Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Mosquito C-type lectins maintain gut microbiome homeostasis

Nature Microbiology volume 1, Article number: 16023 (2016) Cite this article

Subjects

Abstract

The long-term evolutionary interaction between the host immune system and symbiotic bacteria determines their cooperative rather than antagonistic relationship. It is known that commensal bacteria have evolved a number of mechanisms to manipulate the mammalian host immune system and maintain homeostasis. However, the strategies employed by the microbiome to overcome host immune responses in invertebrates still remain to be understood. Here, we report that the gut microbiome in mosquitoes utilizes C-type lectins (mosGCTLs) to evade the bactericidal capacity of antimicrobial peptides (AMPs). Aedes aegypti mosGCTLs facilitate colonization by multiple bacterial strains. Furthermore, maintenance of the gut microbial flora relies on the expression of mosGCTLs in A. aegypti. Silencing the orthologues of mosGCTL in another major mosquito vector (Culex pipiens pallens) also impairs the survival of gut commensal bacteria. The gut microbiome stimulates the expression of mosGCTLs, which coat the bacterial surface and counteract AMP activity. Our study describes a mechanism by which the insect symbiotic microbiome offsets gut immunity to achieve homeostasis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The role of mosGCTLs in systemic bacterial inoculation in A. aegypti.
Figure 2: mosGCTLs facilitate the colonization of the A. aegypti midgut by gut bacteria.
Figure 3: mosGCTLs contribute to the maintenance of gut microbiota in A. aegypti and C. pipiens pallens.
Figure 4: mosGCTLs and AMPs are simultaneously regulated by the Imd pathway.
Figure 5: mosGCTLs are antagonists for AMP-mediated bacterial elimination.
Figure 6: mosGCTLs interrupt the deposition of AMPs onto bacteria cells.

Similar content being viewed by others

References

  1. Valiente Moro, C., Tran, F. H., Raharimalala, F. N., Ravelonandro, P. & Mavingui, P. Diversity of culturable bacteria including Pantoea in wild mosquito Aedes albopictus. BMC Microbiol. 13, 70–80 (2013).

    Article  Google Scholar 

  2. Lemaitre, B. & Hoffmann, J. The host defense of Drosophila melanogaster. Annu. Rev. Immunol. 25, 697–743 (2007).

    Article  CAS  Google Scholar 

  3. Ha, E. M., Oh, C. T., Bae, Y. S. & Lee, W. J. A direct role for dual oxidase in Drosophila gut immunity. Science 310, 847–850 (2005).

    Article  CAS  Google Scholar 

  4. Buchon, N., Broderick, N. A. & Lemaitre, B. Gut homeostasis in a microbial world: insights from Drosophila melanogaster. Nature Rev. Microbiol. 11, 615–626 (2013).

    Article  CAS  Google Scholar 

  5. Kumar, S., Molina-Cruz, A., Gupta, L., Rodrigues, J. & Barillas-Mury, C. A peroxidase/dual oxidase system modulates midgut epithelial immunity in Anopheles gambiae. Science 327, 1644–1648 (2010).

    Article  CAS  Google Scholar 

  6. Dong, Y., Manfredini, F. & Dimopoulos, G. Implication of the mosquito midgut microbiota in the defense against malaria parasites. PLoS Pathog. 5, e1000423 (2009).

    Article  Google Scholar 

  7. Drickamer, K. Two distinct classes of carbohydrate-recognition domains in animal lectins. J. Biol. Chem. 263, 9557–9560 (1988).

    CAS  PubMed  Google Scholar 

  8. Zelensky, A. N. & Gready, J. E. The C-type lectin-like domain superfamily. FEBS J. 272, 6179–6217 (2005).

    Article  CAS  Google Scholar 

  9. Holmskov, U., Thiel, S. & Jensenius, J. C. Collections and ficolins: humoral lectins of the innate immune defense. Annu. Rev. Immunol. 21, 547–578 (2003).

    Article  CAS  Google Scholar 

  10. Tailleux, L. et al. DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. J. Exp. Med. 197, 121–127 (2003).

    Article  CAS  Google Scholar 

  11. Halary, F. et al. Human cytomegalovirus binding to DC-SIGN is required for dendritic cell infection and target cell trans-infection. Immunity 17, 653–664 (2002).

    Article  CAS  Google Scholar 

  12. Klimstra, W. B., Nangle, E. M., Smith, M. S., Yurochko, A. D. & Ryman, K. D. DC-SIGN, and L-SIGN can act as attachment receptors for alphaviruses and distinguish between mosquito cell- and mammalian cell-derived viruses. J. Virol. 77, 12022–12032 (2003).

    Article  CAS  Google Scholar 

  13. Tassaneetrithep, B. et al. DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. J. Exp. Med. 197, 823–829 (2003).

    Article  CAS  Google Scholar 

  14. Miller, J. L. et al. The mannose receptor mediates dengue virus infection of macrophages. PLoS Pathog. 4, e17 (2008).

    Article  Google Scholar 

  15. Waterhouse, R. M. et al. Evolutionary dynamics of immune-related genes and pathways in disease-vector mosquitoes. Science 316, 1738–1743 (2007).

