using one of two primer sets, one amplifying a region of the 23S rRNA gene, and the other amplifying a gene fragment specific for Leptospira spp (G1/G2 primers). Overall, 29% (40 of 136) of the mammals tested showed evidence of renal infection by Leptospira spp., including 20% (13 of 64) of the rodents, 39% (20 of 51) of the marsupials, and 35% (7 of 20) of the chiropterans (bats). Marsupials and chiropterans were implicated as more significant reservoir hosts of leptospires pathogenic to humans than previously recognized.

Development and distribution of pathologic lesions are related to immune status and tissue deposition of human granulocytic ehrlichiosis agent-infected cells in a murine model system.

To evaluate pathology and the role of immune status in a murine model system of human granulocytic ehrlichiosis (HGE), C3H/HeJ, C3H-SCID, and Peromyscus leucopus mice were infected with an HGE agent. All mice remained healthy. Ehrlichemia was not detected after day 14 in P. leucopus and C3H/HeJ mice but increased between days 14 and 90 in C3H-SCID mice. In tissues examined at day 21 and later, infection was rarely detected in immunocompetent mice but was present in all C3H-SCID mice and included pulmonary endothelialitis and hepatic mononuclear cell aggregates with apoptoses. HGE agent was demonstrated in mature and immature myeloid cells in hematopoietic tissues and infrequently in lung and liver lesions with deposition of infected cells. HGE agent infection in immunocompromised mice progresses slowly, has a higher infectious burden and more tissue pathology and is persistent. A murine model for HGE may be useful to assess pathologic lesions, transmission, and persistence.

Infection of laboratory mice with the human granulocytic ehrlichiosis agent does not induce antibodies to diagnostically significant Borrelia burgdorferi antigens.

Laboratory diagnosis of Borrelia burgdorferi is routinely made by an enzyme-linked immunosorbent assay, with positive results confirmed by Western blot analysis. Concern has been raised that false-positive diagnoses may be made on the basis of serologic cross-reactivity with antibodies directed against other bacterial pathogens, in particular the agent of human granulocytic ehrlichiosis (HGE). The present study made use of a mouse model to ascertain the validity of these concerns. Two different strains of mice were inoculated with the HGE agent and assayed for production of polyclonal and monoclonal antibodies to antigens of both of these bacteria. Infection of mice with the HGE agent does not induce diagnostically significant B. burgdorferi serologic cross-reactions.

Retrospective serosurvey for human granulocytic ehrlichiosis agent in urban white-footed mice from Maryland.

Archived serum samples from 111 Peromyscus leucopus, collected 1984-88 in Baltimore City (Maryland, USA), were analyzed by indirect immunofluorescence assay. Sera from two (2%) individuals contained antibodies reactive to Ehrlichia equi and the human granulocytic ehrlichiosis (HGE) agent. This suggests that the HGE agent or an antigenically related organism has been present in rodent populations in this locality for more than a decade, and was present in the region at least 12 yr before a case of human disease was recognized.