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Scientific reports2023; 13(1); 1486; doi: 10.1038/s41598-023-27956-y

TLR4 and MD2 variation among horses with differential TNFα baseline concentrations and response to intravenous lipopolysaccharide infusion.

Abstract: Gram-negative bacterial septicemia is mediated through binding of lipopolysaccharide (LPS) to mammalian toll-like receptor protein 4 (TLR4). TLR4 and its cognate protein, myeloid differentiation factor 2 (MD2) form a heterodimeric complex after binding LPS. This complex induces a cascade of reactions that results in increased proinflammatory cytokine gene expression, including TNFα, which leads to activation of innate immunity. In horses, the immune response to LPS varies widely. To determine if this variation is due to differences in TLR4 or MD2, DNA from 15 healthy adult horses with different TNFα dynamics after experimental intravenous LPS infusion was sequenced across exons of TLR4 and MD2. Haplotypes were constructed for both genes using all identified variants. Four haplotypes were observed for each gene. No significant associations were found between either TNFα baseline concentrations or response to LPS and haplotype; however, there was a significant association (P value = 0.0460) between the baseline TNFα concentration and one MD2 missense variant. Three-dimensional structures of the equine TLR4-MD2-LPS complex were built according to haplotype combinations observed in the study horses, and the implications of missense variants on LPS binding were modeled. Although the sample size was small, there was no evidence that variation in TLR4 or MD2 explains the variability in TNFα response observed after LPS exposure in horses.
© 2023. The Author(s).
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Publication Date: 2023-01-27 PubMed ID: 36707633PubMed Central: PMC9883502DOI: 10.1038/s41598-023-27956-yGoogle Scholar: Lookup
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  • Journal Article
  • Research Support
  • N.I.H.
  • Extramural
  • Research Support
  • Non-U.S. Gov't
  • Research Support
  • U.S. Gov't
  • Non-P.H.S.

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research explored why the immune response to bacterial septicemia varies among horses, investigating if it relates to genetic differences in key immune proteins. The study used DNA from 15 healthy horses, but found no significant association between the immune response of these animals and variations in these crucial proteins, contrary to initial assumptions.

Understanding the Research Objectives

  • The primary purpose of this research study was to discern the reason for the observed variation in horses’ immune response to lipopolysaccharide (LPS), a molecule associated with gram-negative bacterial infections.
  • The consideration was given to the underlying roles of two proteins – Toll-Like Receptor Protein 4 (TLR4) and Myeloid Differentiation Factor 2 (MD2) that typically bind LPS, inducing an immune response.
  • The researchers hypothesized that genetic variation in the genes encoding TLR4 and MD2 might account for the differences in horses’ immune responses.

Methodological Approach

  • The researchers selected 15 healthy adult horses and artificially induced an immune response through experimental intravenous LPS infusion.
  • They observed and categorized the horses based on their immune response, especially their TNFα dynamics – the level of a crucial pro-inflammatory cytokine triggered by LPS.
  • DNA was extracted from each horse and sequenced, targeting the gene exons (protein-coding regions) of TLR4 and MD2. The observed genetic variations were used to construct haplotypes – specific combinations of alleles on a single chromosome passed down from one generation to the next.
  • Three-dimensional structures of the TLR4-MD2-LPS complex were modeled according to the observed haplotype combinations.

Main Findings

  • Four haplotypes were found for both TLR4 and MD2 genes. However, no significant associations were found between either the baseline TNFα concentrations or the response to LPS, and the haplotypes of either gene.
  • A singularly significant association was found between the baseline TNFα concentration and one uncommon variant in the MD2 gene (a missense variant).
  • Despite the rendering of 3D structures and haplotype combinations, the researchers found no conclusive evidence to link variation in TLR4 or MD2 with the variability in TNFα response observed after LPS exposure in horses.

Implications of the Study

  • This study contributes to the understanding of equine immune responses. Though the hypothesis was not proven, it may guide future research towards other potential explanations for the variation in horses’ immune responses.
  • The finding of a significant association between one MD2 missense variant and the baseline TNFα concentration hints at a possible role of certain MD2 genetic variations in differential immune response, a point that could be explored in larger studies.

The research concludes that the variability in immune response among horses exposed to LPS may not be explained by genetic differences in TLR4 and MD2 genes, contrary to what the initial hypothesis proposed. Nonetheless, the impact of certain MD2 missense variant on baseline TNFα concentration suggests the need for additional research regarding other potentially influential factors on the immune response.

Cite This Article

APA
Mukhopadhyay A, Cook SR, SanMiguel P, Ekenstedt KJ, Taylor SD. (2023). TLR4 and MD2 variation among horses with differential TNFα baseline concentrations and response to intravenous lipopolysaccharide infusion. Sci Rep, 13(1), 1486. https://doi.org/10.1038/s41598-023-27956-y

Publication

Scientific reports
ISSN: 2045-2322
NlmUniqueID: 101563288
Country: England
Language: English
Volume: 13
Issue: 1
Pages: 1486
PII: 1486

Researcher Affiliations

Mukhopadhyay, Abhijit
  • Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA.
Cook, Shawna R
  • Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA.
SanMiguel, Phillip
  • Bindley Bioscience Center, Purdue University, West Lafayette, IN, USA.
Ekenstedt, Kari J
  • Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA.
Taylor, Sandra D
  • Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN, USA. taylo248@purdue.edu.

MeSH Terms

  • Animals
  • Horses
  • Lipopolysaccharides
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Lymphocyte Antigen 96 / metabolism
  • Toll-Like Receptors / metabolism
  • Lipopolysaccharide Receptors / metabolism
  • Mammals / metabolism

Grant Funding

  • K01 OD027051 / NIH HHS

Conflict of Interest Statement

The authors declare no competing interests.

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