Correction: Complement activity and autophagy are dysregulated in the lungs of patients with nonresolvable COVID‑19 requiring lung transplantation

Correction to: Respiratory Research (2025) 26:68

https://doi.org/10.1186/s12931-025-03152-6

In the original publication of this article [1], the significance levels are missing for all the figures. The corrected Figs. 1, 2, 3, 4, 5, 6 and 7 are presented with this correction article.

Fig. 1

The lungs of patients with NR-COVID-19 exhibit altered expression of the classical complement factors C1q and C1s. A The schematic depicts the complement 1 (C1) complex. The C1 complex is made up of dimers of three C1q subunits, C1qA (blue), C1qB (magenta), and C1qC (pink), and dimers of the serine proteases C1r (green) and C1s (orange). The bar graphs show the mRNA levels of B C1qA, C C1qB, D C1qC, E C1r, and F C1s measured via RT‒qPCR in lung RNA extracts. The values represented in the bar graphs are the means ± SEs of the fold change in expression in lung explants from NR-COVID-19 patients normalized to that in control lungs (control expression set to 1.00). The expression levels in both cohorts were normalized to those of the internal housekeeping gene GAPDH. Statistical significance was determined at the level of *P < 0.05; ***P < 0.001 (N = 12 for each cohort)

Fig. 2

The lungs of patients with NR-COVID-19 show upregulation of the complement factors C3 and C4. A A schematic representation of three distinct complement pathways is shown here. The classical pathway is activated by antigen (from pathogens or self-antigens) and antibody (IgM and IgG) interactions. Once hexameric C1q binds to the antigen‒antibody complex, the activated C1s cleaves C4 and C2 into C4a and C4b and C2a and C2b, respectively. C4a and C2b bind to form classical C3 convertase (C2aC4b), leading to the cleavage of C3 into C3a and C3b. The lectin pathway independently activates C3 convertase (C2aC4b) via MBL-associated serine proteases (MASP-1 and MASP-2) that cleave C2 and C4, leading to the formation of C3a and C3b. The alternative complement pathway is activated during infections and chronic inflammatory conditions through spontaneous hydrolysis of C3, giving rise to alternative C3b, which binds factor D to cleave factor B into Bb. C3b and Bb binding leads to the generation of alternative C3 (C3bBb) and C5 convertases (C3bBbC3b), which initiate an activation loop for the uncontrolled generation of C3a and C5a anaphylatoxins. The C5b fragments further participate in activating membrane attack complex (MAC, C5b-C9) formation. Regulatory C4-binding proteins (C4bp: 2 subunits, C4bpA and C4bpB) inhibit the lectin pathway and C3 convertase activity to mitigate the generation of C3a and C5a anaphylatoxins and MAC formation. The bar graphs show the mRNA levels of B C2, C C3, D C4a, E C4b, F C4bpA, and G C4bpB measured via RT‒qPCR in lung RNA extracts. The values represented in the bar graphs are the means ± SEs of the fold change in expression in lung explants from NR-COVID-19 patients normalized to that in control lungs (control expression set to 1.00). The expression levels in both cohorts were normalized to those of the internal housekeeping gene GAPDH. Statistical significance was determined at the level of *P < 0.05; ***P < 0.001 (n = 12 for each cohort)

Fig. 3

Expression of C7 autophagy markers in the lungs of NR-COVID-19 patients. A The bar graphs show the mRNA levels of C7, which were measured via RT‒qPCR assays, in control lung tissues and lung tissues from NR-COVID-19 patients. The values are presented as the means ± SEs of the fold change in expression in the lung explants from NR-COVID-19 patients normalized to that in the control lungs (control expression levels set to 1.00). B Representative western blots showing the protein levels of clusterin, PPARγ, and LC3a/b along with the loading control β-actin in control lung homogenates and lung homogenates from NR-COVID-19 patients. The bar graphs shown below represent the mean densitometric quantification as arbitrary ratios of the protein levels to those in the loading control. Statistical significance was determined at the level of *P < 0.05; ***P < 0.001 (N = 6 for control; N = 4 for NR-COVID-19)

