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Innate Mucosal Immunity

Research Team:

Overview:

With the September 2009 appointment of Dr. Philip Griebel as the Canada Research Chair (CRC) in Neonatal Mucosal Immunology, Philip Griebel and VIDO-InterVac are establishing a research program to identify vaccine strategies that prevent or clear persistent viral and bacterial enteric infections that are established during the neonatal period. The primary objective of this research program is to identify vaccine strategies that prevent or clear persistent viral and bacterial enteric infections that are established during the neonatal period.

Previous studies have demonstrated that the neonatal mucosal immune system has a remarkable capacity to respond to vaccination, however there are significant regional differences in the functional capacity between the respiratory mucosal immune system and the intestinal mucosal immune system. Mucosal-associated lymphoid tissue (MALT) in the temrinal small intesting of the neonate is restricted and lacks the capacity to respond to foreign antigens and vaccines, hence the terminal small intestine provides a unique site for pathogen invasion, replication, and persistence. Understanding the full capacity of neonatal mucosal immune system, Identifying key factors that influence mucosal immune development, and developing vaccine strategies that effectively prevent or clear both viral and bacterial infection will singificantly change neonatal health management.

Objectives:

  1. Develop relevant animal models for persistent enteric infections which facilitate vaccine development and evaluation for clinical application
  2. Analyze innate mucosal immune responses throughout persistent infections to identify mechanisms of immune protection and escape from immune surveillance
  3. Investigate homing of immune effector cells to site of mucosal infection to identify optimum vaccination strategies for each pathogen

Background:

Accumulating evidence has demonstrated that most pathogens invade the host via mucosal surfaces. The challenge for the mucosal immune system is to prevent invasion without disrupting key biological functions. Failure to achieve this delicate balance occurs most frequently during the neonatal period resulting in viruses and bacteria, such as HIV and mycobacteria, invading mucosal surfaces and establishing persistent infections. Infected individuals then serve as a reservoir for subsequent infections. Therefore, effective vaccine delivery leading to induction of strong local mucosal immunity may be critical for disease protection and mucosal vaccination could be used to reduce infectious diseases in the vulnerable neonatal population.

Previous research has demonstrated that although newborn mucosal immune systems respond to vaccination, there is a significant regional differences in the functional capacity between the respiratory mucosal immune system and the intestinal musocal immune system. Several of our experimental studies have shown that mucosal-associated lymophoid tissue (MALT) in the terminal small intestine of the neonate is restricted in both immune induction capacity and effector cell recruitment. In addition, there is clinical evidence suggesting that the terminal small intestine of the neonate lacks the capacity to respond to foreign antigens and vaccines. We therefore hypothesize that the terminal small intestine provides a unique site for pathogen invasion, replication, and persistence. Given this, different vaccination strategies may be required for enteric and respiratory pathogens and special considerations need to be taken when developing vaccine strategies against enteric infection.

Progress:

  1. Animal models for persistent mucosal infections
    • An Intestinal Mycobacterium avium subspecies paratuberculosis (MAP) infection mdoel of newborn calves is currently being developed. We are studying this animal model to develop specific vaccine delivery towards MALT and to analyze local mucosal immune responses to both acute and chronic infections.
  2. Regional development of innate mucosal defences
    • Mucosal epithelial cells are the site of the first interaction between host and pathogen, and dendritic cells (DCs) function as key communicators between the epithelial barrier and the host immune system. We are studying changes in both epithelial cell function and DC function in the neonate at the time of infection and throughout each persistent infection.
  3. Trafficking of immune effector cells to and from the terminal ileum
    • Persistent MAP enteric infection is associated with systemic suppression of immune responses. We are investigating to see if this immune suppression is unique to MAP infection in the terminal ileum or if immune suppresion follows infection at any MALT.

Funding:

(Contract Research Partner: Fort Dodge, Intervet-Schering Plough, Virexx)