Anti–spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection

Liu, Li; Wang, Qiang; Lin, Qingqing; Fang, Jun; Wang, Haibo; Kwok, Hau-Yee; Tang, Hangying; Nishiura, Kenji; Peng, Jie; Tan, Zhiwu; Wu, Tongjin; Cheung, Kmc; Chan, Kwok-Hung; Álvarez, Xavier; Qin, Chuan; Lackner, Andrew A.; Perlman, Stanley; Yuen, Kwok‐Yung; Chen, Zhiwei

doi:10.1172/jci.insight.123158

Cited by 814 publications

(940 citation statements)

References 53 publications

(84 reference statements)

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“…In a SARS-CoV macaque model, anti-spike IgG stimulated pulmonary proinflammatory responses and caused acute lung injury. 26 The detrimental effect of antispike IgG was attributable to the effect on wound-healing macrophages, which was mediated via the Fcγ receptor. Our findings showing correlation between antibody level detected by EIA and virus neutralisation titre are especially important for design of vaccine studies, and use of convalescent plasma or therapeutic monoclonal antibodies, which could improve clinical outcome or paradoxically cause immuno pathological damage to the recipient.…”

Section: Discussionmentioning

confidence: 99%

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

Tsang²,

Leung³

et al. 2020

The Lancet Infectious Diseases

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2,977

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Background Coronavirus disease 2019 (COVID-19) causes severe community and nosocomial outbreaks. Comprehensive data for serial respiratory viral load and serum antibody responses from patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not yet available. Nasopharyngeal and throat swabs are usually obtained for serial viral load monitoring of respiratory infections but gathering these specimens can cause discomfort for patients and put health-care workers at risk. We aimed to ascertain the serial respiratory viral load of SARS-CoV-2 in posterior oropharyngeal (deep throat) saliva samples from patients with COVID-19, and serum antibody responses.Methods We did a cohort study at two hospitals in Hong Kong. We included patients with laboratory-confirmed COVID-19. We obtained samples of blood, urine, posterior oropharyngeal saliva, and rectal swabs. Serial viral load was ascertained by reverse transcriptase quantitative PCR (RT-qPCR). Antibody levels against the SARS-CoV-2 internal nucleoprotein (NP) and surface spike protein receptor binding domain (RBD) were measured using EIA. Whole-genome sequencing was done to identify possible mutations arising during infection.Findings Between Jan 22, 2020, and Feb 12, 2020, 30 patients were screened for inclusion, of whom 23 were included (median age 62 years [range 37-75]). The median viral load in posterior oropharyngeal saliva or other respiratory specimens at presentation was 5·2 log 10 copies per mL (IQR 4·1-7·0). Salivary viral load was highest during the first week after symptom onset and subsequently declined with time (slope -0·15, 95% CI -0·19 to -0·11; R²=0·71). In one patient, viral RNA was detected 25 days after symptom onset. Older age was correlated with higher viral load (Spearman's ρ=0·48, 95% CI 0·074-0·75; p=0·020). For 16 patients with serum samples available 14 days or longer after symptom onset, rates of seropositivity were 94% for anti-NP IgG (n=15), 88% for anti-NP IgM (n=14), 100% for anti-RBD IgG (n=16), and 94% for anti-RBD IgM (n=15). Anti-SARS-CoV-2-NP or anti-SARS-CoV-2-RBD IgG levels correlated with virus neutralisation titre (R²>0·9). No genome mutations were detected on serial samples.Interpretation Posterior oropharyngeal saliva samples are a non-invasive specimen more acceptable to patients and health-care workers. Unlike severe acute respiratory syndrome, patients with COVID-19 had the highest viral load near presentation, which could account for the fast-spreading nature of this epidemic. This finding emphasises the importance of stringent infection control and early use of potent antiviral agents, alone or in combination, for highrisk individuals. Serological assay can complement RT-qPCR for diagnosis.

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Section: Discussionmentioning

confidence: 99%

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

Tsang²,

Leung³

et al. 2020

The Lancet Infectious Diseases

Self Cite

2,977

194

3,284

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“…Consistent with this observation, adoptive transfer of purified anti-S-IgG-neutralizing antibody (i.v. injection) to macaques, despite the fact that it reduced viral loads following subsequent challenge with SARS-CoV PUMC , led to acute diffuse alveolar damage in all infected animals, whereas in the control group (injected with non-specific IgG), only minor to moderate inflammation in the lungs was observed (Liu et al 2019). This animal study suggests that despite viral suppression, the presence of anti-spike protein antibody at the acute stage of SARS-CoV infection can actually cause severe acute lung injury that persists until the late stages.…”

Section: Inflammation Caused By Virus-induced Ace2 Downregulation Andmentioning

confidence: 88%

“…These previous studies suggest that sACE2 Inflammatory Responses Induced by Anti-Spike IgG (Anti-S-IgG) Antiviral neutralizing antibodies play an important role in viral clearance. However, previous studies in animal models have shown that in SARS-CoV infection, such anti-S protein-neutralizing antibodies (anti-S-IgG) can also cause severe lung injury by altering inflammatory responses (Liu et al 2019). In SARS-CoV/macaque models, it has been found that S-IgG present in infected lungs can facilitate severe lung injury; in these SARS-CoV S proteinvaccinated Chinese macaques, acute lung injury was more pronounced than in unvaccinated control animals that showed only minor to moderate lung inflammation (Liu et al 2019).…”

Section: Inflammation Caused By Virus-induced Ace2 Downregulation Andmentioning

confidence: 99%

“…Anti-S-IgG can promote proinflammatory monocyte/ macrophage accumulation and the production of MCP-1 and IL-8 in the lungs. Such anti-S-IgG-initiated proinflammatory responses appear to be mediated through the binding of the virus-anti-S-IgG complex to the Fc receptors (FcR) present on monocytes/macrophages, as FcR blockade reduces the production of inflammatory cytokines (Liu et al 2019). It is also possible that such a virus-anti-S-IgG complex may additionally activate the classical pathway of the complement system, leading to cellular damages, although this has not been investigated.…”

Section: Inflammation Caused By Virus-induced Ace2 Downregulation Andmentioning

confidence: 99%

See 1 more Smart Citation

Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools

2020

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Currently there is no effective antiviral therapy for SARS-CoV-2 infection, which frequently leads to fatal inflammatory responses and acute lung injury. Here, we discuss the various mechanisms of SARS-CoV-mediated inflammation. We also assume that SARS-CoV-2 likely shares similar inflammatory responses. Potential therapeutic tools to reduce SARS-CoV-2 -induced inflammatory responses include various methods to block FcR activation. In the absence of a proven clinical FcR blocker, the use of intravenous immunoglobulin to block FcR activation may be a viable option for the urgent treatment of pulmonary inflammation to prevent severe lung injury. Such treatment may also be combined with systemic anti-inflammatory drugs or corticosteroids. However, these strategies, as proposed here, remain to be clinically tested for effectiveness.

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“…The findings reveal a mechanism responsible for virus-mediated ALI and define a pathologic consequence of viral-specific antibody response, in addition to providing some insight on a potential target for treatment of SARS-CoV. 41…”

Section: Immune Responses and Immunopathologymentioning

confidence: 94%

Severe Acute Respiratory Syndrome

Hui

Zumla

2019

Infectious Disease Clinics of North America

422

163

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Anti–spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection

Cited by 814 publications

References 53 publications

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools

Severe Acute Respiratory Syndrome

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