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Lupus nephritis
Original research
SARS-CoV-2 spike aggravates lupus nephritis and lung fibrosis in systemic lupus erythematosus
  1. Yeon Su Lee1,2,3,
  2. Jin Seok Woo1,
  3. JooYeon Jhun1,2,3,
  4. Jeong Won Choi1,2,
  5. A Ram Lee1,2,3,
  6. Kun Hee Lee1,2,3,
  7. Haeyoun Choi4,5,
  8. Sung-Hwan Park6 and
  9. Mi-La Cho1,2,3
  1. 1Lab of Translational ImmunoMedicine (LaTIM), Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea
  2. 2Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, South Korea
  3. 3Department of Medical Sciences, Graduate School of The Catholic University of Korea, The Catholic University of Korea, Seoul, South Korea
  4. 4Department of Microbiology, The Catholic University of Korea, Seoul, South Korea
  5. 5Catholic Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, South Korea
  6. 6Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
  1. Correspondence to Professor Mi-La Cho; iammila{at}catholic.ac.kr

Abstract

Objective COVID-19 induces the development of autoimmune diseases, including SLE, which are characterised by inflammation, autoantibodies and thrombosis. However, the effects of COVID-19 on SLE remain unclear.

Methods We investigated the effects of COVID-19 on SLE development and progression in three animal models. Plasmids encoding SARS-CoV-2 spike protein and ACE2 receptor were injected into R848-induced BALB/C lupus mice, R848-induced IL-1 receptor antagonist knockout (KO) lupus mice and MRL/lpr mice. Serum levels of albumin and autoantibodies, lymphocyte phenotypes and tissue histology were evaluated.

Results In R848-induced BALB/C lupus mice, the SARS-CoV-2 spike protein increased autoantibody and albumin levels compared with vehicle and mock treatments. These mice also exhibited splenomegaly, which was further exacerbated by the spike protein. Flow cytometric analysis revealed elevated T helper 1 cell counts, and histological analysis indicated increased levels of the fibrosis marker protein α-smooth muscle actin. In KO mice, the spike protein induced splenomegaly, severe kidney damage and pronounced lung fibrosis. In the MRL/lpr group, spike protein increased the serum levels of autoantibodies, albumin and the thrombosis marker chemokine (C-X-C motif) ligand 4.

Conclusion COVID-19 accelerated the development and progression of lupus by inducing autoantibody production, fibrosis and thrombosis.

  • lupus nephritis
  • lupus erythematosus, systemic
  • pulmonary fibrosis
  • COVID-19

Data availability statement

All data relevant to the study are included in the article.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/lupus-2023-001104

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • COVID-19 infection induces the development of autoimmune diseases; however, detailed mechanisms remain unclear.

    WHAT THIS STUDY ADDS

    • We investigated the effects of COVID-19 on SLE development and progression in three animal models.

    • COVID-19 accelerated the development and progression of lupus by inducing autoantibody production, fibrosis and thrombosis.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Our results offer insights into potential therapeutic and preventive strategies for COVID-19 and other viral infections in patients with autoimmune diseases, including SLE.

    Introduction

    SLE is a systemic autoimmune disease characterised by elevated levels of autoantibodies and cytokines in multiple organs.1 Pro-inflammatory factors, including type I interferon (IFN), interleukin (IL)-6, IL-17 and IL-1β, are involved in its pathogenesis.2 3 Several studies have demonstrated that inflammation is related to thrombotic factors and endothelial dysfunction during the development of atherothrombosis in patients with SLE.4 5 Additionally, such patients have a higher incidence of venous thromboembolism, including deep vein thrombosis and pulmonary embolism.5–7 A recent study suggested that patients with SLE are at higher risk for COVID-19 infection, COVID-19-related hospitalisation and death compared with individuals without SLE.8

    The COVID-19 pandemic, caused by SARS-CoV-2, has created an unprecedented global health crisis.9 COVID-19 patients commonly experience fever, cough, shortness of breath, anosmia, ageusia and diarrhoea.10 Thrombosis can also occur and is associated with increased disease severity and mortality.11 12

