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.

  • Correspondence
  • Published:

Ficolin A exacerbates severe H1N1 influenza virus infection-induced acute lung immunopathological injury via excessive complement activation

Cellular & Molecular Immunology volume 18, pages 2278–2280 (2021)Cite this article

Subjects

Access through your institution
Buy or subscribe

Severe pandemic influenza A (H1N1) 2009 virus (pH1N1) infection causes significant morbidity and mortality. We and other groups have reported that immunopathological damage induced by excessive pulmonary inflammation plays a critical role in the pathogenesis of severe pneumonia and provides novel strategies for the treatment of severe influenza infection [1,2,3]. The complement system plays critical roles in both innate and adaptive immunity by activating the classical, alternative and lectin pathways [4]. As soluble pattern recognition lectin molecules, ficolins are enriched in the lungs and are essential for protecting the host from invading pathogens [5]. In our previous report, low-dose lipopolysaccharide (LPS) inoculation simulated bacterial infection-induced mild pneumonia without death in mice. We found that intranasal LPS administration induced local pulmonary inflammation and increased the recruitment of macrophages and neutrophils and the expression of ficolin A and ficolin B. LPS-challenged ficolin A-knockout (Fcna−/−) mice showed more severe lung injury than LPS-challenged wild-type (WT) mice. These results suggest that the protective effect of ficolin A may be associated with complement activation, as well as the neutralization of LPS [6]. However, complement is a double-edged sword. Complement activation also triggers potent detrimental hyperinflammatory responses that cause tissue damage and organ failure when these responses are dysregulated or overactivated [7]. Therefore, whether ficolins play protective or detrimental roles in severe pH1N1 infection and their mechanisms need to be investigated. Our results demonstrated that ficolin A-mediated excessive complement activation exacerbates pulmonary proinflammatory responses and contributes to lung immunopathological injury. Targeting ficolin A may be a potential adjunctive therapeutic strategy for alleviating severe influenza-induced viral pneumonia.

Fcna−/− and Ficolin B-knockout (Fcnb−/−) mice were further used to assess the roles of these genes in pH1N1-induced severe pneumonia. Notably, compared with WT and Fcnb−/− mice, Fcna−/− mice showed significant improvements in survival rates (62.5% in Fcna−/− mice vs 25% in WT and Fcnb−/− mice), less weight loss and faster weight recovery (Fig. 1b). Moreover, lung histopathological injury [the total protein concentration in bronchoalveolar lavage fluid (BALF) and lung bronchial and parenchymal destruction, including hemorrhage, alveolar edema, alveolar fusion, and bronchiolar epithelial sloughing] was significantly ameliorated, and inflammatory cell infiltration was attenuated in Fcna−/− mice compared with WT mice (Fig. 1c,d and S2a). These results suggested that ficolin A but not ficolin B could exacerbate pH1N1-induced lung injury and decrease the survival rate.

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

Relevant articles

Open Access articles citing this article.

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1

References

  1. Cao B, Li XW, Mao Y, Wang J, Lu HZ, Chen YS, et al. Clinical features of the initial cases of 2009 pandemic influenza A (H1N1) virus infection in China. N Engl J Med. 2009;361:2507–17.

    Article  CAS  Google Scholar 

  2. Jia X, Liu B, Bao L, Lv Q, Li F, Li H, et al. Delayed oseltamivir plus sirolimus treatment attenuates H1N1 virus-induced severe lung injury correlated with repressed NLRP3 inflammasome activation and inflammatory cell infiltration. PLoS Pathog. 2018;14:e1007428.

    Article  Google Scholar 

  3. Liu Q, Zhou YH, Yang ZQ. The cytokine storm of severe influenza and development of immunomodulatory therapy. Cell Mol Immunol. 2016;13:3–10.

    Article  CAS  Google Scholar 

  4. Reis ES, Mastellos DC, Hajishengallis G, Lambris JD. New insights into the immune functions of complement. Nat Rev Immunol. 2019;19:503–16.

