Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused an emergency disease pandemic worldwide, named coronavirus disease 2019 (COVID-19), which led to a considerable threat to public health and economic development (1). SARS-CoV-2 is a positive-sense single-stranded RNA (ssRNA) virus that belongs to the genus Betacoronavirus. It owns six typical functional open reading frames (ORFs), namely, replicase (ORF1a/ORF1b), spike (S), envelope (E), membrane (M), and nucleocapsid (N), which are shared by other betacoronaviruses (2). Notably, the distribution and replication of SARS-Cov-2 were found in the respiratory system and the genitourinary, gastrointestinal, and even central neural systems (3). Therefore, SARS-CoV-2 can be detected in urine and stool, except in samples from the respiratory tract, which increased the risk of infection via sewage networks and wastewater systems (4).

The transmissibility of viruses was increasing with the evolution of new variants. The primary reproduction number (R ₀) indicates the average number of patients who would be infected by a primary case in a totally susceptible population, elevating from the original SARS-CoV-2 (R ₀: 2-2.5) to Delta (R ₀: 3.2-8). Currently, the Omicron variant, which has sparked a wave of infections worldwide, has an R ₀ value 3.2 times higher than the Delta variant (5, 6). Various vaccines were produced to prevent the spread of SARS-CoV-2. However, as an ssRNA virus, SARS-CoV-2 reduces the efficiency of vaccines with high-frequency mutation. Vaccine breakthrough has been observed in different variants, such as Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529) (7–9). It is no longer realistic to resist SARS-CoV-2 with vaccines alone, but support from research on innate immunity aspects is required.

Growing studies have clarified that innate immunity plays a key role in SARS-CoV-2 infection. After SARS-CoV-2 entered the targeting cells, virion or viral RNA was detected by cGAS/STING or melanoma differentiation-associated gene 5 (MDA-5) or both, leading to the release of type I/III interferon by activating interferon regulatory factor 3 (IRF3) and the nuclear factor-kappa B (NF-kB) pathway. Otherwise, SARS-CoV-2 infected permissible cells via angiotensin-converting enzyme 2 (ACE2) and was taken up by the endosome. Furthermore, viruses were recognized by toll-like receptors (TLRs) 7/9 or TRL 3, which induce the secretion of massive inflammatory cytokines via activating the NF-kB pathway (10).

Various cytokines, particularly interleukin-1b, interleukin-6 (IL-6), and tumor necrosis factor-α, were elevated in mild and severe COVID-19 patients (11). Cytokine storm (CS) was considered a major concern in acute respiratory distress syndrome (ARDS), multiorgan failure, and even death among COVID-19 patients (12). A sharply increased level of cytokines always induces CS, mainly caused by innate immune cells, despite both innate and adaptive immunity inducing CS (13, 14). Among the elevated cytokines in COVID-19 patients’ sera, IL-6 has been proven to be associated with CS (15). Thus, tocilizumab, a monoclonal IL-6R antibody that blocks the IL-6 signaling pathway and potentially reduces the risk of CS, was a recommended therapy for COVID-19. In addition, more medicines targeting innate immunity were recommended, such as Janus kinase inhibitors, RNA-dependent RNA polymerase (RdRp) inhibitors, and soluble ACE2 fused with the immunoglobulin Fc domain (ACE2-Fc). However, the efficacy is unclear and more investigation is necessary (16). Taken together, innate immunity was crucial to the emergence of COVID-19 and may offer a potential treatment.

Bibliometric analysis offered an intuitive and effective foundation for integrating information, reflected interconnections between them, and predicted the development of cutting-edge advances in the area based on publications in this field (17, 18). Recently, bibliometric analysis was widely adopted by scholars in neurology (19), vaccination (20), and otorhinolaryngology (21) related to COVID-19, especially the bibliometric analysis based on VOSviewer and CiteSpace software (22, 23). However, bibliometric analysis of innate immunity in COVID-19 remains lacking. Therefore, this study aims to show the progress, hotspots, and frontiers in the field based on the published literature and provide a strong foundation for future research.

