Inflammatory and Immunoregulatory Roles of Microbial Superantigens in Bovine Mastitis
Subclinical infectious mastitis is associated with persistent accumulation of immune cells in milk, resulting from an imbalance between bacterial virulence and host defense mechanisms, the consequence of which is a fluctuating increase in somatic cell count (~ 250,000 cells/ml). The negative influence of subclinical mastitis on milk production causes a typical cost of approx. $200 per year per cow for a case of subclinical mastitis. Staphylococcus aureus can elicit clinical mastitis but more frequently causes subclinical infections that tend to become chronic and difficult to eradicate by conventional antimicrobial therapies. Efforts to develop vaccines that prevent staphylococcal mastitis have met with limited success. Treatment with anti-inflammatory drugs and antibiotics has had some beneficial effect but such treatments are expensive and
present other shortcomings. A more effective control strategy is clearly needed. To accomplish this objective it will be necessary to gain a better understanding of how S. aureus modulates the immune response. One group of S. aureus virulence factors, staphylococcal enterotoxins (SE) are prototypic pyrogenic toxin superantigens (PTSAgs) highly correlated with mastitis. They are potential immunomodulatory virulence factors in mastitis. However, direct evidence for their role in mastitis is lacking, largely due to insufficient bovine immunological reagents and tools. Several lines of evidence in this proposal suggest that PTSAg immunosuppression plays a role in chronic staphylococcal mastitis. The purpose of this proposal is to extend preliminary studies to directly assess the roles of PTSAg in immunomodulation and in developing bovine mastitis. To address these question, we will 1)
Determine the mechanisms by which immune cell recruitment and persistence are differentially and temporally regulated by PTSAg; 2) Characterize the kinetics of immuno-suppressive T cell development in the mammary gland following exposure to PTSAg, and 3) Assess the effects of PTSAg-induced immunopathology in experimental intramammary infection. This study will build upon our knowledge regarding immunomodulation by PTSAg, and take advantage of new reagents and methods developed by our groups. Obtaining such knowledge is critical to developing more efficacious methods for treatment and prevention, both of which are critically lacking for this important bovine infectious disease.