    Currently, seven COVID-19 vaccines are approved. Antiviral agents targeting SARS-CoV-2 replication and SARS-CoV-2-neutralising antibodies are considered for COVID-19 treatment. Some individuals may experience mild-to-moderate vaccine-related side effects, including fever, tiredness, muscle ache and pain at the injection site. However, thrombosis has also been reported after COVID-19 vaccination. Greinacher et al13 reported that 11 patients, including 9 females, developed one or more thromboses, including cerebral venous thrombosis, splanchnic vein thrombosis and pulmonary embolism, 5–16 days after vaccination. Schultz et al14 reported five patients, including four females, who developed venous thrombosis and thrombocytopenia 7–10 days after vaccination. The mechanisms underlying postvaccination thrombosis remain unclear.

    It has also been reported that viral infection induces inflammation and fibrosis.15–17 The spike protein of COVID-19 induces pro-inflammatory cytokines by triggering macrophages.18 Respiratory fibrosis is the most common symptom of COVID-19 infection.19 SLE and COVID-19 share common symptoms, including lymphopenia, a cytokine storm and tissue damage.20 Several studies have reported an association between COVID-19 and autoimmune diseases, including SLE. Bruera et al found that patients with SLE were at increased risk for severe COVID-19-related outcomes compared with patients without SLE.21 Patients with rheumatic diseases, particularly those using immunosuppressive agents, are at increased risk for severe infections, including viral infections.22 There are also reports of SLE and Sjögren’s syndrome developing after COVID-19 infection.23 24

    While clinical criteria have been helpful for diagnosing SLE, the significant variation in disease expression has made it challenging to define the condition precisely and develop mechanistic studies. Consequently, many researchers are now using animal models, which produce a uniform illness that mimics the histological and serological characteristics of SLE. Many animal models are also being used to understand the role of COVID-19 in SLE.25 In this study, we investigated the effects of SARS-CoV-2 on SLE development and progression using three lupus mouse models.

    Materials and methods

    Animals

    Female BALB/c and MRL/lpr mice aged 7 weeks were purchased from Orient Bio (Seongnam, Korea), and IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice were provided by Professor Yoichiro Iwakura (University of Tokyo, Japan). Experiments were performed in duplicate with five mice per group for each replicate in R848-inducced BALB/c lupus model and MLR/lpr mice. Additionally, the R848-induced IL-1Ra deficient mouse lupus model was performed in triplicate with three mice per group for each experiment.

    Resiquimod-induced BALB/c and IL-1Ra KO mice

    Resiquimod (R848, Sigma-Aldrich, St. Louis, Missouri, USA) was administered at a concentration of 50 μg/mL in 50 µL acetone into the right ear of BALB/c and IL-1Ra KO mice, three times a week for 6 weeks. Vehicle-treated mice received 50 µL acetone (vehicle group).

    Spike protein administration in the R848-induced BALB/c and IL-1Ra KO lupus model

    The plasmids mini-puro (158448; Addgene, Watertown, Massachusetts, USA) and pcDNA3.1-SARS2-SPIKE (145032; Addgene) were injected intravenously in 1 mL saline into R848-treated mice (spike group). Controls for the spike group were administered empty plasmids in 1 mL saline (mock group).

    Spike protein administration in MRL/lpr lupus-prone mice

    MRL/MpJ-Faslpr (MRL/lpr) mice were purchased from SLC (Shizuoka, Japan). The treatment group (spike group) received weekly intravenous injections of 200 µg pLEX307-ACE2-puro and pcDNA3.1-SARS2-SPIKE in 1 mL saline for 6 weeks. Controls were administered empty plasmids in 1 mL saline (mock group). Urine and serum samples were collected every 2 weeks and analysed at the last time point.

