key: cord-0907580-ip8ldo6w
authors: Wang, Le-Le; Yang, Jia-Wei; Xu, Jin-Fu
title: Coronavirus (SARS-CoV-2) causes lung inflammation and injury
date: 2021-12-01
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.11.022
sha: 658c85d34f72578c59deed6eaa66362628375766
doc_id: 907580
cord_uid: ip8ldo6w

BACKGROUND: As of October 14, 2021, COVID-19 has affected more than 246 million individuals and caused more than 4.9 million deaths worldwide. COVID-19 has caused significant damage to the health, economy, and lives of people worldwide. Although SARS-CoV-2 is not as lethal as SARS-CoV or Middle East Respiratory Syndrome (MERS)-CoV, its high transmissibility has had disastrous consequences for public health and healthcare systems worldwide given the lack of effective treatment at present. OBJECTIVES: To clarify the mechanisms by which SARS-CoV-2 caused lung inflammation and injury, from the molecular mechanism to lung damage and tissue repair, from research to clinical practice, and then presented clinical requirements. SOURCES: References for this review were identified through searches “(COVID-19[Title]) OR (SARS-CoV-2[Title])” on PubMed, and focused on the pathological damage and clinical practice of COVID-19. CONTENT: We comprehensively reviewed the process of lung inflammation and injury during SARS-CoV-2 infection, including pyroptosis of alveolar epithelial cells, cytokine storm, and thrombotic inflammatory mechanisms. IMPLICATIONS: This review describes SARS-CoV-2 from SARS and explores why most people have mild inflammatory responses, even asymptomatic infections, while only a few develop severe disease. It suggests that future therapeutic strategies may be targeted antiviral therapy, the pathogenic pathways in the lung inflammatory response, and enhancing repair and regeneration in lung injury.

In December 2019, Li et al. first confirmed the human-to-human transmission of a novel coronavirus among close contacts [1] . On February 17, 2020, the disease was termed coronavirus disease 2019 (COVID-19) by the WHO [2] . The International renamed 2019-nCoV as acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in May 2020 [3] . There are nearly one million new cases of COVID-19 every day in the worldwide. In addition, there were frequent mutations in the novel coronavirus.

Although the virulence was decreasing, the transmission was increasing, especially the Delta (Lineage B.1.617.2) mutation [4] . Mutations not only bring about challenges to epidemic control, but also greatly reduce the effectiveness of vaccines [5] .

SARS-CoV-2 has had a devastating impact on human lives and prompted global efforts to develop countermeasures. Social prevention and control measures include traffic restrictions, increasing social distancing, personal protection, environmental J o u r n a l P r e -p r o o f hygiene, social mobilization, publicity and education; The confirmed cases, suspected cases and close contacts will be treated or put under medical observation in a standardized manner; Right population is encouraged to be vaccinated. This review started with the pathogenesis of SARS-CoV-2 and provides some strategies and basis for clinical treatment and management of COVID-19.

Coronaviridae is a family of enveloped viruses with a single-strand, positive-sense RNA genome of 26-32 kilobases [6] , which consist of 4 structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins [6] , which are encoded in the order S-E-M-N (Figure 1 ). The S protein, a type I glycoprotein, which forms peplomers on the virion surface; the small membrane protein E, a highly hydrophobic protein, has a short ectodomain, a transmembrane domain, and a cytoplasmic tail [7] ; the M protein, which spans the membrane three times and has a short N-terminal ectodomain and a cytoplasmic tail; and the N protein, which forms a helical capsid [8] . SARS-CoV-2 has a similar receptor-binding domain (RBD) structure of the S protein to SARS-CoV (nearly 80%) [9] . The RBD directly binds to the peptidase domain of angiotensin-converting enzyme 2 (ACE2), mainly expressed in type II alveolar cells of the lung, to gain entry into host cells (Figure 1 ) [10] .

