Leukocyte trafficking to the lungs and beyond: lessons from influenza for COVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). Understanding of the fundamental processes underlying the versatile clinical manifestations of COVID-19 is incomplete without comprehension of how different immune cells are recruited to various compartments of virus-infected lungs, and how this recruitment differs among individuals with different levels of disease severity. As in other respiratory infections, leukocyte recruitment to the respiratory system in people with COVID-19 is orchestrated by specific leukocyte trafficking molecules, and when uncontrolled and excessive it results in various pathological complications, both in the lungs and in other organs. In the absence of experimental data from physiologically relevant animal models, our knowledge of the trafficking signals displayed by distinct vascular beds and epithelial cell layers in response to infection by SARS-CoV-2 is still incomplete. However, SARS-CoV-2 and influenza virus elicit partially conserved inflammatory responses in the different respiratory epithelial cells encountered early in infection and may trigger partially overlapping combinations of trafficking signals in nearby blood vessels. Here, we review the molecular signals orchestrating leukocyte trafficking to airway and lung compartments during primary pneumotropic influenza virus infections and discuss potential similarities to distinct courses of primary SARS-CoV-2 infections. We also discuss how an imbalance in vascular activation by leukocytes outside the airways and lungs may contribute to extrapulmonary inflammatory complications in subsets of patients with COVID-19. These multiple molecular pathways are potential targets for therapeutic interventions in patients with severe COVID-19.

Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19

“…These data suggest that lung macrophages contribute to inflammatory responses in SARS-CoV-2 infection, favouring excessive inflammation in severe pneumonia. Similar to other respiratory infections, leukocyte recruitment to the lungs is finely tuned by specific molecules 31 , the uncontrolled activity of which may result in complications observed in patients with COVID-19 in both the lungs and other organs 5 , 32 .…”

Thymic Aging May Be Associated with COVID-19 Pathophysiology in the Elderly

“…One is likely due to the SARS-CoV-2 spike proteins directly interacting with CD26 on T cells, leading to T cell apoptosis and immune dysfunction [ 37 , 38 ]. The second is due to the relocation of T cells, assuming that a large number of T cells in the blood are recruited to the lung [ 15 , 39 ]. Additionally, the third, seen in aged patients, is possibly attributed to the aged patient’s low thymopoiesis [ 40 , 41 ], which in conjunction with immunosenescence, reduces efficient peripheral T cell activation and differentiation for the necessary anti-infection response [ 42 ].…”

Functional and Transcriptional Adaptations of Blood Monocytes Recruited to the Cystic Fibrosis Airway Microenvironment In Vitro

“…For example, it is unclear whether CFTR may independently affect NO production, and other targets identified in our study (ISG15, CXCL11) are even less well characterized in CF pathophysiology in vivo and therefore warrant more attention. More broadly, the ability to mass-produce airway-like monocytes using this transmigration model should open opportunities for research into the roles played by these cells in chronic lung pathologies including but not limited to CF [ 45 , 46 ] and in acute infection by agents such as influenza or SARS-CoV-2 [ 47 ], which are known to modulate immune effectors such as NO [ 48 ] and ISG15 [ 49 ].…”