COVID-19, caused by the single-stranded RNA virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant global morbidity and mortality. Extensive research has explored the immune response to this virus, with particular attention to interferon (IFN) responses, cytokine storms, and mitochondrial dysfunction. RNA sequencing (RNAseq) analyses have shown altered immune responses correlating with COVID-19 severity, highlighting disruptions in both innate and adaptive immunity.
Early studies indicated that deficits in classic IFN-driven responses might lead to overactive innate immunity. However, subsequent analyses confirmed that IFN genes are robustly upregulated, especially in the nasopharynx. Severe COVID-19 patients exhibit excessive cytokine levels linked to immune system dysregulation, as seen in bronchoalveolar lavage fluid (BALF), blood, and serum analyses. These findings suggest that immune overactivation contributes to organ damage and mortality.
One critical mechanism identified is RAAS (renin-angiotensin-aldosterone system) overactivation, which exacerbates systemic inflammation. This dysregulation can lead to a cascade of harmful events, including vascular leakage and organ damage. ACE2, a key receptor for SARS-CoV-2 entry, regulates RAAS activity, and reduced ACE2 levels are implicated in these effects. Altered levels of RAAS components, such as bradykinin and hyaluronic acid, contribute to severe pulmonary inflammation and thrombosis in COVID-19 patients.
Mitochondrial dysfunction also plays a pivotal role in COVID-19 pathogenesis. Viral proteins such as ORF8 and ORF10 inhibit mitochondrial oxidative phosphorylation, leading to excessive reactive oxygen species production and release of mitochondrial DNA (mtDNA) into the cytosol. This mtDNA activates immune responses, exacerbating inflammation and cell death pathways.
Histopathology studies of COVID-19 patients revealed fibrosis and immune alterations in thoracic lymph nodes, correlating with RAAS overactivation and mitochondrial dysfunction. This connection highlights the persistent immune dysregulation that may contribute to long COVID or post-acute sequelae (PASC). Furthermore, upregulated pathways like PANoptosis and associated immune cell infiltration are key factors in understanding the lethal outcomes of COVID-19.
These findings provide insights into COVID-19’s underlying mechanisms, suggesting that interventions targeting mitochondrial dysfunction and RAAS signalling could mitigate severe disease outcomes. Future research into these pathways could reveal potential therapeutic strategies to reduce inflammation and organ damage associated with COVID-19.
Katie Wright, EMJ
Reference
Topper MJ et al. Lethal COVID-19 associates with RAAS-induced inflammation for multiple organ damage including mediastinal lymph nodes. Proc Natl Acad Sci U S A. 2024;121(49):e2401968121.
