In narrow sense, uveitis includes inflammation of the choroid, ciliary body, and iris, but more broadly it includes widespread inflammation affecting the vitreous body, retina, and optic nerve [9]. By anatomical location, uveitis can be classified as anterior, posterior, intermediate uveitis and panuveitis. The most frequent type is anterior uveitis, which is featured by anterior chamber inflammation, which may include anterior cilitis, iridocyclitis and iritis. The next most common is posterior uveitis, which is featured by choroid or retina inflammation. Intermediate uveitis is a relatively rare type characterized by vitreous inflammation. Viral infections often induce uveitis, such as rubella virus, varicella zoster virus, cytomegalovirus, and herpes simplex virus, which could lead to the occurrence of anterior uveitis after the infection of the eye [10], and some cases have also shown similar manifestations after COVID-19 infection. Mazzotta et al. [11] reported a 30-year-old Italian female COVID-19 patient with acute anterior non-granulomatous uveitis, which was featured by diffuse pigmentation on the anterior lens capsule, as well as initial anterior lens opacity, mild pupil reduction, accompanied by mild anterior chamber flashing, and no posterior corneal deposits. Bettach et al. [12] also reported an Israeli patient with acute binocular anterior uveitis associated with COVID-19 infection. A 54-year-old female patient, developed redness in both eyes and decreased vision after COVID-19 infection, accompanied by multiple posterior corneal lesions and anterior chamber flash. In addition, two case reports have described panuveitis associated with COVID-19 [13, 14]. In addition to directly causing uveitis, COVID-19 is also believed to be the cause of an immune system disorder that activates preexisting uveitis. To mitigate the widespread and devastating impact of COVID-19, regulators have approved the use of vaccines to combat the disease. Current vaccines focus on the production of antibodies that stimulate COVID-19 spike proteins to create immunity to the virus. Over a three-month period, about 70 patients at 40 transnational centers developed an eye inflammatory event within 2 weeks of COVID-19 vaccination. The most commonly reported cases were 41 anterior uveitis cases, posterior uveitis in 9 cases and scleritis in 7 cases. It was suggested that the pathological mechanism of uveitis after COVID-19 vaccination mainly included: (1) direct virus infection; (2) Molecular mimicry caused by similarity between uveal peptide and vaccine peptide fragments; (3) hypersensitivity mediated by antigen-specific cells and antibodies; (4) Inflammatory damage caused by adjuvants in vaccines [15–17]. Although multiple cases of uveitis associated with COVID-19 and uveitis associated with COVID-19 vaccination have been reported, the exact pathophysiology remains unelucidated and many potential hypotheses have been proposed, so further research is urgently needed to identify its underlying mechanisms.
In this study, 50 genes were found to be significantly co-expressed in uveitis and COVID-19. These genes are functionally enriched in cytokine-mediated signaling pathways, response to viruses, cytokine receptor binding. Moreover, these genes were enriched in the viral protein interaction with cytokine and cytokine receptor, cytokine-cytokine receptor interaction, and IL-17 signaling pathway. The pathogenic mechanism of uveitis is complex, and the consensus of domestic and foreign experts suggests that autoimmune uveitis is an important mechanism of target organ damage caused by inflammation mediated by CD4 + T cells, abnormal proliferation of CD4 + T cell subgroup helper T cells 1(Th1) and secretion of inflammatory cytokines, leading to the destruction of the stability of the immune microenvironment in the eye, and the occurrence and aggravation of non-infectious uveitis. In addition, imbalances in helper T cells 17 (Th7) and T regulatory cells lead to overproduction of IL-17, triggering inflammatory pathways and exacerbating uveitis. After entering the era of biological therapy, the drug treatment of uveitis is mainly specific cytokine inhibitors, such as TNF-a inhibitors and IL-6 blockers, in addition to hormones [18]. In addition, it was found that cytokines such as TNF-a play an important role in the entry of COVID-19 infection virus into host cells and lead to abnormal inflammatory responses that lead to organ damage. The life-threatening cases associated with COVID-19 were due to strong upregulation in the production of pro-inflammatory cytokines, known as "cytokine storm syndrome". Various cytokines are involved in storms, among which IL-17 is a major mediator of lung inflammation. It is a dysfunctional type of response to COVID-19, leading to what is known as "immune failure" [19] and is correlated with poor outcomes of the disease (including mortality) [20, 21]. Some studies have shown that previous long-term use of cytokine inhibitors prevents the effects of high levels of cytokines and may alleviate COVID-19 severity [22–24].
We screened five hub genes by using the maximum clustering centrality algorithm, including MX1, ISG15, IFI44, IFI44L and IFI27. Myxovirus resistance protein 1 (MX1) encodes a metabolic protein of guanoside triphosphate (GTP) that inhibits RNA and DNA virus replication in the nucleus. It has been reported that MX1 expression is elevated in COVID-19 patients. In addition, studies have reported the involvement of MX1 in antiviral response of cells to SARS-COV-2 [25]. Pathogens recognition receptors and Toll like receptors are critical for blocking pathogen invasion through interferons stimulating genes (IFNs) and interferons stimulating genes (ISGs) production [26, 27]. Many inflammatory mediators IFNs and ISGs have been reported to be produced in human primary retinal vascular endothelial cells and retinal pigment epithelial cells [28]. ISG15 encodes a ubiquitin-like protein that interacts with viral proteins and loses its function during infection [29]. In addition, free extracellular ISG15 acts as a potentiator of inflammation and increases cytokine production by macrophages [30]. Regarding the mechanisms by which COVID-19 evades the antiviral immune responses, Papain-like protease (PLpro) has been reported as a deISGylation enzyme that dissociates ISG15 from its substrate and facilitates evasion from the host’s immune system [31]. FI44 is an IFN-inducing protein, which is associated with innate immune response after viral infection. Previous studies have confirmed that IFI44 may therefore be a therapeutic target for relieving virus-mediated disease and regulating diseases associated with excessive immune signaling [32, 33]. IFI44L is involved in many autoimmune diseases. In addition, studies have shown that rhinovirus infection causes upregulation of IFI44L expression, and overexpression of IFI44L dampens Zika virus replication, which has great prospects in immunotherapy, antiviral therapy and cancer therapy [34–36]. IFI27(IFN-α Inducible Protein 27, also known as ISG12) is expressed at high levels in many tumors, such as hepatocellular carcinoma, breast cancer, etc. It is believed that IFI27 might serve both as a prognostic factor and a therapeutic target for cancer. High expression of IFI27 inhibited apoptosis, while lack of IFI27 promoted apoptosis. IFI27 is also involved in the transition from S phase to G2 phase in the cell cycle and affects the expression of VEGF-A, which is required to promote angiogenesis [37]. In addition, IFI27 is critical in the transcriptional response to COVID-19 infection [38].
LASSO regression analysis identified the potential biomarker as HORMAD1. HORMAD1 (encoding HORMA domain-containing protein 1) is a prognostic biomarker and attractive therapeutic target in a variety of cancers. Studies have shown that HORMAD1 is abnormally expressed in many cancers, such as breast, ovarian, and lung cancers. The aberrant expression of HORMAD1 in tumor cells was associated with alterations in DNA repair and genome instability [39–41]. New evidence suggests that HORMAD1 could promote chemotherapy resistance or sensitivity by targeting homologous recombination repair pathways in different cancers [42–44]. In addition, HORMAD1 has been demonstrated to promote tumor growth in breast tumor xenograft models [45]. The role of HORMAD1 in uveitis and COVID-19 has not been studied. Our current research reveals a possible link between uveitis and COVID-19. Further researches are required.