    Enzyme-linked immunosorbent assay

    Serum from the last time point of R848-treated BALB/c and MRL/lpr mice was separated from blood by centrifugation at 8000 rpm for 8 min. Serum levels of antidouble stranded DNA (anti-dsDNA) antibodies were measured using poly L-lysine, dsDNA-cellulose (Sigma-Aldrich), and mouse IgG detection antibodies (A90-131P; total IgG, A90-105P; anti-dsDNA IgG1, A90-107P; anti-dsDNA IgG2a; Bethyl Laboratories, Montgomery, Texas, USA). Total IgG (DY595; R&D Systems, Minneapolis, Minnesota, USA), IgG2a (DY595; R&D Systems) and chemokine (C-X-C motif) ligand 4 (CXCL4)/platelet factor 4 (PF4) (DY595; R&D Systems) were measured using an ELISA. Absorbance was measured using an ELISA microplate reader (Molecular Devices, Sunnyvale, California, USA).

    Urine albumin assay

    Urine samples were collected from R848-induced BALB/c mice every 2 weeks, with samples from the final time point used for further analysis. Albumin levels were measured using a mouse albumin ELISA assay (Bethyl Laboratories) according to the manufacturer’s instructions.

    Flow cytometry

    Peripheral blood cells were collected at the final time point from R848-treated BALB/c mice. Peripheral blood was stained with the following antibodies: PC5.5-CD4 (45-0042-82, eBioscience; Thermo Fisher Scientific, Waltham, Massachusetts, USA), APC-CD25 (102012; BioLegend, San Diego, California, USA), PC7-IFN-γ (557649; BD Biosciences, Franklin Lakes, New Jersey, USA), PE-IL-4 (12-7049-42; eBioscience), APC-IL-17 (17-7177-81; eBioscience), PE-FOXP3 (12-5773-82; eBioscience) for T cells, PE-CD138 (553714; BD Pharmingen, San Diego, California, USA), APC-B220 (17-0542-83; eBioscience), PercpCy7-CD95 (557653; BD Biosciences) and FITC-GL-7 (144612; BioLegend) for B cells. Samples were examined via flow cytometry (CytoFLEX; Beckman Coulter, Fullerton, California, USA), and data were analysed using FlowJo (BD Biosciences).

    Histopathological analysis

    The animals were sacrificed, and kidney and lung tissues from each animal were dissected, fixed in 10% formalin after decalcification using Decalcifying Solution-Lite (Calci-Clear Rapid; National Diagnostics, Atlanta, Georgia, USA), and embedded in paraffin. Tissues were cut into sections 5 µm thick using a microtome (Leica Biosystems, Wetzlar, Germany) and stained with H&E and Masson’s trichrome. Lung fibrosis was evaluated using the Lung Ashcroft Scale,26 and glomerular pathology was evaluated as described previously.27

    Immunohistochemistry

    Lung tissues from R848-treated BALB/c mice were collected at the end point. Immunohistochemistry was performed using a Vectastain ABC kit (Vector Laboratories, Burlingame, California, USA). The sections were incubated with alpha-SMA (ab7817; Abcam) overnight at 4°C and then with a biotinylated secondary antibody.

    Statistical analysis

    Statistical analysis was performed using GraphPad Prism software (V.5; GraphPad Software, San Diego, California, USA). Data are presented as means±SEMs. Statistical significance for comparisons among multiple quantitative groups (vehicle, mock and spike groups in R848-treated BALB/c and IL-1Ra KO mice) was evaluated using the Kruskal-Wallis test, and comparisons between two quantitative groups (mock and spike groups in MRL/lpr mice) were analysed using the Student’s t-test. A critical significance value of p<0.05 was used throughout the study.

