Coronavirus disease 2019 (COVID-19) is a worldwide epidemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has had a catastrophic effect, leading to over 700 millions confirmed cases and nearly 7 million deaths worldwide [1]. The mortality rate is higher in individuals with co-existing chronic diseases or underlying health conditions [2], [3]. Although on May 5, 2023, the World Health Organization declared that the COVID-19 pandemic no longer constituted a public health emergency of international concern, it is still necessary to focus on new diagnostic indicators and treatment methods. The ongoing mutations of the virus strains could lead to recurrent infections, long-term sequelae, and even death [4].

Clinical observations have revealed that the clinical course often follows a biphasic pattern in severe cases of COVID-19. This is characterized by a subsequent deterioration in respiratory function occurring approximately 9–12 days after an initial mild-to-moderate presentation [5], [6]. As shown in Fig. 1, the deterioration of respiratory function, featured by dyspnea, tachypnea and chest tightness [7], correlates with the characteristic findings on chest computed tomography (CT) scans. These include interstitial lung abnormalities, expansion of ground-glass lung opacities, and interstitial lung abnormalities [7], as well as the presence of lymphocytopenia, elevated prothrombin time, and increased levels of D-dimer [5]. The elevation in acute phase reactants in the blood indicates a disrupted inflammatory response in the host, leading to an imbalance between pro-inflammatory and anti-inflammatory mediators [8].

Patients with severe COVID-19 exhibit numerous biomarker abnormalities in hematology, including lymphocytopenia, hypercytokinaemia, and a decrease in platelet counts, compared to those with mild cases [9]. Notably, interleukin 6 (IL-6), interleukin 10 (IL-10), and serum ferritin are robust indicators for severe cases [10]. Additionally, increased levels of biomarkers for inflammation, liver and kidney dysfunction, and abnormal coagulation measures are observed [10]. An impaired IFN-I response, associated with a high inflammatory response, is noted in critically ill COVID-19 patients [8]. According to clinical statistics and research, patients with higher rates of severe illness and mortality are primarily elderly individuals over 60, especially those with underlying health conditions such as pre-existing cardiovascular comorbidities, hypertension, and obesity [11], [12].

Interferon (IFN) was firstly discovered as a non-haemagglutinating macromolecular particle during experiments with heat-inactivated influenza in 1957 [13]. These initial studies also described IFN as an abortive product of viral replication and noted its inhibitory effect on the growth of the influenza virus [13]. In 1981, Pestka et al. classified IFNs into three classes based on their primary structures and proven biological activities: leukocyte (IFN-α), fibroblast (IFN-β) and immune (IFN-γ) [14]. They further categorized leukocyte and fibroblast types as IFN-I, immune as type II interferon (IFN-II) [14], [15], [16]. To date, researchers have identified 13 forms of IFN-α in human [17], a single species of IFN-β, and several other types, including putative IFN-δ, pseudogene IFN-τ, IFN-ω, IFN-ε, and IFN-κ as IFN-I, while only one form of IFN-II, known as IFN-γ, has been discovered [15], [16], [17], [18], [19], [20]. Members of IFN-I bind through a receptor complex consisting of the interferon alpha receptor 1 (IFNAR1) and interferon alpha receptor 2 (IFNAR2), while members of IFN-II engage the chains of the interferon gamma receptor 1 (IFNGR1) and interferon gamma receptor 2 (IFNGR2), thereby exerting their biologically active effects [15]. In 2003, three novel interferon-like cytokines were reported, named IFN-λ1 (interleukin-29, IL-29), IFN-λ2 (interleukin-28A, IL-28A), IFN-λ3 (interleukin-28B, IL-28B), and 10 years later another cytokine IFN-λ4 was discovered. These four IFNs constitute type III interferon (IFN-III) [19], [21]. IFN-III members signal through binding to a complex receptor composed of the specific IL‑28 receptor α (IL-28RA) and the shared IL-10 receptor 2 (IL-10R2) [15]. (Table 1)