    Article  CAS  Google Scholar 

  16. Osta, M. A., Christophides, G. K. & Kafatos, F. C. Effects of mosquito genes on Plasmodium development. Science 303, 2030–2032 (2004).

    Article  CAS  Google Scholar 

  17. Wang, Y. H. et al. A critical role for CLSP2 in the modulation of antifungal immune response in mosquitoes. PLoS Pathog. 11, e1004931 (2015).

    Article  Google Scholar 

  18. Cheng, G. et al. A C-type lectin collaborates with a CD45 phosphatase homolog to facilitate West Nile virus infection of mosquitoes. Cell 142, 714–725 (2010).

    Article  CAS  Google Scholar 

  19. Liu, Y. et al. Transmission-blocking antibodies against mosquito C-type lectins for dengue prevention. PLoS Pathog. 10, e1003931 (2014).

    Article  Google Scholar 

  20. Wang, X. W., Xu, Y. H., Xu, J. D., Zhao, X. F. & Wang, J. X. Collaboration between a soluble C-type lectin and calreticulin facilitates white spot syndrome virus infection in shrimp. J. Immunol. 193, 2106–20117 (2014).

    Article  CAS  Google Scholar 

  21. Schnitger, A. K., Yassine, H., Kafatos, F. C. & Osta, M. A. Two C-type lectins cooperate to defend Anopheles gambiae against Gram-negative bacteria. J. Biol. Chem. 284, 17616–17624 (2009).

    Article  CAS  Google Scholar 

  22. Tanji, T., Ohashi-Kobayashi, A. & Natori, S. Participation of a galactose-specific C-type lectin in Drosophila immunity. Biochem. J. 396, 127–138 (2006).

    Article  CAS  Google Scholar 

  23. Wang, X. W., Xu, J. D., Zhao, X. F., Vasta, G. R. & Wang, J. X. A shrimp C-type lectin inhibits proliferation of the hemolymph microbiota by maintaining the expression of antimicrobial peptides. J. Biol. Chem. 289, 11779–11790 (2014).

    Article  CAS  Google Scholar 

  24. Suryawanshi, R. K. et al. Mosquito larvicidal and pupaecidal potential of prodigiosin from Serratia marcescens and understanding its mechanism of action. Pestic. Biochem. Physiol. 123, 49–55 (2015).

    Article  CAS  Google Scholar 

  25. Bahia, A. C. et al. Exploring Anopheles gut bacteria for Plasmodium blocking activity. Environ. Microbiol. 16, 2980–2994 (2014).

    Article  CAS  Google Scholar 

  26. Ramirez, J. L. et al. Reciprocal tripartite interactions between the Aedes aegypti midgut microbiota, innate immune system and dengue virus influences vector competence. PLoS Negl. Trop. Dis. 6, e1561 (2012).

    Article  Google Scholar 

  27. Dada, N. et al. Comparative assessment of the bacterial communities associated with Aedes aegypti larvae and water from domestic water storage containers. Parasit. Vectors 7, 391 (2014).

    Article  Google Scholar 

  28. Gaio, A. O. et al. Use of the checkerboard DNA–DNA hybridization technique for bacteria detection in Aedes aegypti (Diptera: Culicidae) (L.). Parasit. Vectors 4, 237 (2011).

    Article  CAS  Google Scholar 

  29. Leulier, F. et al. The Drosophila immune system detects bacteria through specific peptidoglycan recognition. Nature Immunol. 4, 478–484 (2003).

    Article  CAS  Google Scholar 

  30. Lemaitre, B., Reichhart, J. M. & Hoffmann, J. A. Drosophila host defense: differential induction of antimicrobial peptide genes after infection by various classes of microorganisms. Proc. Natl Acad. Sci. USA. 94, 14614–14619 (1997).

    Article  CAS  Google Scholar 

  31. Geuking, M. B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794–806 (2011).

    Article  CAS  Google Scholar 

  32. Palm, N. W., de Zoete, M. R. & Flavell, R. A. Immune–microbiota interactions in health and disease. Clin. Immunol. 159, 122–127 (2015).

    Article  CAS  Google Scholar 

  33. Zhou, D. et al. Cloning and characterization of prophenoloxidase A3 (proPOA3) from Culex pipiens pallens. Comp. Biochem. Physiol. B. Biochem. Mol. Biol. 162, 57–65 (2012).

    Article  CAS  Google Scholar 

  34. Moita, L. F., Wang-Sattler, R., Michel, K., Zimmermann, T. & Blandin, S. In vivo identification of novel regulators and conserved pathways of phagocytosis in Anopheles gambiae. Immunity 23, 65–73 (2005).

    Article  CAS  Google Scholar 

  35. Yassine, H., Kamareddine, L. & Osta, M. A. The mosquito melanization response is implicated in defense against the entomopathogenic fungus Beauveria bassiana. PLoS Pathog. 8, e1003029 (2012).

    Article  CAS  Google Scholar 

  36. Xiao, X. P. et al. Complement-related proteins control Flavivirus infection of Aedes aegypti by inducing antimicrobial peptides. PLoS Pathog. 10, e1004027 (2014).

