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Project
Effect of lactoferrin on pediatric infections
Every year ≈ 6 million children younger than 5 years of age die, almost exclusively in low and middle-income countries. The main causes of death are neonatal problems (44%), pneumonia (13%) and diarrhea (9%) (Liu 2015). One third of all deaths are associated with malnutrition. Among those surviving, many suffer with long-term consequences in growth and development.
Multiple preventive interventions have been designed to decrease mortality and disability in children. Among these, early and exclusive breastfeeding is one of the most important interventions to reduce neonatal and infant mortality (Walker, 2011). Breastfeeding is the most cost-effective intervention for protecting children against diarrhea and all causes of mortality (Jones, 2003). Human breast milk helps protect infants by serving as a source of nutrition uncontaminated by pathogens in addition to protection due to its multiple anti-microbial, anti-inflammatory and immunoregulatory components (Walker, 2010).
Lactoferrin is one of the major factors responsible for these protective effects. This iron binding glycoprotein is found in most exocrine secretions including milk, tears, saliva, intestinal mucus and genital secretions, as well as the specific granules of neutrophils. The main biological properties of lactoferrin that contribute to its physiological functions are its high affinity for iron and its cationic character which is responsible for its ability to bind various cells, nucleic acids, proteins and other molecules (Baker, 2012). Lactoferrin protects against bacteria in a variety of ways: it sequesters iron that is essential for bacterial growth; binds to LPS on the cell surface, disrupting the bacterial cell membrane; peptide fragments (lactoferricin) are bactericidal in vitro (Brock, 2012). Lactoferrin reduces inflammation by decreasing production of tumor necrosis factor alpha and other proinflammatory molecules, and by regulating the immune response, protecting against severe inflammation related to infection and septic shock (Vogel, 2012).
My early research has focused on the mechanisms of action of lactoferrin on enteric pathogens. We have demonstrated that lactoferrin impairs function of surface expressed virulence factors, by disruption of the type III secretory system of enteropathogenic E. coli (EPEC) (Ochoa, 2003). Lactoferrin inhibits enteroaggregative E.coli (EAEC) aggregative adherence “stacked-brick pattern” and biofilm formation (Ochoa, 2006). Lactoferrin decreases the ability of pathogens to adhere or to invade mammalian cells by binding to, or degrading, specific virulence proteins (Ochoa, 2009). We have demonstrated that lactoferrin has a protective effect on enteric infections in several animal models. We found that lactoferrin protects rabbits from Shigella flexneri-induced inflammatory enteritis (Gomez, 2002), and protects against Salmonella ser. Typhimurium infection in mice, reducing the severity, mortality and the degree of inflammation of this infection (Mosquito, 2010). Lactoferrin decreases fluid accumulation in the mice ileal loop model induced by cholera toxin (Rivera, 2013).
Based on these preliminary in vitro and animal studies, we hypothesize that lactoferrin given as an oral supplement to infants in resource-limited settings will improve their health by mimicking its protective roles in breast milk, decreasing the incidence and severity of common pediatric infections due to its antimicrobial and immunomodulatory properties. This PhD proposal will focus on lactoferrin effect on enteric and neonatal infections; it will have five chapters; the first two are based on previous and already published work, and the other three chapters are on ongoing and new work.
Multiple preventive interventions have been designed to decrease mortality and disability in children. Among these, early and exclusive breastfeeding is one of the most important interventions to reduce neonatal and infant mortality (Walker, 2011). Breastfeeding is the most cost-effective intervention for protecting children against diarrhea and all causes of mortality (Jones, 2003). Human breast milk helps protect infants by serving as a source of nutrition uncontaminated by pathogens in addition to protection due to its multiple anti-microbial, anti-inflammatory and immunoregulatory components (Walker, 2010).
Lactoferrin is one of the major factors responsible for these protective effects. This iron binding glycoprotein is found in most exocrine secretions including milk, tears, saliva, intestinal mucus and genital secretions, as well as the specific granules of neutrophils. The main biological properties of lactoferrin that contribute to its physiological functions are its high affinity for iron and its cationic character which is responsible for its ability to bind various cells, nucleic acids, proteins and other molecules (Baker, 2012). Lactoferrin protects against bacteria in a variety of ways: it sequesters iron that is essential for bacterial growth; binds to LPS on the cell surface, disrupting the bacterial cell membrane; peptide fragments (lactoferricin) are bactericidal in vitro (Brock, 2012). Lactoferrin reduces inflammation by decreasing production of tumor necrosis factor alpha and other proinflammatory molecules, and by regulating the immune response, protecting against severe inflammation related to infection and septic shock (Vogel, 2012).
My early research has focused on the mechanisms of action of lactoferrin on enteric pathogens. We have demonstrated that lactoferrin impairs function of surface expressed virulence factors, by disruption of the type III secretory system of enteropathogenic E. coli (EPEC) (Ochoa, 2003). Lactoferrin inhibits enteroaggregative E.coli (EAEC) aggregative adherence “stacked-brick pattern” and biofilm formation (Ochoa, 2006). Lactoferrin decreases the ability of pathogens to adhere or to invade mammalian cells by binding to, or degrading, specific virulence proteins (Ochoa, 2009). We have demonstrated that lactoferrin has a protective effect on enteric infections in several animal models. We found that lactoferrin protects rabbits from Shigella flexneri-induced inflammatory enteritis (Gomez, 2002), and protects against Salmonella ser. Typhimurium infection in mice, reducing the severity, mortality and the degree of inflammation of this infection (Mosquito, 2010). Lactoferrin decreases fluid accumulation in the mice ileal loop model induced by cholera toxin (Rivera, 2013).
Based on these preliminary in vitro and animal studies, we hypothesize that lactoferrin given as an oral supplement to infants in resource-limited settings will improve their health by mimicking its protective roles in breast milk, decreasing the incidence and severity of common pediatric infections due to its antimicrobial and immunomodulatory properties. This PhD proposal will focus on lactoferrin effect on enteric and neonatal infections; it will have five chapters; the first two are based on previous and already published work, and the other three chapters are on ongoing and new work.
Date:12 Jan 2017 → 15 May 2020
Keywords:B780-tropical-medicine