THE IMPACT OF LIPID METABOLISM ON STAPHYLOCOCCAL MASTITIS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。金黄色葡萄球菌在人类和动物中引起多种疾病。虽然大多数未报告，但乳腺葡萄球菌感染或乳腺炎每年影响数百万妇女-近33%的哺乳母亲。不幸的是，研究已经确定，妇女的乳腺炎是停止母乳喂养的一个重要原因。鉴于母乳喂养的好处现已得到充分记载，这一点尤为重要。例如，这些益处包括保护婴儿免受疟疾和呼吸道疾病的侵害，最终降低新生儿后期死亡的风险。此外，母乳喂养的婴儿在成年后患肥胖症和心血管疾病的风险降低。也许更令人震惊的是，研究表明，感染艾滋病毒的妇女患乳腺炎是这种病毒从母亲传染给婴儿的一个主要危险因素。尽管乳腺炎对人类健康的影响，很少有人知道发生与乳腺炎的宿主-病原体相互作用。最近的研究表明，牛奶中的脂质对病原体如沙门氏菌有深远的影响。金黄色。例如，甘油单月桂酸酯（GML）对S.金黄色葡萄球菌毒力因子的表达。金黄色葡萄球菌在亚抑制浓度。如我们的初步研究所示，GML中的活性剂似乎是游离脂肪酸月桂酸。此外，我们的研究表明，牛奶中常见的其他脂肪酸具有抗菌活性。因此，脂质可能不仅仅是哺乳期婴儿的能量来源;通过细菌和哺乳动物脂肪酶的作用获得的许多脂肪酸也可能通过抑制细菌生长和毒力在最大限度地减少病原体对宿主的影响方面发挥作用。因此，本提案的总体目标是检验特定脂肪酸和脂肪酶影响葡萄球菌性乳腺炎进展的假设。本研究将从以下三个方面对这一假说进行验证：1）确定调节沙门氏菌生长和毒力因子表达的脂肪酸和脂质形式;金黄色。在这一目标中，我们将确定牛奶中存在的脂肪酸的范围，这些脂肪酸会影响沙门氏菌的生长和毒力因子的产生。金黄色。2)探讨脂肪酶活性的调控及其意义。金黄色葡萄球菌和乳腺作为向病原体和/或宿主提供益处的机制。在这里，我们将研究病原体和宿主编码的脂肪酶对牛奶脂质代谢的作用，并确定它们在乳腺组织疾病进展中的潜在作用。3)比较乳脂质成分改变对宿主-病原体对沙门氏菌感染反应的影响。金黄色。这一目标将解决改变牛奶的脂质组成的影响，通过饮食补充，对葡萄球菌乳腺炎的抵抗力和严重程度。这些研究的结果将对我们理解乳腺内发生的宿主-病原体相互作用产生重大影响，并可能导致减少女性这些类型感染的新策略。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Staphylococcus aureus causes a wide variety of diseases in both humans and animals. Although largely unreported, staphylococcal infection of the mammary gland, or mastitis, affects millions of women each year - nearly 33% of nursing mothers. Unfortunately, studies have determined that mastitis in women is a significant cause for the cessation of breast-feeding. This is particularly significant given that the benefits of breast-feeding have now been well documented. For example, these benefits include protection of the infant against diarrheal and respiratory diseases, ultimately leading to a lower risk of postneonatal death. In addition, breast-fed infants exhibit a reduced risk of obesity and cardiovascular disease in adulthood. Perhaps more alarming are studies showing that mastitis in HIV-infected women is a major risk factor in the transmission of this virus from mother to infant. Despite the impact of mastitis on human health, little is known about the host-pathogen interactions that occur with mastitis. Recent studies have demonstrated that the lipids found in milk have profound effects on pathogens such as S. aureus. For example, glycerol monolaurate (GML) has an inhibitory effect on the growth of S. aureus and inhibits the expression of virulence factors in S. aureus at subinhibitory concentrations. The active agent in GML as indicated by our preliminary studies appears to be the free fatty acid, lauric acid. In addition, our studies indicate that other fatty acids commonly found in milk possess antimicrobial activity. Thus, lipids may not just be an energy source for the nursing infant; many fatty acids made available by the action of both bacterial and mammalian lipases may also play a role in minimizing the impact of pathogens on the host through inhibition of bacterial growth and virulence. Therefore, the overall objective of this proposal is to test the hypothesis that specific fatty acids and lipases impact the progression of staphylococcal mastitis. This hypothesis will be tested in three specific aims including: 1) To determine the fatty acids and form of lipid that regulate the growth and expression of virulence factors in S. aureus. In this aim we will determine the range of fatty acids present in milk that affect growth and virulence factor production in S. aureus. 2) To examine the regulation and significance of lipase activity in S. aureus and the mammary gland as a mechanism to provide benefits to the pathogen and/or host. Here, we will study the role of both pathogen- and host-encoded lipases on milk lipid metabolism and determine their potential roles in the progression of disease within mammary tissue. 3) To compare the effects of altered milk lipid composition on the host-pathogen response to an infection with S. aureus. This aim will address the impact of altering the lipid composition of milk, through dietary supplementation, on the resistance and severity of staphylococcal mastitis. The results of these studies will have a major impact on our understanding of the host-pathogen interactions that occur within the mammary gland and could lead to novel strategies to reduce these types of infections in women.