Neutrophils as a pallbearer for SARS-CoV-2 disease burden – Authors’ reply
Authors: René Lutter, Bernadette Schurink, Eva Roos, Lihui Guo, Paul van der Valk, Marianna Bugiani
Journal: The Lancet Microbe (2021)

We thank David Twa and colleagues for their interest in our findings and agree that it is intriguing that, despite the apparent systemic responses, some organs from patients who died of COVID-19 are more affected than others by neutrophilic extracellular traps (NETs). Although to the best of our knowledge, NETs have never been studied in much detail for other respiratory viral infections, there is strong evidence from respiratory viral infections that are virulent (influenza),1Zhu L Liu L Zhang Y et al.High level of neutrophil extracellular traps correlates with poor prognosis of severe influenza A infection.J Infect Dis. 2018; 217: 428-437Crossref PubMed Scopus (138) Google Scholar, 2Ravanetti L Dijkhuis A Dekker T et al.IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive antiviral immunity.J Allergy Clin Immunol. 2019; 143 (70.e16): 1355Summary Full Text Full Text PDF PubMed Scopus (76) Google Scholar and also those that are less virulent (rhinovirus),3Toussaint M Jackson DJ Swieboda D et al.Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation.Nat Med. 2017; 23: 681-691Crossref PubMed Scopus (240) Google Scholar that NETs are formed locally and even that markers of NETs can be detected systemically.1Zhu L Liu L Zhang Y et al.High level of neutrophil extracellular traps correlates with poor prognosis of severe influenza A infection.J Infect Dis. 2018; 217: 428-437Crossref PubMed Scopus (138) Google Scholar In fact, Zeng and colleagues1Zhu L Liu L Zhang Y et al.High level of neutrophil extracellular traps correlates with poor prognosis of severe influenza A infection.J Infect Dis. 2018; 217: 428-437Crossref PubMed Scopus (138) Google Scholar found that markers of systemic NETs correlate with the outcome of influenza infections, which might also be relevant markers in COVID-19-related outcomes, as was proposed.4Ng H Havervall S Rosell A et al.Circulating markers of neutrophil extracellular traps are of prognostic value in patients with COVID-19.Arterioscler Thromb Vasc Biol. 2020; (published online Dec 3.)https://doi.org/10.1161/ATVBAHA.120.315267Google Scholar The differences in NETs between organs indicate organ-specific modulation. On the basis of their analysis, Twa and colleagues suggested that ACE2 expression might underlie the differential presence of NETs. Notably, we found that ACE2 expression in the lungs from patients with COVID-19 was higher than in the control tissue (appendix). Also, we found significantly increased ACE2 expression in the sequential transcriptomes of nasal epithelial cells from patients with asthma5Ravi A Chang M van de Pol M et al.Rhinovirus-16 induced temporal interferon responses in nasal epithelium links with viral clearance and symptoms.Clin Exp Allergy. 2019; 49: 1587-1597Crossref PubMed Scopus (21) Google Scholar at days 3 and 6 after exposure to the common cold virus, rhinovirus 16, compared with one week before the viral challenge (p=0·007 [ANOVA], data not shown). ACE2 degrades proinflammatory peptides such as angiotensin 2 and des-Arg9 bradykinine, and this activity, together with the generation of anti-inflammatory angiotensin (1-7), might attenuate inflammatory and also neutrophilic responses. We therefore suggest that the increase in ACE2 expression is a common response to infection with a respiratory virus and might be a response restoring homoeostasis. A possible explanation for the apparent contradictory association between ACE2 expression and neutrophil activation is that NETs are not being cleared, whereas ACE2 expression is related to the events that triggered NET formation. The differences in NETs between organs might therefore also relate to differences in resolving NETs, which should be considered when the presence of NETs is used as a prognostic factor. Finally, it is important to realise that in the organs of most patients, we found little to no severe acute respiratory syndrome coronavirus 2 particles by both immunohistochemistry and quantitative PCR, indicating that despite the presence of ACE2, the porte d'entrée for severe acute respiratory syndrome coronavirus 2, there is no viral infection and replication and thus the pathology might be related to an autonomous, systemic process. Whether this process depends on the extent of NETs that are present requires further study. We declare no competing interests. We thank Jasper Mol for his help with the transcriptome analysis, and Wim Vos, for doing the ACE2 staining. Download .pdf (13.24 MB) Help with pdf files Supplementary appendix Viral presence and immunopathology in patients with lethal COVID-19: a prospective autopsy cohort studyIn patients with lethal COVID-19, an extensive systemic inflammatory response was present, with a continued presence of neutrophils and NETs. However, SARS-CoV-2-infected cells were only sporadically present at late stages of COVID-19. This suggests a maladaptive immune response and substantiates the evidence for immunomodulation as a target in the treatment of severe COVID-19. Full-Text PDF Open AccessNeutrophils as a pallbearer for SARS-CoV-2 disease burdenWe read the Article by Bernadette Schurink and colleagues,1 and were impressed, similar to the authors, with the heterogeneity of the invasion of end organs by neutrophils, despite a severe and systemic COVID-19 disease burden among the study sample. In other words, it is unclear why some organ systems among patients with COVID-19 are affected more extensively compared with others, despite the assertion of this Article that organ damage is predicated by a reactive infiltrate, perhaps independently of the presence of the replication of active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the specific tissue. Full-Text PDF Open Access