Over the past 30 years, research has helped to elucidate the complexity of the eosinophil's function and establish its role in host defense and immunity. Eosinophils express an array of ligand receptors which play a role in cell growth, adhesion, chemotaxis, degranulation, and cell-to-cell interactions. They play a role in activation of complement via both classical and alternative pathways. Eosinophils synthesize, store and secrete cytokines, chemokines, and growth factors. They can process antigen, stimulate T cells, and promote humoral responses by interacting with B cells. Eosinophils can function as antigen presenting cells and can regulate processes associated with both T1 and T2 immunity. Although long known to play a role in defense against helminth organisms, the interactions of eosinophils with these parasites are now recognized to be much more complex. In addition, their interaction with other pathogens continues to be investigated. In this paper, we review the eosinophil's unique biology and structure, including its characteristic granules and the effects of its proteins, our developing understanding of its role in innate and adaptive immunity and importance in immunomodulation, and the part it plays in defense against parasitic, viral, fungal and bacterial infections. Rather than our worst enemy, the eosinophil may, in fact, be one of the most essential components in host defense and immunity.
В случае с ковидом (итп легочными заболеваниями), активного участия эозинофилов в процессе, желательно избежать, на мой взгляд. Я в этом мнении не одинока- нашлась статья, где хорошо разобрано вовлечение эозинофилов в патологию ковида и сложности создания в прошлом вакцин к коронавирусам, из-за перекоса ответа организма в сторону активации эозинофилов и формирования АУЗИ после прививок (на моделях животных).
..eosinophil depletion occurs in response to multiple triggers of acute inflammation,8 including during sepsis, and multiple studies have consistently shown that low eosinophil levels correlate with poor outcome in critically ill patients.9
..do patients with eosinopenia have unique COVID-19 disease features? This is a particularly relevant question because eosinopenia has already been reported in patients with acute respiratory deterioration during infection with severe acute respiratory syndrome (SARS) coronavirus (CoV) 2 (SARS-CoV-2), the causative agent of COVID-19.Table I).11,12,13,14,15,16,17 On the basis of previous experience with SARS-CoV vaccines, it is expected that COVID-19 vaccines will need careful safety evaluations for immunopotentiation that might increase infectivity and/or eosinophilic infiltration.18
The role of eosinophils in mucosal immune responses in the respiratory tract has largely focused on the detrimental impact that these cells can have in inflammatory responses due to their potent proinflammatory function. However, preclinical studies (mainly in mice) have shown that eosinophils are equipped with an assortment of molecular tools that enable them to recognize, respond, and orchestrate antiviral responses to respiratory viruses.19 Human eosinophils express several endosomal Toll-like receptors (TLRs), including TLR3, TLR7, and TLR9, that detect viral microbe–associated molecular patterns.20,21 22 TLR7 enables eosinophils to recognize single-stranded RNA viruses such as coronavirus, and stimulating this receptor in human eosinophils triggers eosinophil cytokine production, degranulation, superoxide and nitric oxide (NO) generation, and prolonged cellular survival.21,22,23 Eosinophil-derived neurotoxin (EDN/RNAse2) and eosinophil cationic protein (ECP/RNAse3) from human eosinophils reduce infectivity of RSV by a ribonuclease-dependent mechanism.
Although these data substantiate the antiviral potential of eosinophils, the clinical significance of eosinophils in antiviral responses in human disease continues to remain debatable. Patients with eosinophilic asthma have an increased risk for viral-induced asthma exacerbations, and there is mounting evidence that patients with eosinophilic asthma may actually have reduced innate responses against respiratory viruses.35,36,37 Importantly, biologic agents that decrease pulmonary eosinophil levels reduce asthma exacerbations, and patients with asthma treated with these agents have not been reported to have increased viral infections.36,38,39,40,41,42,43 Rosenberg et al
The pathophysiology for eosinopenia in COVID-19 remains unclear but is likely multifactorial, involving inhibition of eosinophil egress from the bone marrow, blockade of eosinophilopoiesis, reduced expression of chemokine receptors/adhesion factors,8,58 and/or direct eosinophil apoptosis induced by type 1 IFNs released during the acute infection.59 Importantly, no eosinophil enrichment into the pulmonary tissue has been observed in samples from patients with COVID-19 at early stages of disease60 or in postmortem analyses.61 Moreover, postmortem analysis of lung tissue from a patient who died from COVID-19 demonstrated signs of acute respiratory distress syndrome that was dominated by mononuclear inflammatory infiltrates, mostly lymphocytes.62
..Eosinopenia, however, may serve as a prognostic indicator for more severe COVID. Following the outbreak of the SARS epidemic in late 2002, investigators raced to develop candidate SARS-CoV-1 vaccines. Diverse strategies were tested, including the use of attenuated or inactivated whole CoV particles, DNA-based vaccines, recombinant viral particles, and recombinant subunit vaccines.64 Sera from patients convalescing from SARS revealed robust antibody titers against the spike protein (S protein) and the nucleocapsid protein.65 Vaccine candidates that induced neutralizing antibodies targeting the S protein demonstrated efficacy in blocking viral replication,66 a concept later confirmed by passive antibody transfer studies.67,68 Unfortunately, anti–SARS vaccine–associated pathology emerged in early ferret (hepatitis69 and pulmonary eosinophilia15,69), cynomolgus monkey (TH2-type immunopathology with eosinophils15,70), and mouse (pulmonary eosinophilia)11 studies. SARS-CoV-1–driven, eosinophil-associated TH2 immunopotentiation also occurred with reinfection (green monkey model), suggesting that immune enhancement of CoV-associated disease may be relevant in future outbreaks of heterologous CoVs.71 Eosinophil-associated disease enhancement following exposure after vaccination is unfortunately not a new phenomenon. Historical reports from the 1960s link administration of a candidate formalin-inactivated RSV vaccine to severe, eosinophil-associated pulmonary disease following natural infection. This severe eosinophilic pulmonary disease hospitalized most study participants and led to at least 2 deaths.72,73,74 Memories of such disease enhancement postvaccination strongly influenced subsequent RSV F protein subunit vaccine development and trial design.75 The development of a safe and efficacious SARS-CoV-2 vaccine will require the development of vaccine candidates that take into account the risk of similar vaccine-associated immunopathology.
