Scientific publications

Neutrophil extracellular traps, local IL-8 expression, and cytotoxic T-lymphocyte response in the lungs of fatal COVID-19

Jun 14, 2022 | Magazine: Chest

Ignacio Melero  1 , María Villalba-Esparza  2 , Borja Recalde-Zamacona  3 , Daniel Jiménez-Sánchez  4 , Álvaro Teijeira  5 , Alan Argueta  4 , Laura García-Tobar  4 , Laura Álvarez-Gigli  4 , Cristina Sainz  4 , David Garcia-Ros  6 , Estefanía Toledo  7 , Marta Abengozar-Muela  4 , Mirian Fernández-Alonso  8 , Mariano Rodríguez-Mateos  9 , Gabriel Reina  8 , Francisco Carmona-Torre  8 , Jorge Augusto Quiroga  10 , Jose L Del Pozo  8 , Amy Cross  11 , Álvaro López-Janeiro  12 , David Hardisson  12 , José I Echeveste  13 , Maria D Lozano  14 , Ling-Pei Ho  15 , Paul Klenerman  16 , Fadi Issa  11 , Manuel F Landecho  10 , Carlos E de Andrea  17

Background: Excessive inflammation is pathogenic in the pneumonitis associated with severe COVID-19. Neutrophils are among the most abundantly present leukocytes in the inflammatory infiltrates and may form neutrophil extracellular traps (NETs) under the local influence of cytokines. NETs constitute a defense mechanism against bacteria but have also been shown to mediate tissue damage in a number of diseases.

Research question: Could NETs and their tissue-damaging properties inherent to neutrophil-associated functions play a role in the respiratory failure seen in severe COVID-19 patients and how does this relate to the SARS-CoV-2 viral loads, IL-8 (CXCL8) chemokine expression, and cytotoxic T-lymphocytes infiltrates?

Study design and methods: Sixteen immediate post-mortem lung biopsies were methodically analyzed as exploratory and validation cohorts. NETs were quantitatively analyzed by multiplexed immunofluorescence and correlated with local levels of IL-8 mRNA and the density of CD8+ T-cell infiltration. SARS-CoV-2 presence in tissue was quantified by RT-PCR and immunohistochemistry.

Results: NETs were found in the lung interstitium and surrounding the bronchiolar epithelium with interindividual and spatial heterogeneity. NET density did not correlate with SARS-CoV-2 tissue viral load. NETs were associated with local IL-8 mRNA levels. NETs were also detected in pulmonary thrombi and in only one out of eight liver tissues. NET focal presence negatively correlated with CD8+ T-cell infiltration in the lungs.

Interpretation: Abundant neutrophils undergoing NETosis are found in the lungs of patients with fatal COVID-19, but no correlation is found with viral loads. The strong association between NETs and IL-8 points to this chemokine as a potentially causative factor. The function of cytotoxic T-lymphocytes in the immune responses against SARS-CoV-2 may be interfered with the presence of NETs.

CITATION  Chest. 2022 Nov;162(5):1006-1016.  doi: 10.1016/j.chest.2022.06.007.  Epub 2022 Jun 15