    Article  CAS  Google Scholar 

  5. Swierzko AS, Cedzynski M. The influence of the lectin pathway of complement activation on infections of the respiratory system. Front Immunol. 2020;11:585243.

    Article  CAS  Google Scholar 

  6. Wu X, Yao D, Bao L, Liu D, Xu X, An Y, et al. Ficolin A derived from local macrophages and neutrophils protects against lipopolysaccharide-induced acute lung injury by activating complement. Immunol Cell Biol. 2020;98:595–606.

    Article  CAS  Google Scholar 

  7. Garred P, Tenner AJ, Mollnes TE, Levy FO. Therapeutic targeting of the complement system: From rare diseases to pandemics. Pharm Rev. 2021;73:792–827.

    Article  CAS  Google Scholar 

  8. Flerlage, T, Boyd, DF, Meliopoulos, V, Thomas, PG & Schultz-Cherry, S. Influenza virus and SARS-CoV-2: pathogenesis and host responses in the respiratory tract. Nat Rev Microbiol. 2021. https://doi.org/10.1038/s41579-021-00542-7.

  9. Guo XJ, Thomas PG. New fronts emerge in the influenza cytokine storm. Semin Immunopathol 2017;39:541–50.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (82071747, 81373114), Beijing Municipal Natural Science Foundation, China (7182013).

Author information

Author notes

  1. These authors contributed equally: Xu Wu, Linlin Bao.

Authors and Affiliations

  1. Department of Immunology, School of Basic Medical Sciences, Capital Medical University, Beijing, China

    Xu Wu, Ziqi Hu, Duoduo Yao, Yunqing An, Xi Wang & Xulong Zhang

  2. Department of Respiratory Medicine, Hunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, China

    Xu Wu

  3. NHC Key Laboratory of Human Disease Comparative Medicine (The Institute of Laboratory Animal Sciences, CAMS & PUMC), Beijing Key Laboratory for Animal Models of Emerging and Reemerging Infection, Beijing, China

    Linlin Bao & Fengdi Li

  4. China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, Clinical Center for Pulmonary Infections, Capital Medical University, Beijing, China

    Hui Li & Bin Cao

  5. Department of Core Facility Center, Capital Medical University, Beijing, China

    Xiaoxue Xu

  6. Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China

    Bin Cao

  7. Tsinghua University-Peking University Joint Center for Life Sciences, Beijing, China

    Bin Cao

Authors
  1. Xu Wu
    View author publications

    Search author on:PubMed Google Scholar

  2. Linlin Bao
    View author publications

    Search author on:PubMed Google Scholar

  3. Ziqi Hu
    View author publications

    Search author on:PubMed Google Scholar

  4. Duoduo Yao
    View author publications

    Search author on:PubMed Google Scholar

  5. Fengdi Li
    View author publications

    Search author on:PubMed Google Scholar

  6. Hui Li
    View author publications

    Search author on:PubMed Google Scholar

  7. Xiaoxue Xu
    View author publications

    Search author on:PubMed Google Scholar

  8. Yunqing An
    View author publications

    Search author on:PubMed Google Scholar

  9. Xi Wang
    View author publications

    Search author on:PubMed Google Scholar

  10. Bin Cao
    View author publications

    Search author on:PubMed Google Scholar

  11. Xulong Zhang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

XW, LB, ZH, DY, FL, HL and XX performed the experiments; YA and XW verified the experimental procedure and data; XW, BC, and XZ analyzed the data and wrote the paper; BC and XZ designed and supervised the study.

Corresponding authors

Correspondence to Bin Cao or Xulong Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, X., Bao, L., Hu, Z. et al. Ficolin A exacerbates severe H1N1 influenza virus infection-induced acute lung immunopathological injury via excessive complement activation. Cell Mol Immunol 18, 2278–2280 (2021). https://doi.org/10.1038/s41423-021-00737-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41423-021-00737-1

This article is cited by

Search

Advanced search

Quick links