The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 (COVID-19) pandemic has challenged the current understanding of the complement cascade mechanisms of host immune responses during infection-induced nonresolvable lung disease. While the complement system is involved in opsonization and phagocytosis of the invading pathogens, uncontrolled complement activation also leads to aberrant autophagic response and tissue damage. Our recent study revealed unique pathologic and fibrotic signature genes associated with epithelial bronchiolization in the lung tissues of patients with nonresolvable COVID-19 (NR-COVID-19) requiring lung transplantation. However, there is a knowledge gap if complement components are modulated to contribute to tissue damage and the fibrotic phenotype during NR-COVID-19. We, therefore, aimed to study the role of the complement factors and their corresponding regulatory proteins in the pathogenesis of NR-COVID-19. We further examined the association of complement components with mediators of the host autophagic response. We observed significant upregulation of the expression of the classical pathway factor C1qrs and alternative complement factors C3 and C5a, as well as the anaphylatoxin receptor C5aR1, in NR-COVID-19 lung tissues. Of note, complement regulatory protein, decay accelerating factor (DAF
CD55) was significantly downregulated at both transcript and protein levels in the NR-COVID-19 lungs, indicating a dampened host protective response. Furthermore, we observed significantly decreased levels of the autophagy mediators PPARγ and LC3a/b, which was corroborated by decreased expression of factor P and the C3b receptor CR1, indicating impaired clearance of damaged cells that may contribute to the fibrotic phenotype in NR-COVID-19 patients. Thus, our study revealed previously unrecognized complement dysregulation associated with impaired cell death and clearance of damaged cells, which may promote NR-COVID-19 in patients, ultimately necessitating lung transplantation. The identified network of dysregulated complement cascade activity indicates the interplay of regulatory factors and the receptor-mediated modulation of host immune and autophagic responses as potential therapeutic targets for treating NR-COVID-19.