Fig. 4

The expression of the C3a and C5a anaphylatoxin receptors in the lungs of NR-COVID-19 patients. A Schematic showing how the C3a and C5a anaphylatoxin receptors C3aR, C5aR1 and C5aR2 interact at the cell membrane. The membrane-bound carboxypeptidase M regulates anaphylatoxin receptor-mediated signaling by cleaving the carboxy-terminal arginine from C3a and C5a, resulting in the formation of less active C3_adesArg and C5_adesArg. The bar graphs show the mRNA levels of B C3aR, C C5aR1, D C5aR2, and E CPM, which were measured via RT‒qPCR in lung RNA extracts. The values represented in the bar graphs are the means ± SEs of the fold change in expression in lung explants from NR-COVID-19 patients normalized to that in control lungs (control expression set to 1.00; (N = 12 per group)). The expression levels in both cohorts were normalized to those of the internal housekeeping gene GAPDH. Statistical significance was determined at the level of P < 0.05 (n = 12 for each cohort). F Representative immunoblots showing the protein levels of C3aR, C5aR1, C5aR2, and CPM in control lung tissues and lung tissues from NR-COVID-19 patients. The bar graphs (G–J) represent the mean densitometric quantification data given as arbitrary ratios of the intensity of bands for receptors to that of their respective loading controls (N = 6 for each cohort; in the C5aR1 blot, sample 5 ratio in the control group was omitted as an outlier measured by the ROUT method (Q = 1%). Statistical significance was determined at the level of *P < 0.05; ***P < 0.001

Fig. 5

The expression of the membrane-bound regulatory proteins CD46, CD55, and CD59 is downregulated in the lungs of patients with NR-COVID-19. A Schematic representation of the membrane-bound regulatory proteins CD46, CD55, and CD59 that regulate C3 and C5 convertase activity and MAC formation. The soluble factor I coactivates CD46 activity to prevent C3b from forming C5 convertase. The bar graphs show the mRNA levels of B CD46, C CD55, and D CD59, which were measured via RT-QPCR in lung RNA extracts. The values represented in the bar graphs are the means ± SEs of the fold change in expression in nrCOVID-19-PF lung explants normalized to that in control lungs (control expression set to 1.00; N = 12 for each cohort). The expression levels in both cohorts were normalized to those of the internal housekeeping gene GAPDH. E Representative immunoblots showing the protein levels of CD46, CD55, and CD59 along with the loading control β-actin in control lung tissues and lung tissues from NR-COVID-19 patients. The bar graphs (F–H) represent the mean densitometric quantification data given as arbitrary ratios of the intensity of bands for receptors to that of their respective loading controls (N = 6 per group). Statistical significance was determined at the level of *P < 0.05; ***P < 0.001

Fig. 6

The expression of soluble regulatory factors is downregulated in the lungs of NR-COVID-19 patients. A Schematic representation of how soluble regulatory proteins function in all three complement pathways. The negative regulator C1-INH (also called SerpinG1) inhibits C1s cleavage of C2 and C4, thereby restricting the formation of the C3 convertase. Factor H and Factor I inhibit the alternative complement pathway from establishing an amplification loop. Factor P stabilizes the binding of C3b to the cell surface to induce pathogen phagocytosis and damage cell apoptosis. The bar graphs show the mRNA levels of the negative regulators B C1-INH, C FH, and D FI and the transcript levels of the soluble positive regulators E FB, F FD, and G FP, as measured via RT‒qPCR assays of lung RNA extracts. The values represented in the bar graphs are the means ± SEs of the fold change in expression in lung explants from NR-COVID-19 patients normalized to that in control lungs (control expression set to 1.00). The expression levels in both cohorts were normalized to those of the internal housekeeping gene GAPDH. Statistical significance was determined at the level of *P < 0.05; ***P < 0.001 (N = 12 for each cohort)

Fig. 7

Expression levels of immune cell receptors in the lungs of NR-COVID-19 patients. The bar graph shows the mRNA levels of A CPD, B CR1, and C CR3, which were measured via RT‒qPCR via lung RNA extracts. The values represented in the bar graphs are the means ± SEs of the fold change in expression in lung explants from NR-COVID-19 patients normalized to that in control lungs (control expression set to 1.00). The expression levels in both cohorts were normalized to those of the internal housekeeping gene GAPDH. Statistical significance was determined at the level of *P < 0.05; ***P < 0.001 (N = 12 for each cohort)