    Article  Google Scholar 

  37. Liu, Y. et al. The roles of direct recognition by animal lectins in antiviral immunity and viral pathogenesis. Molecules 20, 2272–2295 (2015).

    Article  Google Scholar 

  38. Buchon, N., Broderick, N. A., Chakrabarti, S. & Lemaitre, B. Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila. Genes Dev. 23, 2333–2344 (2009).

    Article  CAS  Google Scholar 

  39. Lhocine, N. et al. PIMS modulates immune tolerance by negatively regulating Drosophila innate immune signaling. Cell Host Microbe 4, 147–158 (2008).

    Article  CAS  Google Scholar 

  40. Paredes, J. C., Welchman, D. P., Poidevin, M. & Lemaitre, B. Negative regulation by amidase PGRPs shapes the Drosophila antibacterial response and protects the fly from innocuous infection. Immunity 35, 770–779 (2011).

    Article  CAS  Google Scholar 

  41. Ryu, J. H. et al. Innate immune homeostasis by the homeobox gene caudal and commensal-gut mutualism in Drosophila. Science 319, 777–782 (2008).

    Article  CAS  Google Scholar 

  42. Guo, L., Karpac, J., Tran, S. L. & Jasper, H. PGRP-SC2 promotes gut immune homeostasis to limit commensal dysbiosis and extend lifespan. Cell 156, 109–122 (2014).

    Article  CAS  Google Scholar 

  43. Zaidman-Rémy, A. et al. The Drosophila amidase PGRP-LB modulates the immune response to bacterial infection. Immunity 24, 463–473 (2006).

    Article  Google Scholar 

  44. Kim, M., Lee, J. H., Lee, S. Y., Kim, E. & Chung, J. Caspar, a suppressor of antibacterial immunity in Drosophila. Proc. Natl Acad. Sci. USA. 103, 16358–16363 (2006).

    Article  CAS  Google Scholar 

  45. Hartshorn, K. L. et al. Mechanism of binding of surfactant protein D to influenza A viruses: importance of binding to haemagglutinin to antiviral activity. Biochem. J. 351, 449–458 (2000).

    Article  CAS  Google Scholar 

  46. Dillon, R. J. & Dillon, V. M. The gut bacteria of insects: nonpathogenic interactions. Annu. Rev. Entomol. 49, 71–92 (2004).

    Article  CAS  Google Scholar 

  47. Meister, S. et al. Anopheles gambiae PGRPLC-mediated defense against bacteria modulates infections with malaria parasites. PLoS Pathog. 5, e1000542 (2009).

    Article  Google Scholar 

  48. Cirimotich, C. M. et al. Natural microbe-mediated refractoriness to Plasmodium infection in Anopheles gambiae. Science 332, 855–858 (2011).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was funded by grants from the National Natural Science Foundation of China (81301412, 81422028, 81571975 and 61472205), the National Key Basic Research Program of the Chinese Ministry of Science and Technology (MOST) (2013CB911500), the Excellent Young Scientist Foundation of Beijing (2013D009004000002), Grand Challenges Explorations of the Bill & Melinda Gates Foundation (OPP1021992), and the National Institute of Health of the United States (AI103807 and AI099625). We thank the Professor George K. Christophides from Imperial College London, who provided critical suggestions for the manuscript. G.C. is a Newton Advanced Fellow awarded by the Academy of Medical Sciences and the Newton Fund, and a Janssen Investigator of Tsinghua University. We thank the technical supports from the Core Facility of Center for Life Sciences and Center of Biomedical Analysis (Tsinghua University).

Author information

Authors and Affiliations

  1. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Tsinghua University, Beijing, 100084, China

    Xiaojing Pang, Xiaoping Xiao, Yang Liu, Rudian Zhang, Jianying Liu, Qiyong Liu & Gong Cheng

  2. School of Life Science, Tsinghua University, Beijing, 100084, China

    Yang Liu & Rudian Zhang

  3. State Key Laboratory of Infectious Disease Prevention and Control, National Institute for Communicable Disease Control and Prevention, China CDC, Beijing, 102206, China

    Qiyong Liu

  4. Department of Microbiology and Immunology, New York Medical College, Valhalla, 10595, New York, USA

    Penghua Wang

Authors
  1. Xiaojing Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoping Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rudian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jianying Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qiyong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Penghua Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gong Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.C. designed the experiments and wrote the manuscript; X.P. performed the majority of the experiments and analysed data; X.X., R.Z., Y. L. and J.L. helped with the RNA isolation and qPCR detection; Q.L. provided Culex pipiens pallens and contributed to the discussion. P.W. contributed experimental suggestions and strengthened the writing of the manuscript. All authors reviewed, critiqued and provided comments to the text.

Corresponding author

Correspondence to Gong Cheng.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures 1-8 and Tables 1-5 (PDF 1766 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pang, X., Xiao, X., Liu, Y. et al. Mosquito C-type lectins maintain gut microbiome homeostasis. Nat Microbiol 1, 16023 (2016). https://doi.org/10.1038/nmicrobiol.2016.23

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/nmicrobiol.2016.23

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing