Impact of intestinal worms on distal immune response and control of co-infections

Parasitic worm infections have been suggested to impair control of secondary infections and vaccine efficacy. However, the experimental data regarding the capacity of intestinal nematodes to modulate host immune responses was lacking and the mechanism underlying dampened immune responses, particularly those distal to the gut, incompletely understood. In this thesis, we investigated the effect of the intestinal nematode Heligmosomoides polygyrus on the immune response to BCG infection/immunization. We found that H. polygyrus infection impaired CD4+ T cell priming in both spleen and in lymph node distal to the site of the worm infection and reduced the recall immune response, measured as delayed-type hypersensitivity (DTH) to PPD in the skin. Furthermore, products released by the worms such as the excretory-secretory products from H. polygyrus (HES), were found to dampen the expansion of mycobacteria-specific CD4+ T cells both in vitro and when administered at the site of BCG injection. We found that dampened immune responses were not primarily due to dissemination of regulatory immune responses induced by the intestinal worm. If molecules released by the worms can disseminate and contribute to immune suppression at distal sites is however not clear. Importantly, we found that the lymph nodes (LNs) distal to the intestinal worm infection become atrophic and do not reach the same cellularity as worm-free mice upon subsequent BCG infection in the skin. In the smaller LN of worm-infected mice, all lymphocyte populations declined and the composition of lymphocyte subpopulations were found to be altered, seen as a decreased T/B lymphocyte ratio and increased CD4/CD8 T cell ratio. Underlying this phenomenon was the recruitment of lymphocytes to the draining mesenteric LN (mLN). In particular, large numbers of naïve lymphocytes were trapped in the mLN during the chronic infection, which over time resulted in a re-distribution of the lymphocyte pool. De-worming was found to recover the cellularity of distal LN and in turn mend the response to BCG measured in the LN draining the site of injection. Collectively, our findings show that chronic nematode infection causes a paucity of lymphocytes in peripheral LN, which acts to impair the immune response capacity to the subsequent infection.

List of scientific papers

I. Katja Obieglo, Xiaogang Feng, Vishnu Priya Bollampalli, Isabel Dellacasalindberg, Cajsa Classon, Markus Österblad, Helena Helmby, James P. Hewitson, Rick M. Maizels, Antonio Gigliotti Rothfuchs and Susanne Nylén. Chronic gastrointestinal nematode infection mutes immune responses to mycobacterial infection distal to the gut. J immunol. 2016; 196:2262-2271.
https://doi.org/10.4049/jimmunol.1500970

II. Xiaogang Feng, Cajsa Classon, Graciela Terán, Yunlong Yang, Lei Li, Sherwin Chan, Ulf Ribacke, Antonio Gigliotti Rothfuchs, Jonathan Coquet and Susanne Nylén. Atrophy of skin-draining lymph nodes predisposes for impaired immune responses to secondary infection in mice with chronic intestinal nematode infection. Plos Pathog. 2018; 14(5): e1007008.
https://doi.org/10.1371/journal.ppat.1007008

III. Cajsa Classon, Xiaogang Feng, Liv Eidsmo, Susanne Nylen. Intestinal nematode infection exacerbates experimental visceral leishmniasis. [Manuscript]