# COVID-19 Lung Injury: Unique and Familiar Aspects of Pathophysiology
## 3 Pathogenesis of COVID-19-Induced Lung Injury
### COVID-19 Immunopathology
Under hypoxic conditions, HIF-1\(\alpha\) was shown to attenuate HMGB1-induced synthesis of IFN-I but not IL-1\(\beta\) or TNF-\(\alpha\), suggesting that pro-inflammatory activity was not impacted [75]. To make matters worse, approximately 10% of PBMCs may be infected by SARS-CoV-2 via CD16-mediated uptake of antibody-opsonized virus, leading to abortive replication and pyroptosis [76]. These findings demonstrate that the circulating monocyte compartment is heavily shifted towards a pro-inflammatory phenotype in severe COVID-19 with reductions in virus-targeted activity. Neuroptphilis is a consistent finding in patients with severe COVID-19 and appears to be driven by the expansion of immature subpopulations. These immature neutrophils, identified via expression of CD11b/CD16/CD24/CD34/CD38, are suggestive of emergency myelopoiesis and display enhanced myeloperoxidase, inflammasome, HIF-1\(\alpha\), and NETosis activity [77]. NETosis appears to be a significant contributor to COVID-19 pathology and severity [78]. Functionally, NETosis has been experimentally induced in vitro using patient sera and has potential to induce widespread immunothromosis and barrier disruption. The driving mechanism of this may be viral in nature, as S protein has been shown to induce NETosis in vivo, and it remains to be seen whether neutrophils, which express ACE2, can be directly infected by SARS-CoV-2 [79]. In addition to the immature subpopulation, multiple studies have isolated a myeloid-derived suppressor cell (MDSC)-like subpopulation shown to impede T cell proliferation and IFN\(\gamma\) production, suggesting a potential mechanism for the pathogenomic lymphopenia observed in severe COVID-19. Finally, while neutrophils (especially NETs) are prevalent in the pulmonary microcirculation in severe COVID-19, autopsy analysis suggests they may only be a potent infiltrator of alveolar spaces in a minority (25-50%) of cases [80]. Notably, there is a question whether the alveolar neutrophil in some cases might have been attributable to secondary bacterial infection. The function of other innate immune cells may also be compromised in severe COVID-19. Natural killer (NK) cells are depleted in the periphery and have been reported to display signs of functional exhaustion including increased expression of NK group 2 member A (NKG2A) and decreased expression of CD16, suggesting reductions in cytotoxicity and licensing activity, respectively [81]. Findings regarding pulmonary infiltration of NK cells are mixed and may be suggestive of recruitment late in disease course [82]. Plasmacytoid DCs are similarly depleted in the periphery and may increase in the lungs during later stages of disease. Of note, pro-apoptotic programming, reduced migration, and impaired IFN-I production may contribute to a reduced antiviral response [83]. Data regarding NK cells and DCs in severe COVID-19, however, appear to be consistent with reduced killing of infected cells and impaired activation of the adaptive immune response [59; 64; 74; 82]. Additionally, recent single cell RNA sequencing data have suggested that monocyte-derivedsoluble pro-inflammatory mediators could play a role in the development of a dysfunctional NK cell response [84]. The adaptive immune response plays a critical role in controlling infection and is typically activated within several days of symptom onset in COVID-19. Profound lymphopenia and exhaustion of CD4+ and CD8+ T cells have been frequently correlated with poor outcomes among patients with severe COVID-19 [59; 67; 85; 86]. One possible mechanism behind this observation is migration to pulmonary tissues and resulting lung pathology. However, this concept conflicts with inverse association between T cell levels in BALF and mortality, suggesting a protective role of T cell responses within the lung parenchyma [52; 71].