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Adaptation to low parasite abundance affects immune investment and immunopathological responses of cavefish


Reduced parasitic infection rates in the developed world are suspected to underlie the rising prevalence of autoimmune disorders. However, the long-term evolutionary consequences of decreased parasite exposure on an immune system are not well understood. We used the Mexican tetra Astyanax mexicanus to understand how loss of parasite diversity influences the evolutionary trajectory of the vertebrate immune system, by comparing river with cave morphotypes. Here, we present field data affirming a strong reduction in parasite diversity in the cave ecosystem, and show that cavefish immune cells display a more sensitive pro-inflammatory response towards bacterial endotoxins. Surprisingly, other innate cellular immune responses, such as phagocytosis, are drastically decreased in cavefish. Using two independent single-cell approaches, we identified a shift in the overall immune cell composition in cavefish as the underlying cellular mechanism, indicating strong differences in the immune investment strategy. While surface fish invest evenly into the innate and adaptive immune systems, cavefish shifted immune investment to the adaptive immune system, and here, mainly towards specific T-cell populations that promote homeostasis. Additionally, inflammatory responses and immunopathological phenotypes in visceral adipose tissue are drastically reduced in cavefish. Our data indicate that long-term adaptation to low parasite diversity coincides with a more sensitive immune system in cavefish, which is accompanied by a reduction in the immune cells that play a role in mediating the pro-inflammatory response.

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Fig. 1: Adaptation to river and cave habitats with marked differences in parasite diversity results in changes of cellular immune response.
Fig. 2: Cellular composition analysis of HK reveals differences in immune investment strategy between cavefish and surface fish.
Fig. 3: Cell composition analysis of A. mexicanus HK surface and cave morphotypes using cell morphological and genetic features.
Fig. 4: Cellular analysis of acute inflammatory response following LPS injection of A. mexicanus HK cells.
Fig. 5: Adaptive immune response in HK and spleen of surface and cavefish A. mexicanus following LPS injection.
Fig. 6: Reduced immune investment in myeloid cells alters inflammatory and immunopathological responses of A. mexicanus.

Data availability

Original data underlying this manuscript can be accessed from the Stowers Original Data Repository at The scRNA-seq data generated by Cell Ranger can be retrieved from the GEO database with accession number GSE128306.


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We thank the cavefish facility staff at the Stowers Institute for support and husbandry of the fish. We thank the staff from the Histology core at the Stowers Institute for their technical support; J. Blanck from the Cytometry core for performing sorting of HK cells; M. Peterson, A. Peak and A. Perera for support with scRNA-seq; and M. Miller for support with the fish anatomy figure. The authors acknowledge the University of Kansas Medical Center Genomics Core for sequencing support. Furthermore, we thank S. A. McKinney for providing the ImageJ macro for GL-7 quantification. The authors also kindly acknowledge J. Kurtz for helpful discussions. N.R. is supported by institutional funding, funding from the JDRF, the Edward Mallinckrodt Foundation, NIH Grant R01 GM127872 and NSF IOS-1933428 and EDGE award 1923372. R.P. was supported by a grant (no. PE 2807/1-1) from Deutsche Forschungsgemeinschaft.

Author information




R.P. and N.R. conceived the study. R.P. designed and coordinated the experiments with support from A.C.B. and J.K. R.P., J.L.P., A.K. and E.M. collected, dissected and examined cave and surface wild populations with support from J.P.S. R.P. performed and analysed immune assays, flow cytometry experiments and histological analysis, with support from A.C.B., Y.W., D.T. and B.D.S. S.C. performed single-cell sequencing analysis with support from R.P. RNA Scope experiments and analysis were performed by Y.W., D.T. and B.D.S. with support from R.P. and J.K. R.P. and N.R. designed, and R.P. made, the figures. R.P. and N.R. wrote the paper and all authors read and edited the paper.

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Correspondence to Robert Peuß or Nicolas Rohner.

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Extended data

Extended Data Fig. 1 A. mexicanus anatomy.

Cartoon of adult A. mexicanus indicates anatomical position of the main hematopoietic and lymphoid organ, the head kidney (HK) that was used for subsequent in vitro experiments from surface fish and cavefish lab strains.

Extended Data Fig. 2. Gene expression of specific head kidney cell types in cavefish and surface fish.

Relative abundance of specific cell populations of surface fish and cavefish and their location within UMAP representation of specific cell types from, a, myelomonocytes and, b, lymphocytes based on the expression of given gene(s). See Supplementary Data 4 for gene enrichment in each cluster.

Extended Data Fig. 3 HK cell gene expression profiles of PBS injected fish.

Heatmap of enriched genes within each cell cluster of control groups from surface fish and cavefish. Genes that were used for cell cluster identification are shown. For a complete heatmaps for PBS and LPS injected groups see Supplementary Data 69.

Supplementary information

Supplementary Information

Supplementary methods, Figs. 1–7, Tables 1–3 and Data 1, 3 and 6–9.

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Supplementary Data

Contains Supplementary Data 2, 4, 5 and 10–14. Supplementary Data 2: Statistical summary of phagocytosis experiment shown in Fig. 1g. Supplementary Data 4: List of enriched genes for each cluster for scRNA-seq experiment shown in Fig. 3g. Supplementary Data 5: List of enriched genes for each cluster for scRNA-seq experiment shown in Fig. 4. Supplementary Data 10: Up- and downregulated genes of haematopoietic stem cells in the ‘cavefish PBS’ treatment group compared to the ‘surface PBS’ treatment group from the experimental data shown in Fig. 4. Supplementary Data 11: Up- and downregulated genes of CD4 T cells in the ‘cavefish PBS’ treatment group compared to the ‘surface PBS’ treatment group from the experimental data shown in Fig. 4. Supplementary Data 12: Statistical summary of adaptive immunity response data shown in Fig. 5d,e and Supplementary Fig. 6. Supplementary Data 13: Up- and downregulated genes of neutrophils in the ‘cavefish PBS’ treatment group compared to the ‘surface PBS’ treatment group, and in the ‘cavefish LPS’ treatment group compared to the ‘surface LPS’ treatment group, from the experimental data shown in Fig. 4. Supplementary Data 14: Up- and downregulated genes of macrophages in the ‘cavefish PBS’ treatment group compared to the ‘surface PBS’ treatment group, and in the ‘cavefish LPS’ treatment group compared to the ‘surface LPS’ treatment group, from the experimental data shown in Fig. 4.

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Peuß, R., Box, A.C., Chen, S. et al. Adaptation to low parasite abundance affects immune investment and immunopathological responses of cavefish. Nat Ecol Evol 4, 1416–1430 (2020).

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