SARS-CoV-2 infection is initiated when the RBD binds to ACE2, during which the affinity is 10 times higher than that of SARS-CoV [11, 12] . The binding triggers the cleavage of ACE2, which is highly upregulated by type 2 inflammation through interleukin-13 (IL-13) and interferons (IFNs) [13] . Transmembrane protease serines 2 (TMPRSS2) helps ACE2 binds to the S protein for easy entry into host cells [14] . The upregulation of ACE2 increases the levels of functional cytokines involved in COVID-19, such as IL-1, IL-10, IL-6, and IL-8 [15] . Overexpression of ACE2 increased the rates of viral infection and replication during SARS-CoV infection [16] ; however, for patients with SARS-CoV-2, especially the elderly or those with type II J o u r n a l P r e -p r o o f diabetes, lower expression of ACE2 resulted in COVID-19-related fatality [17] . This difference may be due to an overexpression of mitochondria-localized nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4, which is known to produce reactive oxygen species (ROS) [18] . Clinical outcomes of patients with COVID-19

were improved by transplantation with ACE2-negative mesenchymal stem cells due to decreased tumor necrosis factor-alpha (TNF-α) and increased IL-10 [19] .

In conclusion, the virus is prevented from entering alveolar epithelial cells by antagonizing ACE2 or blocking its downstream signal TMPRSS2.

Human innate immunity is of great importance during SARS-CoV-2 infection.

The single-stranded RNA virus is detected by Toll-like receptor 3 (TLR3), TLR7, or TLR8, and potentially RIG-I and PKR. Next, SARS-CoV-2 nonstructural protein 13 (NSP 13) interacts with signaling intermediate TBK1 [20] , and NSP15 associates with RNF41, an activator of TBK1 and IRF3 [21] . NSP9 and NSP10 induce IL-6 and IL-8 production, potentially by inhibition of NKRF, an endogenous NF-κB repressor factor [22] . Moreover, to prevent signaling downstream of IFN release, SARS-CoV-2 proteins inhibit the receptor subunits (IFNAR1 and IFNAR2) to transduce signals and activate transcription [23] . Compared to patients with asymptomatic or mild disease, those with severe disease had significantly impaired IFN-I signatures, and higher IL-12 and IL-2 levels [24, 25] . The most common deteriorations in patients with COVID-19 were increased in IL-2, IL-6, TNF, IFN-γ-induced CXCL10, granulocyte colony-stimulating factor (G-CSF), CCL3α, CCL2, CCL7. [26] (Figure 2 ).

During the COVID-19 pandemic, macrophage activation appears to facilitate the initiation and propagation of the hyper-inflammatory response [27] . In contrast to Neutrophils are key components of innate immunity and function to resist harmful microorganisms. However, they also produce cytotoxic factors and aggravate lung inflammation through degranulation, lysis, and the expression of chemokines, such as CXCR2 and IL-8, during severe pneumonia [31] . SARS-CoV-2 infection caused more neutrophil infiltration than other forms of pneumonia [32] . The neutrophil/lymphocyte ratio (NLR) was an independent risk factor for in-hospital mortality for patients with COVID-19, and the NLR increased significantly in severe cases [33] . Patients also overexpressed complement 3 (C3) and the receptor for the C3a anaphylatoxin [34] . However, other studies found that the NLR does not reflect the severity of COVID-19 [35] . More interestingly, the autopsy pathology of two patients with COVID-19 revealed that secreted cytokines and chemokines attract immune cells, notably monocytes and T lymphocytes, but not neutrophils [36] .

Neutrophils may play important roles in the late stage of this disease.

The most common feature of severe COVID-19 is lymphopenia, particularly a drastic reduction in CD8+ T cells [37] [38] [39] . Persistent viral stimulation contributes to T cell exhaustion, leading to loss of cytokine production and reduced function [40] .

infection [41] . The counts of total T cells of patients in the intensive care unit (ICU), CD4+ T cells, and CD8+ T cells were prominently reduced and were negatively associated with patient survival [42] . Autopsies of the spleen and lymph nodes J o u r n a l P r e -p r o o f identified high levels of T cell apoptosis by P53 signaling pathway and increased expression of the death receptor FAS, which suggested that activation-induced cell death is likely responsible for T cell depletion in patients with severe disease [43] .

Cytokines such as IFN-I and TNF-α facilitate the retention of T cells in lymphoid organs and their attachment to the endothelium rather than recirculation in the blood [44] (Figure 2) . The higher serum IL-6, IL-10, and TNF-α concentration, the fewer T cell numbers [45] . In addition, T cells recruited to infection sites decreased T cells in the peripheral blood compartment [37, 46] . While the extensive lymphocyte infiltration observed in the lungs [47] , another study found only neutrophilic infiltration by post-mortem biopsies [48] . Therefore, further studies are needed to determine the reason for the lymphopenia in patients with COVID-19.

