Characterisation of host immune responses to Burkholderia mallei

Rowland, Caroline A. (2006). Characterisation of host immune responses to Burkholderia mallei. PhD thesis The Open University.



Burkholderia mallei is an intracellular, gram-negative bacterium which causes the disease Glanders in humans and mice. Little research has been performed to examine host immune responses to this organism. Therefore, the purpose of this work was to characterise host immunity to B. mallei by analysing splenic cellular and cytokine responses and systemic cytokine responses during intra-peritoneal infection in BALB/c mice. In summary, chronic B. mallei infection was characterised by an initial period of bacterial colonisation which was limited by the host immune system. This was followed by extensive bacterial replication within abscessed spleens. IFN-γ was essential for controlling early infection and was accompanied by expression of type 1 cytokines and macrophage and neutrophil activation within 24 hours post-infection (p.i.). The IFN-γ response was induced predominantly in NK cells by IL-12 and IL-18 in vitro, further demonstrating the requirement for type 1 immunity to B. mallei infection. TNFα and Gr-1+ cells (predominantly neutrophils) were also important in innate host immune responses. T cells were not important during this phase but played an important role in adaptive immune responses to infection. Downregulation of immune responses occurred 72h p.i. followed by an additional period of macrophage and neutrophil activation 5-7 days p.i.. A heterogeneous infection developed 14-36 days p.i., with mice either forming abscesses or apparently clearing the infection. Abscesses were associated with high bacterial loads and inflammation: TNFα and T cells were involved in controlling the infection, although this did not prevent bacterial colonisation or eventual lethality 8 weeks p.i.. In conclusion, this data shows that early, type 1 immune responses are ultimately overcome leading to extensive replication of B. mallei within abscessed tissues. Maintenance of the type 1 cell-mediated immune responses observed during early infection is likely to be crucial for the development of effective therapies and vaccines against B. mallei.

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