Protective Roles of Folic Acid in the Responses of Bovine Mammary Epithelial Cells to Different Virulent Staphylococcus aureus Strains

Abstract

Mastitis caused by Staphylococcus aureus (S. aureus) infection is one of the most difficult diseases to treat in dairy cattle. Exploring the biological progression of S. aureus mastitis via the interaction between host, pathogen, and environment is the key to an effective and sustainable improvement of animal health. Here, two strains of S. aureus and a strain of MRSA (Methicillin-resistant Staphylococcus aureus) isolated from cows with different inflammation phenotypes were used to challenge Mac-T cells and to investigate their effects on the global transcriptome of the cells, then to explore the potential regulatory mechanisms of folic acid on S. aureus mastitis prevention. Differential gene expression or splicing analysis showed that different strains of S. aureus led to distinct transcriptional responses from the host immune system. Folic acid could protect host defense against the challenge of S. aureus and MRSA partially through activating cytoplasmic DNA sensing and tight junction pathway. ZBP1 at the upstream of cytoplasmic DNA sensing pathway was verified and related to anti-pathogen through RNA interference. Further enrichment analysis using these transcriptome data with cattle large-scale genome-wide association study (GWAS) data confirmed that ZBP1 gene is highly associated with bovine somatic cell score (SCS) trait. Our data shed light on the potential effect of FA through regulating key gene and then protect host cells’ defense against S. aureus and MRSA.

Enhancing bovine immune, antioxidant and anti-inflammatory responses with vitamins, rumen-protected amino acids, and trace minerals to prevent periparturient mastitis

“…Moreover, we documented that folic acid effectively enhanced dairy cattle’s antioxidant capabilities and augmented their resistance to mammary gland infections during the periparturient phase. Aligning with this, ( 166 ) recently conducted an experimental study showing that S. aureus- induced mastitis in MAC-T cells resulted in the downregulation of the noncoding RNA associated with progenitor renewal (PRANCR). Notably, in MAC-T cells treated with folic acid, this expression exhibited an increase, suggesting folic acid’s potential as a prime therapeutic agent in mastitis prevention ( 166 ).…”

“…Aligning with this, ( 166 ) recently conducted an experimental study showing that S. aureus- induced mastitis in MAC-T cells resulted in the downregulation of the noncoding RNA associated with progenitor renewal (PRANCR). Notably, in MAC-T cells treated with folic acid, this expression exhibited an increase, suggesting folic acid’s potential as a prime therapeutic agent in mastitis prevention ( 166 ). Treatment with 5 μg/mL of folic acid significantly curtailed apoptosis in Mac-T cells and offered robust defense against MRSA treatment through enhanced cytosolic DNA sensing and tightened junction signaling ( 173 , 176 ).…”

“…The significance of vitamins in their capacities as antioxidants and immune regulators has been extensively deliberated in the literature ( 16 , 150 , 162 ). Consequently, the inclusion of vitamin supplementation in mastitis control strategies has been well-documented ( 163 – 166 ).…”

“…The period around calving presents a vulnerability to lowered immunity in dairy cattle due to folic acid deficiency ( 165 ). Folic acid’s pivotal contributions to immunity and anti-inflammatory processes have led to its exploration for mitigating bovine mastitis in periparturient dairy cattle ( 166 , 170 , 171 ). Recently a published research demonstrated that folic acid treatment significantly regulated LnRNA MSTRG.11108.1 in mastitic cows.…”

“…They observed the upregulation of ZBP1, IRF3, IRF7, and IFNAR2 within the cytosolic DNA-sensing pathway in folic acid-treated MAC-T cells. ZTP1, a factor associated with milk SCC ( 166 ), also assumes a critical role in activating anti-pathogenic mechanisms and inflammation ( 177 ). Furthermore, it was found that ZTP1 gene cytosolic DNA sensing pathway upregulated by folic acid treatment which has key role in activation of antipathogenic mechanism thereby enhancing the anti-inflammatory response ( 173 ).…”