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Cited by 54Viral Infections and Immunology ResearchImmune Response and InflammationCardiac Fibrosis and Remodeling

Sex-specific signaling through Toll-Like Receptors 2 and 4 contributes to survival outcome of Coxsackievirus B3 infection in C57Bl/6 mice

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Roberts, Brian J, Dragon, Julie A, Moussawi, Mohamad, Huber, Sally A·2012·Biology of Sex Differences
DOI 10.1186/2042-6410-3-25PMC PMC3586360
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Abstract

Background: Coxsackievirus B3 (CVB3) induces myocarditis, an inflammatory heart disease, which affects men more than women. Toll-like receptor (TLR) signaling has been shown to determine the severity of CVB3-induced myocarditis. No direct role for signaling through TLR2 had been shown in myocarditis although published studies show that cardiac myosin is an endogenous TLR2 ligand and stimulates pro-inflammatory cytokine expression by dendritic cells in vitro. The goal of this study is to determine which TLRs show differential expression in CVB3 infected mice corresponding to male susceptibility and female resistance in this disease. Methods: Male and female C57Bl/6 mice were infected with 10 2 PFU CVB3 and killed on day 3 or 6 post infection. Hearts were evaluated for virus titer, myocardial inflammation, and TLR mRNA expression by PCR array and microarray analysis. Splenic lymphocytes only were evaluated by flow cytometry for the number of TLR+/CD3+, TLR+/CD4+, TLR+F4/80+ and TLR+/CD11c+ subpopulations and the mean fluorescence intensity to assess upregulation of TLR expression on these cells. Mice were additionally treated with PAM3CSK4 (TLR2 agonist) or ultrapure LPS (TLR4 agonist) on the same day as CVB3 infection or 3 days post infection to confirm their role in myocarditis susceptibility. Results: Despite equivalent viral titers, male C57Bl/6 mice develop more severe myocarditis than females by day 6 after infection. Microarray analysis shows a differential expression of TLR2 at day 3 with female mice having higher levels of TLR2 gene expression compared to males. Disease severity correlates to greater TLR4 protein expression on splenic lymphocytes in male mice 3 days after infection while resistance in females correlates to preferential TLR2 expression, especially in spleen lymphocytes. Treating male mice with PAM reduced mortality from 55% in control CVB3 infected animals to 10%. Treating female mice with LPS increased mortality from 0% in control infected animals to 60%. Conclusion: CVB3 infection causes an up-regulation of TLR2 in female and of TLR4 in male mice and this differential expression between the sexes contributes to disease resistance of females and susceptibility of males. While previous reports demonstrated a pathogenic role for TLR4 this is the first report that TLR2 is preferentially up-regulated in CVB3 infected female mice or that signaling through this TLR directly causes myocarditis resistance.

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  • The TLR4, caspase-1, and NLRP3 pathways are upregulated in patients, EAM, autoimmune CVB3 myocarditis, and CVB3-only models and increase IL-1β and IL-18 levels in the heart.

    “Another key pathway upregulated in patients, EAM, autoimmune CVB3 myocarditis, and CVB3only models is the TLR4, caspase-1, and NLRP3 pathways that increase IL-1 β and IL-18 levels in the heart. 124,146,152,156,161-164”

    From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [162]

    The Discussion (page not provided) reports increased TLR4 expression in CVB3-infected male mice and suggests that TLR4 signaling could increase IL-18 production. It does not establish upregulation of caspase-1 or NLRP3, increased cardiac IL-1β, or the combined pathway across patients, EAM, and the other listed models. (LLM, conf=0.88)

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  1. Frisancho-Kiss S, et al: Cutting edge: cross-regulation by TLR4 and T cell Ig mucin-3 determines sex differences in inflammatory heart disease. J Immunol 2007, 178(11):6710-6714.

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Authors
Roberts, B. J., Dragon, J. A., Moussawi, M., & Huber, S. A.
Affiliations
University of Vermont (US)
Corresponding author
Huber, Sally A
ORCID
Venue
Biology of Sex Differences
Publisher
Springer Science and Business Media LLC
Published
2012-12
Volume
3
Issue
1
Pages
25-25
ISSN
2042-6410 (ISSN-L)
DOI
10.1186/2042-6410-3-25
PMC
PMC3586360
OpenAlex
W2157018829
Cited by
54
References
62
Citations by year
2026: 3 · 2025: 2 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 6 · 2020: 6 · 2019: 4 · 2018: 2 · 2017: 3 · 2016: 4 · 2015: 7 · 2014: 4 · 2013: 5
FWCI
3.29
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Biology of Sex Differences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • University of Vermont
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (HL108371, R01HL108371)
  • National Institute of General Medical Sciences (P20GM103496)
  • National Center for Research Resources (P20RR021905, T20-RR021905, P20RR016462)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
coxsackievirus B3, myocarditis, sex differences, TLR2, TLR4, TLR4 mRNA expression, splenocytes, Pam3CSK4, lipopolysaccharide, viral susceptibility, survival outcomes, C57BL/6 mice

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