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Updated: Jul 15, 2025
Humanized Mouse Model to Study Bacterial Infections Targeting the Microvasculature
Published on: April 1, 2014
Concurrent Brain Subregion Microgliosis in an HLA-II Mouse Model of Group A Streptococcal Skin Infection
Suba Nookala1, Santhosh Mukundan1, Bryon Grove1
1Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
Abstract:
The broad range of clinical manifestations and life-threatening infections caused by the Gram-positive bacterium, Streptococcus pyogenes or Group A Streptococcus (GAS), remains a significant concern to public health, with a subset of individuals developing neurological complications. Here, we examined the concurrent neuroimmune effects of subcutaneous GAS infections in an HLA-Class II (HLA) transgenic mouse model of subcutaneous GAS infection. To investigate changes in the skin-brain axis, HLA-DQ8 (DQA1*0301/DQB1*0302) mice (DQ8) were randomly divided into three groups: uninfected controls (No Inf), GAS infected and untreated (No Tx), and GAS infected with a resolution by clindamycin (CLN) treatment (CLN Tx) (10 mg/kg/5 days) and were monitored for 16 days post-infection. While the skin GAS burden was significantly reduced by CLN, the cortical and hippocampal GAS burden in the male DQ8 mice was not significantly reduced with CLN. Immunoreactivity to anti-GAS antibody revealed the presence of GAS bacteria in the vicinity of the neuronal nucleus in the neocortex of both No Tx and CLN Tx male DQ8 mice. GAS infection-mediated cortical cytokine changes were modest; however, compared to No Inf or No Tx groups, a significant increase in IL-2, IL-13, IL-22, and IL-10 levels was observed in CLN Tx females despite the lack of GAS burden. Western blot analysis of cortical and hippocampal homogenates showed significantly higher ionized calcium-binding adaptor-1 (Iba-1, microglia marker) protein levels in No Tx females and males and CLN Tx males compared to the No Inf group. Immunohistochemical analysis showed that Iba-1 immunoreactivity in the hippocampal CA3 and CA1 subregions was significantly higher in the CLN Tx males compared to the No Tx group. Our data support the possibility that the subcutaneous GAS infection communicates to the brain and is characterized by intraneuronal GAS sequestration, brain cytokine changes, Iba-1 protein levels, and concurrent CA3 and CA1 subregion-specific microgliosis, even without bacteremia.
Insights
Subcutaneous Group A Streptococcus (GAS) infection impacts the brain, causing intraneuronal bacteria and neuroinflammation. Treatment reduced skin GAS but not brain burden, indicating a persistent neuroimmune response.
Area of Science:
- Neuroimmunology
- Microbiology
- Infectious Diseases
Background:
- Group A Streptococcus (GAS) causes severe infections with potential neurological complications.
- Understanding the skin-brain axis in GAS infections is crucial for public health.
- Specific host factors, like HLA-DQ8, may influence neuroimmune responses.
Purpose of the Study:
- To investigate the neuroimmune effects of subcutaneous GAS infection in HLA-DQ8 transgenic mice.
- To examine the impact of clindamycin treatment on GAS burden and neuroinflammation.
- To explore the skin-brain axis communication during GAS infection.
Main Methods:
- Subcutaneous GAS infection in HLA-DQ8 mice, with groups receiving no treatment or clindamycin.
- Monitoring of GAS burden in skin and brain (cortex, hippocampus).
- Analysis of cytokine profiles, microglial marker Iba-1 expression, and bacterial presence in neural tissues.
Main Results:
- Clindamycin treatment reduced skin GAS burden but not cortical or hippocampal GAS burden in males.
- GAS bacteria were found within neuronal nuclei in the neocortex of treated and untreated infected mice.
- Increased levels of IL-2, IL-13, IL-22, and IL-10 were observed in female mice post-treatment, despite no detectable GAS burden.
- Elevated Iba-1 protein levels (microglia marker) were found in infected mice, with increased hippocampal immunoreactivity in treated males.
Conclusions:
- Subcutaneous GAS infection can lead to intraneuronal bacterial presence and neuroinflammation in the brain.
- The skin-brain axis is affected, characterized by microgliosis and altered cytokine profiles, even without bacteremia.
- Treatment efficacy may differ between peripheral sites and the central nervous system, highlighting the complexity of GAS neuroinvasion.
