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Lyme disease is the most common human vector-borne disease in the United States and Western Europe, and it is transmitted through infected ticks. The disease is caused by bacteria of the species Borrelia burgdorferi sensu lato (s.l.), including B. burgdorferi sensu stricto (s.s.), B. afzelii, and B. garinii as the major causative species. The clinical picture of Lyme disease is highly variable, ranging from early localized disease resulting in inflammation of the skin around the tick bite (erythema migrans (EM)), to disseminated infections such as neuroborreliosis or carditis, and chronic or persistent forms of the disease resulting in long-term inflammation of large joints or the skin.

One of the major clinical needs is that of robust diagnostic assays to identify Lyme diseases in patients. Both standard serological tests (Elisa or Western blot) and the recently described cellular tests (LTT or Elispot assays) are not optimal, as only 50-60% of the Lyme patients revealed to be positive in these tests.

These data point towards an impaired or weak anti-Borrelia immune response by the host. We found that live Borrelia bacteria strongly downregulate the genes and proteins involved in antigen presentation, mainly MHC class II. Both antigen presentation by monocyte/ macrophages and B-cells was inhibited, crucial steps for optimal T-cell and B-cell response towards Borrelia bacteria or Borrelia antigens. Therefore, this might explain why Lyme disease patients do not develop an accurate immune response, thus leading to survival of the Borrelia spirochetes.

 

The goal of this current grant application is: to unravel the Borrelia-induced inhibition of antigen presentation and to explore pathways to restore the antigen presentation of Borrelia antigens.

 

The following key objectives will be investigated:

I. To identify the molecular mechanism of Borrelia-induced inhibition of antigen presentation in vitro.

 

II. To investigate inhibition of antigen presentation in patients with EM and disseminated Lyme disease and the association with reduced adaptive immune responses (IFNg or weak/absent Borrelia serology).

 

III. How to restore the antigen presentation of Borrelia antigens to improve Th1 responses and B-cell responses?

 

IV. Can we use the knowledge of Borrelia-induced suppression of antigen presentation for the development of novel diagnostic assays for active Lyme disease?

 

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