The central adaptor molecule TRIF influences L. sigmodontis worm development

Abstract

Worldwide approximately 68 million people are infected with lymphatic filariasis (Lf), provoked by Wuchereria bancrofti, Brugia malayi and Brugia timori. This disease can lead to massive swelling of the limbs (elephantiasis) and disfigurement of the male genitalia (hydrocele). Filarial induced immune regulation is characterised by dominant type 2 helper T cell and regulatory immune responses. In vitro studies have provided evidence that signalling via Toll-like receptor-mediated pathways is triggered by filarial associated factors. Nevertheless, until now, less is known about the role of the adapter molecule TRIF during in vivo infections. Here, we used the rodent-specific nematode Litomosoides sigmodontis to investigate the role of TLR signalling and the corresponding downstream adapter and regulatory molecules TRIF, MyD88, IRF1 and IRF3 during an ongoing infection in semi-susceptible C57BL/6 mice. Interestingly, lack of the central adapter molecule TRIF led to higher worm burden and reduced overall absolute cell numbers in the thoracic cavity (the site of infection) 30 days post-infection. In addition, frequencies of macrophages and lymphocytes in the TC were increased in infected TRIF−/− C57BL/6 mice, whereas frequencies of eosinophils, CD4+ and CD8+ T cells were reduced. Nevertheless, cytokine levels and regulatory T cell populations remained comparable between TRIF-deficient and wildtype C57BL/6 mice upon 30 days of L. sigmodontis infection. In summary, this study revealed a crucial role of the adapter molecule TRIF on worm recovery and immune cell recruitment into the site of infection 30 days upon L. sigmodontis infection in C57BL/6 mice.

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Abbreviations

ECP:

eosinophil cationic protein

IFN:

interferon

IL:

interleukin

IRF:

interferon regulatory receptor

LsAg:

L. sigmodontis worm antigen

medLN:

mediastinal lymph nodes

Mf:

microfilariae

MyD88:

myeloid differentiation primary response gene 88

p.i.:

post-infection

PRR:

pattern recognition receptors

TC:

thoracic cavity

TLR:

Toll-like receptors

Treg:

regulatory T cells

TRIF:

Toll/interleukin-1 receptor domain-containing adapter-inducing interferon-β

WT:

wildtype

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Acknowledgements

Special thanks to Ö. Mutluer and K. Wiszniewsky (IMMIP) for the excellent technical assistance.

Funding

LEL is a recipient of DFG funding within the African-German Cooperation Projects in Infectiology (LA 2746/1-1, LA 2746/2-1). AH is a member of the Excellence Cluster Immunosensation (DFG, EXC 1023) and AH and LEL are members of the German Centre of Infectious Disease (DZIF).

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LEL and AH conceived and designed the study. AW, VK and SS performed the experiments. HW provided materials and mouse lines. AW, KA, MR and LEL analysed and interpreted data sets. AW, LEL and MR wrote the manuscript which was then critically assessed and amended by HW, SW and AH. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Laura E. Layland.

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The authors declare that they have no conflict of interest.

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All applicable international, national and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

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Anna Wiszniewsky and Manuel Ritter shared co-authorship.

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Online Resource 1
figure7

Worm burden and development of life stages in TRIF-I- mice on day 40 and 60 p.i. TRIF−/− and WT mice were analysed for (a, b) L. sigmodontis worm burden and (c, d) numbers of L4 stage larvae on day 40 and 60 p.i., respectively. Graphs show mean ± SEM of individually assessed mice from 2-3 independent infection experiments: (a, c) n = 12 TRIF−/−and n = 11 WT and (b, d) n = 10 TRIF−/− and n = 10 WT mice. Statistical significances between the indicated groups were obtained using Mann-Whitney-U-tests (a, b) and Kruskal-Wallis test followed by Dunn’s multiple comparison test for further comparison of the groups (c, d). Asterisks indicate significant differences between the groups indicated by the brackets (**p < 0.01). (PNG 389 kb)

Online Resource 3
figure8

Comparable CD4+FOXP3+ regulatory T cell frequencies in TRIF−/− and wildtype mice on day 30 p.i. Frequencies of CD4+FOXP3+ regulatory T cells were analysed in (a) the thoracic cavity (TC) and (b) mediastinal lymph nodes (medLN). Graphs show mean ± SEM of individually assessed mice from 2 independent infection experiments (n = 9 TRIF−/−/ n = 11 WT). Statistical significances were assessed using unpaired t-test or Mann-Whitney-U-tests: no significances were found. (PNG 192 kb)

High Resolution Image (TIF 61.2 mb)

Online Resource 2

Gating strategy for T cell populations in TC and medLN. Groups of WT and TRIF−/− C57BL/6 mice were infected with L. sigmodontis for 30 days. TC and medLN cells were stained with fluorophore-conjugated anti-mouse CD4, CD8, CD25, CD103 and FOXP3 monoclonal antibodies and frequencies of (a) CD4+CD25highCD103+ Treg and CD8+ T cells and (b) CD4+FOXP3+ Treg were analysed according to the presented gating strategy. (PPTX 78.5 kb)

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Wiszniewsky, A., Ritter, M., Krupp, V. et al. The central adaptor molecule TRIF influences L. sigmodontis worm development. Parasitol Res 118, 539–549 (2019). https://doi.org/10.1007/s00436-018-6159-1

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Keywords

  • Lymphatic filariasis
  • Litomosoides sigmodontis
  • TLR signalling
  • Worm burden
  • Adapter molecule TRIF
  • Semi-susceptible C57BL/6 mice