In summary, this study first summarized the current state, hotspots, and research trends on innate immunity in COVID-19 using bibliometric analysis. Our findings highlight the following: 1) the study on innate immunity in COVID-19 is a hot topic; 2) the USA and China contributed the most publications in this field; 3) collaboration between research teams and countries/regions is a prominent characteristic in this field; 4) the journal with the most publications is Frontiers in Immunology; and 5) studies on “messenger RNA,” “mitochondrial DNA,” and “toll-like receptors” are current and possible potential hotspots in this field.

The average number of publications in all three years was higher than 200. Moreover, the number of citations sharply increased from 2020 to 2022, demonstrating that this topic is currently hot and drawing attention from researchers. In terms of countries or regions, researchers from 87 countries or regions contributed to all publications in this field, and most of the productive countries are developed countries. Among them, the most productive country was the United States, whose Np, Nc, and H-indexes are higher than all the other countries or regions. In addition, half of the top 10 prolific institutions were from the USA. Like in other fields, possessing the most productive institutions was an important reason for the USA to contribute the most publications (30). Six of the top 10 prolific authors were from China, which partly explains why China ranked second among the top 10 productive countries.

Close collaboration between different institutions is a prominent characteristic in this field, and this was greatly facilitated by modern communication technology. Effective collaboration could, to some extent, improve the quality of publications and the academic impact of researchers and institutions. High-impact studies completed by different institutions, nations, or regions are more trustworthy (31). Especially in the context of the ongoing emergence of viral variants, researchers should improve cooperation to promote the development of the field and obtain some breakthroughs.

Frontiers in Immunology had the highest number of publications on innate immunity in COVID-19. On the one hand, Frontiers in Immunology focused on publishing studies on virology, immunology, clinical microbiology, and infection prevention, and many studies on the classification of risk factors, prevention, and treatment of COVID-19 were published in this journal (32, 33). Furthermore, more than 10 papers on innate immunity and COVID-19 have been published in Frontiers in Immunology in the last 3 years (34, 35). On the other hand, the relationship between innate immunity and COVID-19 is complicated and needs multidisciplinary research to determine the pathogenesis and molecular mechanisms and provide a foundation for effective treatment that matched well with the scope of Frontiers in Immunology.

The shifting trends of hotspots and frontiers in this field were revealed by analyzing keywords from all publications included. The top 20 most frequent keywords included “receptor,” “protein,” “cytokine storm,” “I interferon,” and “dendritic cell,” and all keywords were separated into 11 major clusters named after the highest occurring keyword in this cluster.

In cluster 0 (vitamin D cluster), vitamin D was a steroid hormone created endogenously or obtained from external dietary sources. Multiple research studies revealed that vitamin D insufficiency recently induced a wide spectrum of diseases although vitamin D research was limited to the skeletal system for a long time (36, 37). Recently, investigators found that vitamin D strengthens the immune system against viruses by various mechanisms, including the release of antiviral peptides (38). Supplementation with vitamin D may slow the disease process, and vitamin D levels are negatively correlated to the severity of COVID-19 (39, 40). Furthermore, a recent research study indicated that vitamin D may boost the host type I interferon response by increasing RIG-1/MDA-5 signaling to eradicate SARS-CoV-2 infection (41). The potential therapeutic role of vitamin D in SARS-CoV-2 infection should be further confirmed.

In cluster 1 [dendritic cell (DC) cluster], DCs bridge the innate and adaptive immune systems (42). Most DCs including plasmacytoid DCs, myeloid/conventional type 1 DCs, and myeloid/traditional type 2 DCs produced from the lymphoid primed multipotent progenitors (43). The latest studies found that reducing DCs induced type I interferon insufficiency and delayed adaptive immune activation, which would impair the ability to fight SARS-CoV-2 (44, 45). However, the function of DCs in SARS-CoV-2 infection has not been fully explored.