Interestingly, lymphocytes from 20% to 50% of unexposed donors displayed significant reactivity to SARS-CoV-2 antigen peptide pools [49] . Pre-existing cross reactivity against COVID-19 is presumably a reflection of T cell memory to circulating "common cold" coronaviruses. Pre-existing T cell immunity to SARS-CoV-2 is relevant to the severity of COVID-19 as it is plausible that people with a high level of pre-existing memory CD4+ T cells to SARS-CoV-2 activates a faster and stronger immune response to better limit disease severity. Memory CD4+ T cells accelerate increasingly and generate rapid neutralizing antibody responses against SARS-CoV-2. Memory T cells also facilitate direct antiviral immunity early after exposure [50] . Furthermore, the observation of a negative correlation between age and lymphocyte count led to heavier clinical manifestations, greater severity, and longer disease courses [51] . Therefore, closer monitoring and greater medical interventions are needed when treating elderly patients with COVID-19.

The effect of SARS-CoV-2 on B cells have mainly focused on the generation of specific neutralizing antibodies. RBD-binding antibodies are found within 4-8 days after symptom onset, and most patients develop neutralizing antibodies by 3 weeks [52] . While the protective duration of antibodies against the disease remains unknown, J o u r n a l P r e -p r o o f 40% of asymptomatic patients and 13% of symptomatic patients became negative for anti-spike IgG in the early convalescent phase, which implies that the host response to SARS-CoV-2 is transient [53] . Recent studies inferred neutralizing antibody maintained over one year with higher antibody titers and longer duration of detectable antibody in those with severe disease [56] . However, antibodies are not always protective, and previous studies in animals infected with SARS-CoV-2 showed that neutralizing antibodies against S protein amplify severe lung injury by exacerbating inflammatory responses [52] . Besides, 80% of patients with Acute Respiratory Distress Syndrome (ARDS) coincided with antiviral IgG seroconversion. Patients who died of infection took an average of 14.7 days to reach the peak level of neutralizing antibody activity, compared with 20 days for those who continued to recover. Surprisingly, convalescent plasma, used to treat moderate COVID-19, did not improve severe disease progression or all-cause mortality [57] . This may be due to the presence of more than 100 substances in the plasma, most of which are pro-coagulant factors, which aggravate thrombosis [58] . Moreover, the antibody-mediated binding of CoV-Fc receptors increases the uptake of the virus by macrophages and reduce the function of macrophages through virus-mediated immunosuppression [59] . Memory B cells express neutralizing antibodies to SARS-CoV-2, and increasing with time of infection [60] . Neutralizing antibodies have entered phase 2 and 3 clinical trials and are expected to treat and prevent COVID-19 [61, 62] .

The reason for the shift from mild to severe disease in COVID-19 is largely unknown. More than 40% of individuals hospitalized for severe and critical COVID-19 developed ARDS, more than 50% of whom died of the disease [63] . The main pathological features of ARDS are increased pulmonary microvascular permeability and exudation of protein-rich fluid from alveoli, leading to pulmonary edema and hyaline membrane formation, which is accompanied by pulmonary interstitial fibrosis [64] . The pathophysiological changes mainly result in decreased J o u r n a l P r e -p r o o f lung volume, decreased lung compliance, and severe ventilation/blood flow imbalance. The clinical manifestations include respiratory distress and refractory hypoxemia, while the lung imaging findings show heterogeneously exudative lesions [65] . The principal characteristics of ARDS in COVID-19 include alveolar epithelial cell damage, cytokine storm, microvasculature endothelial damage, and thrombosis.

In pyroptosis of COVID-19, damage-associated molecular patterns (DAMPs) activate intracellular sensors, leading to activation of the inflammasome, such as caspase 1, which cleaves and activates the precursor forms of Interleukin-1β (IL-1β) and IL-18. IL-1β causes acute lung injury via αvβ5 and αvβ6 integrin-dependent mechanisms [65] . Viral infection and replication in airway epithelial cells cause high levels of virus-associated pyroptosis with vascular leakage [66] . The mechanism of pyroptosis is associated with Ca 2+ leakage, K + leakage, and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-caspase-1-gasdermin-D signal pathway [67, 68] .

