Eosinophils as potential biomarkers in respiratory viral infections

Abstract

Eosinophils are bone marrow-derived granulocytes that, under homeostatic conditions, account for as much as 1-3% of peripheral blood leukocytes. During inflammation, eosinophils can rapidly expand and infiltrate inflamed tissues, guided by cytokines and alarmins (such as IL-33), adhesion molecules and chemokines. Eosinophils play a prominent role in allergic asthma and parasitic infections. Nonetheless, they participate in the immune response against respiratory viruses such as respiratory syncytial virus and influenza. Notably, respiratory viruses are associated with asthma exacerbation. Eosinophils release several molecules endowed with antiviral activity, including cationic proteins, RNases and reactive oxygen and nitrogen species. On the other hand, eosinophils release several cytokines involved in homeostasis maintenance and Th2-related inflammation. In the context of SARS-CoV-2 infection, emerging evidence indicates that eosinophils can represent possible blood-based biomarkers for diagnosis, prognosis, and severity prediction of disease. In particular, eosinopenia seems to be an indicator of severity among patients with COVID-19, whereas an increased eosinophil count is associated with a better prognosis, including a lower incidence of complications and mortality. In the present review, we provide an overview of the role and plasticity of eosinophils focusing on various respiratory viral infections and in the context of viral and allergic disease comorbidities. We will discuss the potential utility of eosinophils as prognostic/predictive immune biomarkers in emerging respiratory viral diseases, particularly COVID-19. Finally, we will revisit some of the relevant methods and tools that have contributed to the advances in the dissection of various eosinophil subsets in different pathological settings for future biomarker definition.

Keywords: COVID-19; IL-33; allergic asthma; biomarkers; eosinophils; respiratory virus infection.

Figure 1

Release of soluble mediators by eosinophils. Eosinophils respond to stimuli released in the context of viral or allergic sensitization, by producing various soluble mediators involved in: inflammation (IFN-γ, IL-8, IL-12, IL-2, IL-6), Th2 response (IL-4, IL-5, IL-13), immune regulation (TGF-β, IL-10) and antiviral response, including antiviral factors (IRF-7, NOS-2, IFN-β, and the ribonucleases EAR-1 and EAR-2), chemokines attracting T cell effectors (CXCL10., CCL3, CCL5) and granule-derived cationic proteins (EDN, ECP, MBP).

Figure 2

Role of eosinophils and IL-33/ST2 in the context of virus and allergen exposure in the airways. Virus infection and allergen (e.g., HDM) exposure induce damage in the lung epithelium. Both events result in the release of epithelial-derived alarmins, namely TSLP, IL-25 and IL-33. In particular, IL-33 binds to its specific receptor ST2 expressed by many immune cell types present in the lung. DC respond to IL-33 and migrate to draining lymph node where they prime naive Th cells inducing polarization of Th2 cells, which subsequently migrate to the lung and release IL-5. ST2-expressing ILC2 cells respond to IL-33 producing IL-5 and IL-13. IL-5 stimulates the differentiation of eosinophils from bone marrow. Eosinophils then migrate to the lung where they respond to IL-33, resulting in degranulation (orange dots) and release of different substances. These eosinophils, on the one hand, support Th2 inflammation sustained by ST2-derived IL-13 and recruitment of basophils and mast cells and, on the other hand, may prevent virus replication through the release of ribonucleases, reactive oxygen species (ROS) and nitric oxide synthase (NOS). Conversely, eosinophils may reduce virus-induced type I IFN (IFN-I) production by pDC through release of TGF-β.

Figure 3

Schematic representation for principal methods of isolation and study of eosinophils from peripheral blood. Whole blood samples can be either directely stimulated in culture and stained with a multicolor panel to distinguish eosinophils from other leukocytes, such as neutrophils and basophils, based on indicated surface markers. Alternatively, eosinophils can be isolated from whole blood by density gradient enrichment followed by immunomagnetic or cell sorting purification. Eosinophils can be then assessed for phenotype (by expression of indicated activation markers) and function, either ex vivo or following in vitro stimulation.