According to previous studies, IFN-I has been shown to limit the replication of the influenza virus [22], suppress cytokine production, promote antigen presentation and activate the adaptive immune system [17]. Furthermore, it can also exert antiproliferative activity by inducing the autophagy in cancer cells [23] and resisting bacterial infections [22]. The IFN response of innate immunity serves as a primary frontline defense mechanism against viral infections in the host [24]. Researchers have found that the IFN-I response is necessary for recruiting pro-inflammatory monocytes and macrophages to the infected pulmonary tissue, thus activating the response of immune system [25]. Recent researches showed that inadequate IFN-I immunity was responsible for about 15 %-20 % of patients with severe COVID-19 pneumonia, highlighting the importance of modulating IFN-I signals for potential therapeutic options [26]. Furthermore, based on previous studies, IFN-I is pivotal in different stages of COVID-19 infection, including controlling viral replication and regulating protective immune responses in the early stages, while exacerbating inflammation and organ damage in late stages due to delayed response [25], [27]. Moreover, in severe cases, there is an upregulation of genes linked to the IFN-I signaling pathway, while the expression of IFN-stimulated genes (ISGs) is significantly downregulated [28], which may weaken the body's immune function and further affect the body's ability to clear pathogens. According to clinical data and studies, SARS-CoV-2 is capable of antagonizing IFN production and inhibiting IFN signaling [29], [30]. Severe or critical COVID-19 patients exhibit a significant decrease of IFN activity in serum, primarily impairing the production of IFN-α [8]. Additionally, Xia et al. have identified three proteins of the SARS-CoV-2 virus, namely nonstructural protein 6 (nsp6), nonstructural protein 13 (nsp13), and open reading frame 6 (ORF6), which can antagonize IFN-I production through different mechanisms [31]. By assessing the ISGs scores in patients' blood and IFN-α in their plasma, it can be observed that a reduction in the IFN-I response is often exhibited before progression to critical conditions [28]. This suggests that a low IFN-I response may serve as a harbinger for the deterioration of clinical conditions leading to a critical state [28], hence an impaired IFN-I response can be considered as one of the indicators for severe cases of COVID-19. Notably, by identifying the patients with insufficient IFN-I production but maintained cellular responsiveness, it may be possible to benefit them with IFN-I treatment [8]. The direct use of IFN-I in the treatment of COVID-19 and its complications has not yet been fully clinically proven [32]. However, regulating the relevant targets and signaling pathways of IFN-I has been considered a promising treatment strategy [33], [34].

Traditional Chinese medicine (TCM) and other natural compounds have been identified in numerous studies as having the potential to regulate COVID-19 related signaling pathways [24], [35], [36], [37], [38]. Due to their structural diversity and novel scaffolds, natural products and their derivatives play a pivotal role in drug discovery. Meanwhile, their therapeutic effect and safety profiles have been extensively studied and utilized in clinical treatments for thousands of years [24], [39]. Many TCMs are used in the treatment of COVID-19 and related complications. For instance, the Lianhua Qingwen prescription, which is mainly composed of 11 kinds of herbs such as Lianqiao and Jinyinhua, has been proven to have antiviral, lung-protective, and immune-regulating effects, and is therefore recommended for managing COVID-19 cases in China [40]. Another prescription, Qingfei Paidu Decoction, is also widely used in the clinical treatment of COVID-19 and the pulmonary fibrosis caused by COVID-19 [41]. Given the global scale of the COVID-19 pandemic, understanding the potential immunomodulatory role of IFN-I and identifying natural compounds that regulate the related signaling pathways are urgent needs for the dealing with life-threatening pneumonia.

The intention of this review is to illuminate the complex interactions between IFN-I and the severity of COVID-19, to elucidate the underlying mechanisms, and to explore the potential immunomodulatory role of IFN-I in critical COVID-19 pneumonia. Additionally, by examining various compounds with the potential to modulate IFN-I responses, this review aims to provide novel insights into therapeutic approaches for COVID-19. It also seeks to establish a foundation for novel treatment strategies, contributing to the advancement of effective options in response to this global health crisis.