Defining early entry mechanisms of Mycobacterium avium paratuberculosis into the host

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Johne's disease (JD) is a common and chronic disease of the gut of ruminants caused by infection with the pathogen Mycobacterium avium subspecies paratuberculosis (MAP). At early stages following infection animals show little evidence of the disease, making it difficult to detect and easy for infection to spread unnoticed. JD has a significant impact on the health and welfare of cattle and sheep, with economic losses associated with reduced productivity and high mortality in the chronic stage. JD is an insidious and increasing problem in the UK and world-wide, with no effective control measures in cattle other than test and slaughter. This is partly because MAP is able to hide from and manipulate the immune system but also reflects the relative paucity and integration of researchers in the area, slow growth of MAP and high cost of experimental studies in target hosts.We propose to investigate how MAP interacts with host cells in the gut at early stages following infection with strains of MAP of varying virulence. We will use a combination of methods to determine the critical cell types and mechanisms utilised by MAP for entry into the gut. These include tractable murine models, gut enteroids and surgical gut loops providing a unique overview of the MAP-host interaction. Moreover, we propose to define the role of MAP genes in survival and replication. These studies will address fundamental gaps in current knowledge and will facilitate the rational design of strategies to control and treat MAP infections.Our proposal brings together researchers with complimentary expertise, established models of infection and a proven record of collaboration. We have three inter-linked objectives:1) Define the cell types involved in transit of MAP across the gut mucosa using mouse models to accurately identify the cellular portal of entry2) Characterise the mechanisms by which MAP transits the bovine gut using enteroids and surgical gut loop models to identify critical pathways and mechanisms of entry3) Identify critical MAP genes required for host tissue invasion and survival using targeted and random mutagenesis approaches This project brings together a unique team with expertise in MAP, bovine immunology, mucosal immune responses and intracellular bacteria. The major output will be the definition of key host, and pathogen factors that control entry and that could be targets for future intervention strategies for disease control.