    Results

    COVID-19 spike protein aggravated lupus in the R848-induced BALB/c lupus model

    To investigate the effect of SARS-CoV-2 infection on lupus, we administered plasmids encoding the human SARS-CoV-2 spike protein and its receptor, human ACE2, into R848-treated BALB/c mice (spike group; figure 1A,B). Acetone (vehicle) was administered to BALB/c mice, and an empty vector (mock) was injected into R848-treated mice as a control. The levels of anti-dsDNA antibodies and albumin were higher in the spike group compared with the vehicle and mock groups (anti-dsDNA IgG: vehicle 0.074 mg/mL, mock 0.389 mg/mL, spike 0.499 mg/mL; anti-dsDNA IgG1: vehicle 0.052 mg/mL, mock 0.093 mg/mL, spike 0.153 mg/mL; anti-dsDNA IgG2a: vehicle 0.062 OD, mock 0.223 OD, spike 0.267 OD; albumin: vehicle 21.946 μg/mL, mock 76.226 μg/mL, spike 148.813 μg/mL) (figure 1C,D). The levels of IFN-γ, IL-4 and IL-17 were higher in the mock group compared with the vehicle group, being further elevated in the spike group. The spike group also showed the greatest degree of splenomegaly (figure 1E,F). Kidney and lung damage and fibrosis were more severe in the spike group than in the vehicle and mock groups (figure 2A–D). Additionally, the expression of α-smooth muscle actin, a fibrotic marker, was higher in the spike group (figure 2E,F).

    Figure 1
    Figure 1

    COVID-19 spike protein increases autoantibody levels in the R848-induced BALB/c lupus model. (A) Plasmid map of pcDNA3.1-SARS2-spike and pLEX307-ACE2-puro (Addgene). (B) BALB/c mice were treated with acetone (vehicle, n=5), and plasmids encoding blank (mock, n=5) or spike and ACE2 (spike, n=5) were injected into R848-induced lupus BALB/c mice. (C) Serum samples were harvested at the last time point and used for further analysis. Bar graph shows serum levels of antidouble stranded DNA (anti-dsDNA) total IgG, IgG1 and IgG2a in the indicated group. (D) Urine samples were harvested at the last time point and used for further analysis. Bar graph shows urine albumin levels in the indicated group. (E) Representative image showing spleen size in the indicated group. (F) Isolated peripheral blood cells were stained and subjected to flow cytometry. Bar graphs present the frequencies of interferon (IFN)-γ-positive, interleukin (IL)-4-positive and IL-17-positive cells in the blood. Data are means±SEMs (*p<0.05).

    Figure 2
    Figure 2

    COVID-19 spike protein accelerates lupus nephritis and tissue fibrosis. (A) Representative images showing H&E-stained (top) and Masson’s trichome-stained (bottom) kidney sections in the indicated group. (B) Bar graph shows the glomerulonephritis score (left) and fibrosis area (right) in the indicated group. (C) Representative image showing the H&E-stained (top) and Masson’s trichome-stained (bottom) lung sections in the indicated group. (D) Bar graph showing lung Ashcroft score (left) and fibrosis area (right) in the indicated group. (E) Representative images showing α-smooth muscle actin (α-SMA)-stained lung tissues in the indicated group. (F) Bar graph showing the number of α-SMA-positive cells. Data are means±SEMs (*p<0.05, **p<0.01, ***p<0.001).

    COVID-19 spike protein induced autoantibody production and tissue fibrosis in MRL/lpr lupus-prone mice

    Next, we investigated the effects of the spike protein on the development and progression of SLE in MRL/lpr mice, which developed SLE spontaneously. We administered the same plasmid and receptor (and empty vector for mock, figure 3A) and found that IgG and anti-dsDNA IgG2a levels were higher in the MRL/lpr spike group (total IgG: mock 18.471 mg/mL, spike 22.892 mg/mL; IgG2a: mock 18.828 mg/mL, spike 26.659 mg/mL; anti-dsDNA IgG2a: mock 0.057 OD, spike 0.502 OD) (figure 3B). Kidney and lung damage and fibrosis were more severe in the spike group (figure 3C–F), which also had higher levels of albumin and the thrombosis marker CXCL4/PF4 (albumin: mock 7.454 μg/mL, spike 18.26 μg/mL; CXCL4/PF4: mock 188.7 pg/mL, spike 273.72 pg/mL) (figure 3G). Our data suggest that the spike protein accelerated SLE development and progression in the MRL/lpr lupus model.

