Defining the Role of Lactoferrin at the Host-Microbe Interface
Group B Streptococcus (GBS), or Streptococcus agalactiae, is one of the leading causes of infection-related adverse pregnancy and neonatal outcomes, which include stillbirth, chorioamnionitis, preterm birth, and neonatal sepsis and meningitis. Despite antibiotic treatment and vaccine attempts, GBS remain a leading cause of perinatal infections. With the rise of antibiotic resistant strains of GBS, novel therapies independent of traditional chemical antibiotics are warranted. Lactoferrin is a glycoprotein with two iron binding domains, each of which chelates a single iron ion with high affinity, starving invading bacteria of this crucial metal. In addition to chelating iron, two regions of the protein exhibit potent antimicrobial activity against a range of bacteria, fungi, and viruses. There is a gap of knowledge between GBS and its interaction with the human host. In my research, I sought out to expand the relationship between our innate immune response and the bacterium. The field has studied the antimicrobial effects against a range of bacterial pathogens. Furthermore, there is evidence that lactoferrin can interact with the immune system to modulate inflammation. With this knowledge in mind, I hypothesized that lactoferrin possesses antimicrobial and antibiofilm against GBS. Additionally, I hypothesized that lactoferrin can interact with resident placental macrophages and dampen their response during GBS infection to provide an environmental suitable for fetal development while combatting the pathogen. To address this gap in knowledge, my thesis research aimed to (I) review the current understanding of lactoferrin and streptococcal infection, (II) define the antimicrobial and antibiofilm properties of lactoferrin against GBS, (III) determine if these properties are broadly potent against a clinical bank of GBS strains, (IV) understand how lactoferrin interactions with placental macrophages to dampen their function, (V) explore the antimicrobial peptide’s protective properties against the ESKAPE pathogens, and finally (VI) assess the utility of lactoferrin to enhance antibiotic efficacy. My work has defined an aspect of the host-pathogen interaction and proposes purified human lactoferrin as a chemotherapeutic strategy against GBS and other bacterial infections.