# COVID-19 Lung Injury: Unique and Familiar Aspects of Pathophysiology
## 3 Pathogenesis of COVID-19-Induced Lung Injury
### Viral Structure, Tropism, Replication, and Evasion  
SARS-CoV-2 is classified under the genus _Betaoronavirus_ and exhibits the characteristic crown-like appearance attributed to viruses in the _Coronaviridae_ family. Four canonical proteins--nucleocapsid (N), spike (S), membrane (M), and envelope (E)--form the structure of the virus. 5 protein, a transmembrane protein, contains the receptor-binding domain responsible for interaction with host cell receptors. M and E proteins also span the lipid bilayer viral envelope and have multiple functions including roles in viral assembly and budding. Inside the viral envelope, N protein interacts with and organizes the ~30 kb positive-sense single-stranded RNA genome and adopts important functions throughout the viral life cycle [52]. Coronavirus tropism is predominantly determined by the S protein structure, which in the case of SARS-CoV-2, displays a high affinity for the human angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 is quite ubiquitous in the human body and is highly expressed in the upper respiratory tract, cardiac muscle, alveolar epithelium, vascular endothelium, liver, kidney, intestine, brain, testes, and immune cells [53]. As a result, SARS-CoV-2 displays a broad tropism and capability to impact numerous body systems, although initial infection typically targets the upper respiratory tract. Additionally, SARS-CoV-2 variants may differ in their tropism [54]. SARS-CoV-2 infection typically begins in multiciliated and sustentacular cells of the upper respiratory tract [55; 56]. The viral replication cycle is initiated by binding of the S1 subunit to host ACE2. Next, host transmembrane protease serine 2 (TMPRSS2) cleaves the S protein, causing S2 subunit-mediated fusion of viral and host lipid bilayers and release of the viral RNA-N protein complex into the cytoplasm [52]. Notably, other cell entry routes including endocytosis and use of alternative co-receptors have been reported. Once inside the cell, SARS-CoV-2 exploits host ribosomes to synthesize a full suite of 16 non-structural proteins (NSPs). The NSPs form replication-transcription complexes (RTCs) and remodel the endoplasmic reticulum (ER) and Golgi apparatus to establish double-membrane vesicles (DMVs) that protect viral replication from innate immune detection. As new copies of structural proteins and RNA genomes are synthesized, fully formed SARS-CoV-2 virions are released via ER budding and exocytosis. The cytopathic replication cycle of SARS-CoV-2 can extend in this manner until cell homeostasis is sufficiently disrupted to trigger cell death pathways [57; 58]. To induce severe illness, SARS-CoV-2 must infect the lower respiratory tract. In this environment, direct tissue damage mediated by viral replication largely determines the extent of tissue damage caused by activation of local and systemic inflammatory responses. Thus, the ability (or inability) to limit initial viral replication and propagation plays a critical role in determining disease severity [59]. Airway immune cells such as AMs and plasmacytoid dendritic cells (DCs) play a key role in detecting endocytosed SARS-CoV-2 ssRNA. Infected epithelial cells can invoke cytosolic PRRs that identify non-self RNA PAMPs. The activated PRRs then induce IFN-I and IFN-III transcription [52]. These \"early\" IFNs signal through IFN-activated receptors (IFNARs) to induce transcription of IFN-stimulated genes (ISGs), promoting an antiviral cell-state which restrains infection through numerous mechanisms [59; 60]. The importance of these signaling pathways in COVID-19 has been suggested by several studies. In vitro experiments have shown that SARS-CoV-2 is highly susceptible to IFN I treatment [61]. Consistent with this, patient samples from mild-to-moderate cases of COVID-19 show higher expression of ISGs than in patients with severe illness [62]. Thus, sufficient release of IFN-I and III early in infection may be an important determinant of COVID-19 severity [59].