Lung SARS-CoV-2-specific IgA in severe COVID-19 might contribute to fatal outcome

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muqueuse pulmonaire

In a study published in Frontiers in Immunology, the team led by Morgane Bomsel characterised the antibodies in the lung mucosa of intensive care patients with severe Covid-19. The study shows that mortality is correlated with high levels of mucosal IgA that persist even after elimination of the virus but which lose their protective function, and with a decrease in IL-1beta preventing regeneration of the pulmonary epithelium.

After its first occurrence in Wuhan, China on December 2019, Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease of 2019 (COVID-19) has spread rapidly throughout the world and has reached pandemic proportions affecting all continents.

Typical symptoms of COVID-19 include fever, cough, fatigue, and in severe cases respiratory difficulties, indicating that the lung epithelium is the primary target of the virus, though other less frequent and atypical symptoms have also been described. Hence, the virus infects via the nasal mucosa establishing in turn infection in the lung. To infect cells, the virus uses its surface protein referred to as the spike (S). One region of the spike controls viral entry into human target cells by binding opportunistically a receptor at the target cell surface. In turn, the virus multiplies in the cell leading to the production of viruses and its propagation to more cells. Besides, viral infection leads to a hyperactivation of both arm of the immune system, the innate and adaptive ones, that can turn harmful for the patient as observed by tissue damages and cytokine deregulation observed in severe COVID-19.

The immune system is highly compartmentalized and the antibodies in the circulation have different specificities and functions than those produced locally at mucosal level including the respiratory tracts. Although the virus mainly replicates in the lung and is rarely detected in the blood, researches have mainly focused on understanding the immune antibody response in the blood, and no large studies have evaluated the lung antibody response in COVID-19, and the role of the mucosal pulmonary antibody response against SARS-Cov-2 remains to be elucidated.

Thus, to clarify the mucosal pulmonary antibody response in severe COVID-19, we have characterized the mucosal humoral immune response to various parts of the SARS-CoV-2 spike and nucleoprotein in 48 broncho-alveolar lavages from severe COVID-19 patients admitted in ICUs. We show that patients with fatal COVID-19, in contrast to survivors, developed higher levels of mucosal spike-specific IgA than IgG but lost neutralizing activities over time. Specifically, in severe COVID-19 patients, sustained levels of mucosal pulmonary non-neutralizing SARS-CoV-2 IgA persisted after viral clearance in the lung and are associated with COVID-19 fatal outcomes several days/ weeks after sampling. Therefore, mucosal SARS-CoV-2-specific antibodies may have adverse functions in addition to protective neutralization.  In addition, fatal outcome was also associated with a decrease in lung IL-1beta, a cytokine involved in epithelial surface regeneration that could have contributed to the lung tissue deterioration observed in critical COVID-19.

Altogether, our results highlight the importance of lung antibody responses in severe COVID-19, at the site where the virus infects and replicates. The loss of neutralizing activity in non-survivors at later stages of COVID-19 suggested that the persisting antibodies might be non-neutralizing although preserving their capacity to interact with the innate immune system causing deleterious effects. More studies are needed to understand the role of these non-protective lung antibodies in the pathogenesis of fatal COVID-19 disease. Thus, evaluate the interaction of these mucosal deleterious antibodies with the innate immune cells leading to their activation and the cytokine storm followed by locally and systemic tissue damage worth to be investigated.



Ruiz MJ, Siracusano G, Cottignies-Calamarte A, Tudor D, Real F, Zhu A, Pastori C, Capron C, Rosenberg AR, Temperton N, Cantoni D, Liao H, Ternette N, Moine P, Godement M, Geri G, Chiche J-D, Annane D, Cramer Borde´ E, Lopalco L and Bomsel M (2022). Persistent but dysfunctional mucosal SARS-CoV-2- specific IgA and low lung IL-1b associate with COVID-19 fatal outcome: A crosssectional analysis. Front. Immunol. 13:842468. doi: 10.3389/fimmu.2022.842468

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Morgane Bomsel

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