In the decade following these early observations, a series of mouse studies (see Table I) evaluated the factors driving the observed TH2-skewed vaccine immunopathology. Two independent studies using recombinant viral particles (Venezuelan equine encephalitis virus or vaccinia) used isolated SARS structural proteins to investigate the source of immunopathology.11,13 Nucleocapsid protein vaccination was implicated as a major driver of vaccine-associated pulmonary eosinophilia, although passive transfer of anti– nucleocapsid protein antibody was not sufficient to drive enhanced TH2 disease, suggesting a possible role for anti–nucleocapsid protein–specific T cells.11 TH2-mediated disease enhancement was also linked to age, as vaccination of aged mice (>12 months old) with double-inactivated SARS-CoV-1 led to increased morbidity/mortality and accentuated eosinophilic pulmonary disease.14 Follow-up studies comparing vaccination strategies, vaccine preparations (whole virus/virus-like particles vs subunits vs subunit fragments), boosting strategies and timing, and the inclusion of alum versus other adjuvants (TLR agonists) have yielded variable results. In early studies, chimeric recombinant virus–like particle vaccines displaying only the SARS S protein did not induce eosinophilia.11,13 In contrast, isolated S protein subunit vaccines (SpikeΔTM [SΔTM]) appeared capable of TH2 immunopotentiation.15,16,17 S protein–derived fragments containing just the receptor-binding domain have also been proposed as vaccine antigens, but these vaccine formulations have required more aggressive use of adjuvants and more boosters (3-4 times more) than other approaches.64 Investigations into the TH2 immunopotentiation capacity of these compounds have been limited but reassuring, with 1 study showing no evidence of pulmonary eosinophilia in postchallenge animals12 and a follow-up study showing balanced TH1/TH2 cytokine induction following vaccination.76 Some investigators have implicated the inclusion of the TH2-skewing adjuvant alum in causing the immunopotentiation, and subsequent studies have shown that the inclusion of TH1-skewing adjuvants with both whole virus and subunit vaccine candidates has attenuated or blocked the development of pulmonary eosinophilia with SARS-CoV-1 challenge.16,17 Alternatively, contaminating exogenous proteins from serum-containing media (ie, BSA) in vaccine preparation or viral stocks may explain the observed TH2 skewing in certain experiments; however, the absence of eosinophilic infiltrates in mock-vaccinated control animals makes this possibility less likely. Overall, the SARS-CoV-1 vaccination literature documents recurrent, postvaccination disease enhancement in diverse vaccine preparations and across multiple animal models; however, this side effect declines with the use of more tightly defined antigens (S protein receptor-binding domain peptide) and the use of TH1-skewing adjuvants
Finally, and likely most importantly, there is considerable concern about whether SARS-CoV-2 exposure postvaccination would cause eosinophil-associated lung pathology through immunopotentiation (see Fig 1). Although these concerns mainly have been derived from murine studies using vaccine candidates from the original SARS-CoV-1 virus, similar responses have also been seen in other species (eg, ferrets and monkey studies); it is also notable that SARS-CoV-1 and SARS-CoV-2 share more than 80% identity. Although the ongoing COVID-19 outbreak places new emphasis on the critical need for an effective SARS-CoV-2 vaccine, safety must be a central focus for any vaccine designed for general use. Current clinical reports show that most (up to 81%) patients with COVID-19 have mild disease,77and therefore, trials of vaccine candidates must rigorously demonstrate the absence of eosinophil-associated disease enhancement before widespread deployment.
Eosinophil responses related to COVID-19
|Atopy-related eosinophilia||Atopy does not appear to have an exacerbating role in COVID-19|
|Eosinophil antiviral activity||The antiviral activity of eosinophils is unlikely involved in COVID-19 because the antiviral activity of eosinophils has not yet been observed in humans|
|Biological drug–induced eosinopenia||There are no data to date substantiating any risk for infections following depletion of eosinophils|
|COVID-19–associated eosinopenia||The eosinopenia associated with COVID-19 is likely a secondary phenomenon and not directly contributing to the disease course|
|Lung eosinophilia associated with immunopotentiation by SARS vaccines||Vaccine candidates must demonstrate the absence of eosinophil-associated disease enhancement before widespread deployment|