TLR4 fuels activation of human dendritic cells and CD4+ T cell responses to human filarial parasite

Our new research suggest that a novel phosphorylcholine-binding sheath antigen (70 kDa) from the filarial parasite Wuchereria bancrofti mediates immunopathogenesis of lymphatic filariasis by exploiting human dendritic cells to evoke Th1 and regulatory T cell (Treg) responses. Interaction between filarial antigen and toll-like receptor 4 (TLR4) of human dendritic cells plays a central role in inducing the immunological responses.

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May 08, 2019
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Dr. Suprabhat Mukherjee working in the cell culture lab


Being a member of “Neglected Tropical Diseases”, lymphatic filariasis or commonly known as 'elephantiasis' globally affects over 120 million people1. The disease is caused by microfilariae Wuchereria bancrofti and two species of Brugia (B. malayi and B. timori). Lymphatic filariasis is transmitted through biting of parasite-infected mosquitoes like Culex. Therapeutic intervention of lymphatic filariasis through global filariasis elimination programme has not been satisfactorily accomplished due to incomplete knowledge on the molecular basis of immunopathogenesis. Most of the work so far in the field has been performed by using Brugia spp., but they are the least pathogenic ones. Despite being accountable for nearly 90% of filarial cases, the molecular basis of immune response to this parasite remain uncharacterized.

In general, cross-talk between filaria and antigen presenting cells, and subsequent CD4+ T cell polarization dictates final outcome of filarial infection and immunopathogenesis. However, the interaction of W. bancrofti with human dendritic cells, the professional antigen presenting cells critical for initiating the both primary and secondary CD4+ T cell responses remain unknown. During late 2016, Suprabhat (Dr. S. Mukherjee) from the Department of Zoology (Centre for Advanced Studies), Visva-Bharati University, Santiniketan, India contacted me with an intention to address this outstanding question in my lab. By that time, his work performed under the supervision of Prof. Santi P. Sinha Babu has already identified 70 KDa sheath antigen of W. bancrofti that interacts with toll-like receptor 4 (TLR4) on macrophages to induce inflammatory responses2. I thought it was a good opportunity to further bolster Indo-French scientific ties that I already had. 

Major problem in studying the mechanisms of filarial immunopathogenesis is that human cells isolated from the filaria-endemic region respond poorly to filarial antigens. As France is a non-endemic country for filaria, this problem was sorted out in the beginning it self. Although Suprabhat had minimal background on human immunology research, he received full support from the doctoral fellows of my group: Mrinmoy Das and Anupama Karnam.

Our data show that W. bancrofti sheath antigen induces human dendritic cell maturation and secretion of several pro-inflammatory cytokines3. Moreover, filarial antigen-educated dendritic cells polarize CD4+ T cell responses predominantly towards Th1 and regulatory T cell (Treg)3. These finding are significant ones in the context of filarial immunopathogenesis. It is well known that Th1 cells contribute to immunopathogenesis of lymphatic filariasis. Tregs although could reduce the inflammation and tissue damage, they also support survival of filaria and establishment of chronic, asymptomatic infection4,5. Thus, our data revealed that by targeting dendritic cells, W. bancrofti sheath antigen elicits distinct CD4+ T cell responses.

Initially, the antigen was isolated as a ligand of macrophage-TLR42. In the current report, blockage of surface TLR4 and the inhibition of TLR4 signaling pathway confirmed that sheath antigen binds and signals human dendritic cell activation via TLR43. The most interesting aspect of the project was the identification of filarial sheath antigen as a phosphorylcholine-binding protein. This antigen was previously purified based on its affinity to phosphorylcholine but the biophysical basis of the purification was not verified2. In this study, we found that the parasitic protein forms direct hydrogen bonds with phosphorylcholine3. As far as we know, this is the first report of a phosphorylcholine-binding protein in the human filarid W. bancrofti with a potent stimulatory ability on antigen presenting cells. Whether W. bancrofti exploits phosphorylcholine-binding properties to mediate immunopathogenesis remain to be investigated in the future.

We believe that our findings add new dimension to the existing knowledge on the filarial immunobiology and will be useful in the conception of a novel immunotherapeutics by targeting either the filarial antigen or TLR4, for reducing the inflammatory pathology of lymphatic filariasis.

For more details, check out the full manuscript here: https://www.nature.com/articles/s42003-019-0392-8

 

 

References:  

  1. World Health Organization. Lymphatic filariasis. http://www.who.int/ mediacentre/ factsheets/ fs102/en/ (2018).
  2. Mukherjee, S., Maiti, T. K., Bhattacharya, S. & Sinha Babu, S. P. A novel ligand of toll-like receptor 4 from the sheath of Wuchereria bancrofti microfilaria induces proinflammatory response in macrophages. J. Infect. Dis. 215, 954–965 (2017).
  3. Mukherjee, S., Karnam,A., Das, M.,. Sinha Babu, S.P. & Bayry, J. Wuchereria bancrofti filaria activates human dendritic cells and polarizes T helper 1 and regulatory T cells via Toll-like receptor 4. Commun. Biol. 2, Article number: 169 https://doi.org/10.1038/s42003-019-0392-8. (2019).
  4. Babu, S. & Nutman, T. B. Immunology of lymphatic filariasis. Parasite Immunol. 36, 338–346 (2014).
  5. Babu, S. et al. Filarial lymphedema is characterized by antigen-specific Th1 and th17 proinflammatory responses and a lack of regulatory T cells. PLoS Negl. Trop. Dis. 3, e420 (2009).

 

 

 

 

 

Go to the profile of Jagadeesh Bayry

Jagadeesh Bayry

Director of Research, INSERM

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