    Figure 3
    Figure 3

    COVID-19 spike protein increases autoantibody production and tissue fibrosis in MRL/lpr lupus-prone mice. (A) Plasmids encoding blank (mock, n=5) or spike and ACE2 (spike, n=5) were injected in MLR/lpr mice. (B) Serum samples were harvested at the last time point and used for further analysis. Bar graph shows serum levels of total IgG, IgG2a and antidouble stranded DNA (anti-dsDNA) IgG2a in the indicated group. (C) Representative images showing H&E-stained and Masson’s trichome-stained kidney sections in the indicated group. (D) Bar graph showing glomerulonephritis, vasculitis and fibrosis in kidneys. (E) Representative images showing H&E-stained and Masson’s trichome-stained lung sections in the indicated group. (F) Bar graph showing lung Ashcroft score and lung fibrosis. (G) Serum and urine samples were harvested at the last time point and used for further analysis. Bar graphs show urine albumin levels (left) and serum chemokine (C-X-C motif) ligand 4 (CXCL4)/platelet factor 4 (PF4) levels (right) in the indicated group. Data are means±SEMs (*p<0.05, **p<0.01).

    COVID-19 spike protein aggravated tissue fibrosis in IL-1Ra KO mice

    In a previous study, we found that the suppression of IL-10 production accelerates autoimmune arthritis progression in IL-1Ra) KO mice.28 In the present study, we investigated the effects of the spike protein on R848-treated IL-1Ra KO mice. We administered the same plasmid/receptor, with an empty vector as a control (mock) and found that the spike group showed worsening kidney damage and lung fibrosis (figure 4).

    Figure 4
    Figure 4

    COVID-19 spike protein increases tissue fibrosis in IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice. (A) BALB/c mice were treated with acetone (vehicle, n=3), and plasmids encoding blank (mock, n=5) or spike and ACE2 (spike, n=3) were injected into R848-induced lupus IL-1Ra KO mice. (B) Representative images showing H&E-stained kidney images in the indicated group. (C) Bar graphs showing glomerulonephritis and vasculitis score. (D) Representative MT-stained lung images in the indicated group. (E) Bar graphs show lung Ashcroft score and lung fibrosis. Data are means±SEMs (*p<0.05, **p<0.01).

    Discussion

    The transmission of viral infections, including COVID-19, is often unavoidable. Therefore, understanding their effects is crucial to minimising their impact, particularly on autoimmune diseases, including SLE.29–31 In this study, we explored the effects of COVID-19 on SLE development and progression using three animal models.

    R848 is an agonist of toll-like receptors 7 and 8, which are known to increase the risk of SLE.32 33 R848 is frequently used to study SLE pathogenesis in mice. The MRL/lpr mouse strain, associated with the proliferation of aberrant T cells, is also used to study SLE pathogenesis. IL-1 is a potent pro-inflammatory mediator involved in multiple inflammatory and autoimmune diseases, including SLE. IL-1Ra naturally inhibits IL-1 signalling by binding to the IL-1 receptor without signal transduction.34 In this study, we investigated the pathophysiology underlying COVID-19 infection in three different mouse lupus models.

    Lupus nephritis is a common complication in patients with SLE.35 36 Dysregulated immune responses due to viruses, including COVID-19, exacerbate SLE.37 38 In our three lupus mouse models, tissue damage and kidney fibrosis were increased and worsened by spike protein administration. Previous studies have shown that serum levels of IL-6, IL-8, tumor necrosis factor (TNF)-α and IL-1β are higher in hospitalised COVID-19 patients. Additionally, pro-inflammatory cytokines, including IL-6, IL-15 and IL-1, correlate with disease severity in MERS-CoV, SARS-CoV and SARS-CoV-2 infections.39 40 A dysregulated immune response caused by spike protein administration may have contributed to kidney damage and fibrosis in our lupus mouse models.

