The glycosaminoglycan-binding chemokine fragment CXCL9(74-103) reduces inflammation and tissue damage in mouse models of coronavirus infection

Front Immunol. 2024 Apr 15:15:1378591. doi: 10.3389/fimmu.2024.1378591. eCollection 2024.

Abstract

Introduction: Pulmonary diseases represent a significant burden to patients and the healthcare system and are one of the leading causes of mortality worldwide. Particularly, the COVID-19 pandemic has had a profound global impact, affecting public health, economies, and daily life. While the peak of the crisis has subsided, the global number of reported COVID-19 cases remains significantly high, according to medical agencies around the world. Furthermore, despite the success of vaccines in reducing the number of deaths caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there remains a gap in the treatment of the disease, especially in addressing uncontrolled inflammation. The massive recruitment of leukocytes to lung tissue and alveoli is a hallmark factor in COVID-19, being essential for effectively responding to the pulmonary insult but also linked to inflammation and lung damage. In this context, mice models are a crucial tool, offering valuable insights into both the pathogenesis of the disease and potential therapeutic approaches.

Methods: Here, we investigated the anti-inflammatory effect of the glycosaminoglycan (GAG)-binding chemokine fragment CXCL9(74-103), a molecule that potentially decreases neutrophil transmigration by competing with chemokines for GAG-binding sites, in two models of pneumonia caused by coronavirus infection.

Results: In a murine model of betacoronavirus MHV-3 infection, the treatment with CXCL9(74-103) decreased the accumulation of total leukocytes, mainly neutrophils, to the alveolar space and improved several parameters of lung dysfunction 3 days after infection. Additionally, this treatment also reduced the lung damage. In the SARS-CoV-2 model in K18-hACE2-mice, CXCL9(74-103) significantly improved the clinical manifestations of the disease, reducing pulmonary damage and decreasing viral titers in the lungs.

Discussion: These findings indicate that CXCL9(74-103) resulted in highly favorable outcomes in controlling pneumonia caused by coronavirus, as it effectively diminishes the clinical consequences of the infections and reduces both local and systemic inflammation.

Keywords: betacoronavirus; chemokine; coronavirus; glycosaminoglycan; inflammation; neutrophil.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COVID-19 Drug Treatment
  • COVID-19* / immunology
  • Chemokine CXCL9* / metabolism
  • Disease Models, Animal*
  • Female
  • Glycosaminoglycans* / metabolism
  • Humans
  • Inflammation / immunology
  • Lung* / immunology
  • Lung* / metabolism
  • Lung* / pathology
  • Lung* / virology
  • Mice
  • Mice, Inbred C57BL
  • SARS-CoV-2* / immunology

Substances

  • Glycosaminoglycans
  • Chemokine CXCL9
  • Cxcl9 protein, mouse

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research received support from grants provided by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES/Brazil (Project: CAPES - Program: 9951 - Programa Estratégico Emergencial de Prevenção e Combate a Surtos, Endemias, Epidemias e Pandemias AUX 0641/2020 - Process 88881.507175/2020-01), as well as CAPES 11/2020 Epidemias, No. 88887.506690/2020-00. Additionally, it was funded by the National Institute of Science and Technology in Dengue and Host-Microorganism Interaction (INCT em Dengue), and by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; Brazil) (Process CNPQ: 465425/2014-3), the Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG; Brazil) (Process FAPEMIG: 25036), and FINEP - Financiadora de Estudos e Projetos under MCTI/FINEP – MS/SCTIE/DGITIS/CGITS (6205283B-BB28-4F9C-AA65-808FE4450542) grant. Furthermore, this study was funded by the Fundação de Amparo à Pesquisa do Estado de Minas Gerais under grant number APQ02618-23. Additionally, financial support was provided by KU Leuven (C14/23/143 and C3/22/054 projects) and by The Research Foundation – Flanders (FWO project G067123N).