Cytokines play a vital role against viruses, but excessive and dysregulated immune responses cause immune damage. Compared to patients with mild disease, those with severe disease present with lymphopenia, neutrophilia, lower levels of antiviral factors and IFNs, and higher serum concentrations of IL-6, TNF, and TGF-β [69] . These inflammatory cytokines activate the T help type 1 (Th1) cell response, which is the trigger of adaptive immunity [37, 70] . However, in contrast to patients with SARS, patients with COVID-19 also have elevated levels of cytokines from Th2 cells (such as IL-4 and IL-10), which function to inhibit the inflammatory response.

Reports on COVID-19 have shown mean IL-6 levels of 25 pg/mL [71] , which is far less than the 282 pg/mL observed in "hypo-inflammatory" ARDS [72] , 1,618 pg/mL in "hyper-inflammatory" ARDS [73] . The onset time of COVID-19-related J o u r n a l P r e -p r o o f ARDS is 8-12 days, which is inconsistent with the ARDS Berlin criteria, which defines a 1-week onset limit. Lung compliance might be relatively normal in some patients with COVID-19 and ARDS who meet ARDS Berlin criteria [75] .

Mechanically ventilated patients with ARDS infected with COVID-19 have been similar to other causes of ARDS with high compliance, and increasing mortality with the degree of ARDS severity [76] . Although early reports suggested that COVID-19-associated ARDS has distinctive features, emerging evidence indicates that COVID-19-associated ARDS is similar to historical ARDS [77] .

Glucocorticoid is a broad-spectrum anti-inflammatory drug that can regulate immune function in many aspects, inhibit innate and adaptive immunity, inhibit the release of pneumonia-related cytokines and induce apoptosis of lymphocytes. Therefore, glucocorticoid therapy is recommended for critical ill COVID•19 patients.

Abnormal coagulation parameters are associated with high mortality in patients with COVID-19 [80] . Thrombosis mechanisms in COVID-19 include endothelial inflammation, disruption of intercellular junctions, microthrombi formation, increased cytokines, and increased activation of platelets, endothelium, and complement [81] ( Figure 2) .

In the early phases of infection, ACE2 consumption by viral entry increases the concentration of Angiotensin-II (AngII), which is mainly metabolized to the J o u r n a l P r e -p r o o f anti-inflammatory peptide angiotensin (1-7) by endothelial ACE2. AngII has effects on endothelial activation, vasoconstriction, pro-inflammatory cytokine release, platelet activation, and even accelerates lymphocyte recruitment and suppression [82] .

Interestingly, the basal level of AngII increases microvascular permeability, but a higher level decrease permeability, which is attributed to the inflammation-induced shift from ACE1 to ACE2 [83] .

Less ACE2 leads to reduced Ang1-7 and reduced activation of the MAS receptor, which results in a pro-thrombotic endothelial cell phenotype [84] . Reduced expression of ACE2 indirectly activates the kallikrein-kinin system (KKS), which ultimately increases vascular permeability [8, 18] . High levels of bradykinin might explain the majority of severe symptoms, spanning from blood vessel injury to neurological complications [85] . Therefore, it is important to regulate the thrombosis resistance of endothelial cells by balancing the KKS and renin-angiotensin systems (RAS) [15, 86, 87] . The anti-C5 monoclonal antibody eculizumab may be a valuable tool for preventing complement activation in patients with COVID-19 [88] .

Furthermore, neutrophil extracellular traps (NETs) play a prominent role in promoting severe cytokine release and exacerbate lung damage by directly killing epithelial and endothelial cells [89] . NET formation is initiated by hypoxia-induced release of von Willebrand factor (VWF) and P-selectin from the endothelium, which recruits and activates neutrophil NETosis. Neutrophil accumulation is P-selectin-dependent and leads to the recruitment of platelets to promote thromboxane A2 production, which induces endothelial cell expression of intercellular adhesion molecule 1 (ICAM1) to strengthen neutrophil interactions with the endothelium [90] .

Postmortem from COVID-19 patients demonstrated the presence of NETs in the airway compartment and neutrophil-rich inflammatory areas, while NET-prone primed neutrophils were present in arteriolar microthrombi [91] . Thus, more attention should be paid to neutrophils given their involvement in inflammation, the immune response, and thrombosis. 

The authors have declared no conflicts of interest. 

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Abbreviations: IL1β, interleukin 1β; IFN-γ

MCP1, mitochondrial pyruvate carrier 1

Huang, et al. [34] Total (n=41) ICU (n=13) Non-ICU (n=28) Higher risks of inhospital death Lower median lymphocyte, CD3 + T