COVID19's cytokine storm ushers in a local complement storm in the lungs

A new study published in the journal Science Immunology analyzed lung epithelial cells from patients infected with COVID-19 and found the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces the complement system as a dangerous weapon for viral infection.

The complement system is an extension of the innate immune system to recognize pathogens and remove them. Prior research has shown a correlation between severe COVID-19 infection and high levels of complement.

The mechanism of action is driving the JAK1/2-dependent local complement hyperactivation. Using the JAK1/2 inhibitor ruxolitinib alone or with remdesivir normalized interferon signature genes inhibited the C3a protein of the complement system created from infected lung cells.

Study: SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation. Image Credit: sciencepics / Shutterstock
Study: SARS-CoV-2 drives JAK1/2-dependent local complement hyperactivation. Image Credit: sciencepics / Shutterstock

‘Unexpected’ SARS-CoV-2 takeover of complement system through transcription

The team collected RNA-sequencing data from lung tissue samples of two patients with confirmed COVID-19 infection and uninfected controls. Of 36 upregulated pathways, 14% were complement pathways. “Traditionally, complement is considered a mostly hepatocyte-derived and serum-effective system. Thus, the dominance of the SARS-CoV-2-induced lung cell-intrinsic complement signature was unexpected,” wrote the authors.

The researchers next investigated how SARS-CoV-2 affects the complement system. To do so, they examined the transcriptomes of primary human bronchial epithelial cells in vitro with SARS-CoV-2. Their findings confirmed prior results as upregulated complement pathways were linked to infected lung cells. Complement pathways were also the most enriched of all pathways taken over from infection.

Since SARS-CoV-2 tends to infect type II pneumocytes since they have a high expression of ACE2, they specifically examined the transcriptomes of A549 cells, which exhibit the aforementioned cell type properties. Findings showed complement pathways were the most enriched in ACE2-transduced A549 cells infected with SARS-CoV-2 compared to when the cells were infected with other viruses such as influenza.

When comparing the SARS-CoV-2-induced pathways across collected samples, they found 4 of 14 pathways were related to the complement system. Genetic analysis showed complement transcription most induced by SARS-CoV-2 were encoding parts of the C1 proteases, C1R and C1S, complement factor B, and complement C3.

Infected cells also had significantly elevated intracellular C3a, which acts as the rate-limiting step for complement activation, compared to uninfected and mock-infected cells. A correlation was observed between the N-protein expression of SARS-CoV-2 and C3a levels, suggesting infected lung epithelial cells were a source of complement C3 and its active products.

Severity of SARS-CoV-2 infection induces different complement signatures across cells

The team gathered bronchoalveolar lavage samples from three patients with mild infection and three patients with severe disease. Eight samples from uninfected donors were used as controls.

Findings showed increased C3 expression in AT2 cells, which are major targets for viral entry. The elevated expression was observed more in patients with COVID-19 than uninfected donors, suggesting cell infection induces C3 gene transcription. Further evidence from autopsies showed deceased patients who had COVID-19 infection had a positive correlation between increased C3 mRNA expression and SARS-CoV-2 viral load.

There was high C3AR1 expression, which is the gene that encodes the C3aR protein and CD46 on lymphoid cells. CD46-regulated genes were significantly higher in lung lymphoid cells of patients with more severe COVID-19 expression. C3aR-regulated genes significantly expressed more in monocyte/macrophage cells in patients infected with COVID-19.

When analyzing peripheral blood mononuclear cells, low C3 expression was observed in circulating immune cells along with an absence of CD46 and C3aR activation. “Collectively, these data indicated that C3 was produced locally in the lungs of COVID patients and processed to active fragments that acted on their cognate receptors to drive inflammation.”

SARS-CoV-2 affects the JAK1/2 pathway, and JAK1/2 inhibitors normalize infected cells

Type I IFNs regulated gene expression in cells with elevated expression —including AT1 and AT2 — in patients infected with COVID-19. Observations were seen between CD46, C3aR, and IFN-α/β signaling genes in lymphoid, myeloid, and AT1 and AT2 pneumocyte cells, respectively, and disease severity.

The team evaluated genes regulated by SARS-CoV-2 in epithelial cells and the A549 type II pneumocyte-like cell line to determine a causal relationship. Their results showed SARS-CoV-2 caused further increases and decreases in gene expression in cells.

Further analysis showed half of the transcription factors came from IFN-pathway signaling proteins, including STAT1. Indeed, public datasets of STAT1 and histone 3 lysine 27 acetylation showed significant expression of STAT1 binding in genes regulated by SARS-CoV-2.

Administration of the JAK1/2 inhibitor ruxolitinib blocked STAT1 signaling. Ruxolitinib also normalized elevated expression of the complement system including, C1R, C1S, CFB, and C3.

Ruxolitinib also significantly inhibited C3a production and normalized infected cells. This effect was further enhanced when combined with remdesivir.

Journal reference:
Jocelyn Solis-Moreira

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.


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