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Analysis of Simian Immunodeficiency Virus-specific CD8+ T-cells in Rhesus Macaques by Peptide-MHC-I Tetramer Staining
Published on: December 23, 2016
Potential for Early Diagnosis of Leptospirosis in Experimentally Infected Rhesus Macaques Based on Detection of
Reetika Chaurasia1, Caroline J Zeiss2, Marlena Holter2
1Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
Abstract:
Molecular and cellular mechanisms of leptospirosis pathogenesis remain poorly understood. Recent genomic, in vitro, and animal model data indicate that the novel PF07598 gene family encodes the so-called virulence-modifying proteins (VMPs), secreted exotoxins that are hypothesized to mediate the clinical manifestations of leptospirosis. Key to understanding the mechanistic role of VMPs in disease pathogenesis is testing the hypothesis that VMPs are produced during infection. Rhesus macaques were experimentally inoculated at multiple sites with low-passage Leptospira interrogans serovar Copenhageni strain Fiocruz L1-130. Microscopic agglutination test and polymerase chain reaction confirmed infection, but animals did not develop observable illness. An ELISA using recombinant VMPs demonstrated anti-VMP IgM and IgG antibodies on days 4 and 8, respectively, indicating that the infectious strain produced VMPs expectedly after infection. An antigen-capture ELISA detected VMP antigen in infected monkey urine and blood. Liver, kidneys, and lungs demonstrated mild histopathological abnormalities, demonstrating that target organs were subclinically involved in nonsevere leptospirosis. Elevated serum levels of multiple cytokines (TNFα, IL-15, IL-8, sCD40L, MCP-1, and MIPb) showed systemic host inflammatory responses. This study addresses key gaps in understanding leptospirosis pathogenesis in nonhuman primates, aiming to develop VMP-based biomarkers for improved diagnosis and prognosis.
Insights
This study shows that virulence-modifying proteins (VMPs) are produced during Leptospira infection in nonhuman primates. VMP detection in blood and urine suggests their role in subclinical leptospirosis pathogenesis.
Area of Science:
- Infectious Diseases
- Microbiology
- Immunology
Background:
- Leptospirosis pathogenesis mechanisms are poorly understood.
- The PF07598 gene family encodes virulence-modifying proteins (VMPs), hypothesized to cause leptospirosis symptoms.
- Understanding VMP production during infection is crucial for elucidating disease mechanisms.
Purpose of the Study:
- To test if VMPs are produced during Leptospira infection.
- To investigate the role of VMPs in subclinical leptospirosis.
- To explore VMP-based biomarkers for leptospirosis diagnosis and prognosis.
Main Methods:
- Experimental inoculation of rhesus macaques with Leptospira interrogans.
- ELISA to detect anti-VMP antibodies and VMP antigen in serum, urine, and blood.
- Histopathological examination of target organs (liver, kidneys, lungs).
- Cytokine profiling to assess host inflammatory responses.
Main Results:
- Infection confirmed, but animals remained asymptomatic.
- Anti-VMP IgM and IgG antibodies detected, confirming VMP production.
- VMP antigen found in urine and blood of infected monkeys.
- Mild histopathological changes in liver, kidneys, and lungs.
- Elevated levels of inflammatory cytokines (TNFα, IL-15, IL-8, etc.) observed.
Conclusions:
- VMPs are produced during Leptospira infection in a nonhuman primate model.
- VMPs are detectable in bodily fluids, suggesting potential as diagnostic biomarkers.
- Subclinical organ involvement and systemic inflammation occur in nonsevere leptospirosis.
- This research provides insights into leptospirosis pathogenesis and VMP roles.
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