In cluster 2 (immune evasion cluster), immune evasion was mainly induced by SARS-CoV-2 variants, which significantly increased the difficulty in stopping the virus spread and triggered a more transmissible wave of infections worldwide during the COVID-19 pandemic (46). Compared with the original strain, the infectivity and immune evasion of some variants of SARS-CoV-2, such as Alpha, Beta, Delta, and Omicron, were both higher (47–49). Notably, the Omicron variant, which first emerged at the end of 2021, has become the most prevalent variant and has posed challenges in controlling the outbreak (50). Structural analysis of the spike protein from the Omicron variant using cryoelectron microscopy revealed that the altered amino acid viral structure improved viral adherence and significantly improved immune evasion to avoid recognition by the immune system (51).

Combined with the visual timeline and citation burst of keywords, studies on “messenger RNA,” “mitochondrial DNA,” and “toll-like receptor” were found to be possible directions for current and future research in this field.

Messenger RNA, which transports genetic information from the DNA to the ribosome for protein synthesis, was highlighted by researchers in 1961 (52). The clinical applications of messenger RNA were increasing with the development of nucleoside-modified and lipid nanoparticle-facilitated delivery technologies (53). The first vaccine for COVID-19 added to the WHO emergency use list was the messenger RNA vaccine (BNT162b2) produced by Pfizer and BioNTech, which reflects the rapid deployment of messenger RNA vaccines and the vital role of studying messenger RNA in this field (54).

The mitochondria affect host cell homeostasis and metabolism and are crucial for the activation of cell death and immunological signaling (55). The release of mitochondrial DNA may cause a severe innate immune response by pattern recognition receptors (56). Mitochondrial DNA interacts with cyclic GMP-AMP synthase-stimulator of interferon genes, NOD-like receptor protein inflammasomes, and melanoma inflammasomes, which would induce invasive cytokine storms during SARS-CoV-2 infection and has a negative clinical impact (57). Further research on the mechanism of mitochondrial DNA in COVID-19 may provide a foundation for a new therapeutic target.

TLRs, a kind of type I transmembrane proteins, consist of three structural domains (58). TLRs activate the NF-kB and interferon regulatory factors, which further trigger the production of inflammatory cytokines and interferons by binding to ligands and intracellular immune signaling through myeloid differentiation factor 88 and the toll/interleukin-1 receptor domain (59, 60). The SARS-CoV-2 spike protein has been reported to bind to TLR1/2 or TLR2/6, which further caused an inflammatory response by activating the NF-kB signaling pathways and mitogen-activated protein kinases in macrophages, monocytes, and human lung epithelial cells (61). Additionally, in COVID-19 patients, the level of TLR2 was positively related to disease severity (62). Another study showed that the spike protein could bind to TLR4 which caused the release of inflammatory cytokines like tumor necrosis factor-α and IL-6 by the NF-kB signaling pathway (63). Although moderate TLR activation accelerates virus elimination, excessive TLR activation causes tissue damage and even death (64). The above data implied that TLR2 or TLR4 is a key receptor in establishing inflammatory response. Therefore, further study on TLRs and spike proteins will possibly assist in elucidating the pathogenesis, immune evasion, and treatment of COVID-19.

Research on innate immunity in COVID-19 is a hot topic and deserves global attention. The USA is the leading country with the highest number of publications on innate immunity in COVID-19, followed by China. Collaboration between different institutions and researchers is a significant characteristic of this field. The Frontiers in Immunology journal has the highest number of publications in this field. “Messenger RNA,” “mitochondrial DNA,” and “toll-like receptors” are the three current research hotspots and possible potential directions for future research.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

This study was designed by PL, Y-LL and SX. All data were enrolled by SX, J-HX and PL. All data were analyzed by PL, SX, J-HX, H-ZZ and Y-MZ. PL, SX and Y-LL drew the figures. PL and SX drafted the manuscript. PL, J-HX and Y-LL revised the final version of the manuscript. All authors contributed to the article and approved the submitted version.