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A Mouse Model to Assess Innate Immune Response to Staphylococcus aureus Infection
Published on: February 28, 2019
In Vivo Analysis of Staphylococcus aureus-Infected Mice Reveals Differential Temporal and Spatial Expression Patterns
Marta Bacconi1, Andreas F Haag1, Emiliano Chiarot1
1GSK Vaccines Srl, Siena, Italy.
Abstract:
Staphylococcus aureus is an opportunistic human pathogen and a major cause of invasive infections such as bacteremia, endocarditis, pneumonia, and wound infections. FhuD2 is a staphylococcal lipoprotein involved in the uptake of iron-hydroxymate and is under the control of the iron uptake regulator Fur. This protein is part of an investigational multicomponent vaccine formulation that has shown protective efficacy in several murine models of infection. Even though fhuD2 expression has been shown to be upregulated in murine kidneys infected with S. aureus, it is not known whether the bacterium undergoes increased iron deprivation during prolonged infection. Furthermore, different S. aureus infection niches might provide different environments and levels of iron availability, resulting in different fhuD2 expression patterns among organs of the same host. To address these questions, we characterized the in vitro expression of the fhuD2 gene and confirmed Fur-dependent regulation of its expression. We further investigated its expression in mice infected with a bioluminescent reporter strain of S. aureus expressing the luciferase operon under the control of the fhuD2 promoter. The emission of bioluminescence in different organs was followed over a 7-day time course, and quantitative real-time PCR analysis of the RNA transcribed from the endogenous fhuD2 gene was performed. Using this approach, we were able to show that fhuD2 expression was induced during infection in all organs analyzed and that differences in expression were observed at different time points and in different infected organs. Our data suggest that S. aureus undergoes increased iron deprivation during the progression of infection in diverse host organs and accordingly induces dedicated iron acquisition mechanisms. Since FhuD2 plays a central role in providing the pathogen with the required iron, further knowledge of the patterns of fhuD2 expression in vivo during infection will be instrumental in better defining the role of this antigen in S. aureus pathogenesis and as a vaccine antigen.
Insights
Staphylococcus aureus increases iron uptake via FhuD2 during infection. This study tracked fhuD2 gene expression in mice, revealing its induction across organs and time, indicating iron deprivation drives this crucial mechanism.
Area of Science:
- Microbiology
- Pathogenesis
- Vaccinology
Background:
- Staphylococcus aureus is a major human pathogen causing severe infections.
- FhuD2 facilitates iron uptake and is a target for vaccine development.
- Iron availability influences S. aureus virulence and FhuD2 expression.
Purpose of the Study:
- To investigate fhuD2 gene expression in vivo during S. aureus infection.
- To determine if S. aureus experiences iron deprivation in different infection sites.
- To confirm Fur-dependent regulation of fhuD2.
Main Methods:
- In vitro characterization of fhuD2 expression and Fur regulation.
- Infection of mice with a bioluminescent S. aureus reporter strain.
- In vivo imaging of bioluminescence and qRT-PCR analysis of fhuD2 transcripts.
Main Results:
- FhuD2 expression is upregulated in all infected organs studied.
- Expression levels vary over time and across different organs.
- Fur-dependent regulation of fhuD2 was confirmed.
Conclusions:
- S. aureus actively acquires iron during infection progression in diverse host niches.
- FhuD2 induction reflects host iron limitation and is critical for pathogenesis.
- Understanding fhuD2 in vivo dynamics is key for vaccine design against S. aureus.