    Lung fibrosis, although less common in patients with SLE,41 is a prevalent complication of COVID-19.19 In this study, we evaluated the progression of lung fibrosis, a condition common to both patients with SLE and COVID-19 patients, in a COVID-19-infected lupus mouse model. This model exhibited more severe lung fibrosis compared with non-infected lupus mice.

    Increased autoantibody production is a hallmark of both SLE42 43 and COVID-19.44 45 We observed a further increase in autoantibody levels after spike protein administration in our lupus mouse models. CXCL4 (PF4) plays a key role in thrombosis,46 47 which is common in both lupus and severe COVID-19 cases.5 48 49 Elevated CXCL4 (PF4) levels in spike protein-administered lupus mice suggest that increased autoantibodies and thrombosis-associated factors exacerbate lupus development and progression.

    Autoimmune diseases, such as SLE, Sjögren’s syndrome and rheumatoid arthritis, involve the immune system attacking host cells and tissues.50 51 These diseases are characterised by thrombosis and increased levels of autoantibodies and cytokines. Several cohort studies have demonstrated elevated inflammatory cytokine and autoantibody levels in COVID-19 patients. Thrombosis has also been reported in COVID-19 patients. In a previous study, we found that the spike protein aggravates rheumatoid arthritis.52 In a rheumatoid arthritis animal model, the spike protein increased levels of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β and IFN-γ), chemokine Monocyte Chemoattractant Protein-1 (MCP-1), anti-CXCL4 autoantibodies and antiphospholipid antibodies. Thus, the dysregulated immune response via the SARS-CoV-2 spike protein may exacerbate rheumatoid arthritis. Similarly, the SARS-CoV-2 spike protein may accelerate SLE development and progression by increasing autoantibody and thrombosis-associated factor levels.

    In this study, we investigated the effect of the COVID-19 spike protein on SLE development and progression using three different lupus mouse models, obtaining consistent results across the models. The COVID-19 spike protein injection led to severe lupus symptoms. Our results provide scientific evidence for understanding the molecular mechanisms and developing preventive strategies against COVID-19 and other viral infections in patients with autoimmune diseases, including SLE. However, there were some limitations. First, our system using the spike protein could not completely replicate the conditions of a COVID-19 infection. Second, the characteristics of patients with lupus were not completely matched with the animal model due to the heterogeneity among patients with lupus. Further research and development are required to better reflect the physiological conditions for clinical application. However, our study was significant in understanding the mechanisms of COVID-19 infection within the context of SLE.

    Data availability statement

    All data relevant to the study are included in the article.

    Ethics statements

    Patient consent for publication

    Ethics approval

    The study protocol was approved by the Animal Research Ethics Committee of the Catholic University of Korea. The study was performed in accordance with the National Institutes of Health guidelines (approval no. 2021-0304-01).

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    Footnotes

    • Presented at This paper was presented at the International Conference Korean Society for Molecular and Cellular Biology (ICKSMCB) on 6–8 November 2023 in Seoul, Korea.

    • Contributors Conceptualisation: YSL and M-LC; methodology: YSL, JSW, JYJ, JWC, ARL and KHL; software: YSL; validation: YSL, S-HP and M-LC; formal analysis: YSL, JSW; investigation: YSL and M-LC; original draft preparation: YSL; review and editing: HC, S-HP and M-LC; guarantor: M-LC.

    • Funding This research was supported by Korea Drug Development Fund, funded by Ministry of Science and ICT, Ministry of Trade, Industry and Energy, and Ministry of Health and Welfare (RS-2023-00258617, Republic of Korea), and the GRDC Cooperative Hub (grant number RS-2023-00259341) through the National Research Foundation of Korea, also funded by the Ministry of Science and ICT.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.