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Cellular Nanosponges Inhibit SARS-CoV-2 Infectivity

  • Qiangzhe Zhang
    Qiangzhe Zhang
    Department of NanoEngineering, Chemical Engineering Program and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, United States
    More by Qiangzhe Zhang
    • , 
  • Anna Honko
    Anna Honko
    Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, Massachusetts 02118, United States
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    • , 
  • Jiarong Zhou
    Jiarong Zhou
    Department of NanoEngineering, Chemical Engineering Program and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, United States
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    • , 
  • Hua Gong
    Hua Gong
    Department of NanoEngineering, Chemical Engineering Program and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, United States
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    • , 
  • Sierra N. Downs
    Sierra N. Downs
    Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, Massachusetts 02118, United States
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    • , 
  • Jhonatan Henao Vasquez
    Jhonatan Henao Vasquez
    Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, Massachusetts 02118, United States
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    • , 
  • Ronnie H. Fang
    Ronnie H. Fang
    Department of NanoEngineering, Chemical Engineering Program and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, United States
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    • , 
  • Weiwei Gao
    Weiwei Gao
    Department of NanoEngineering, Chemical Engineering Program and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, United States
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    • , 
  • Anthony Griffiths*
    Anthony Griffiths
    Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, Massachusetts 02118, United States
    *Email: [email protected]
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    • , and 
  • Liangfang Zhang*
    Liangfang Zhang
    Department of NanoEngineering, Chemical Engineering Program and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, United States
    *Email: [email protected]
    More by Liangfang Zhang
    Orcidhttp://orcid.org/0000-0003-0637-0654
Cite this: Nano Lett. 2020, 20, 7, 5570–5574
Publication Date (Web):June 17, 2020
https://doi.org/10.1021/acs.nanolett.0c02278
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Abstract

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We report cellular nanosponges as an effective medical countermeasure to the SARS-CoV-2 virus. Two types of cellular nanosponges are made of the plasma membranes derived from human lung epithelial type II cells or human macrophages. These nanosponges display the same protein receptors, both identified and unidentified, required by SARS-CoV-2 for cellular entry. It is shown that, following incubation with the nanosponges, SARS-CoV-2 is neutralized and unable to infect cells. Crucially, the nanosponge platform is agnostic to viral mutations and potentially viral species, as well. As long as the target of the virus remains the identified host cell, the nanosponges will be able to neutralize the virus.

KEYWORDS:

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an outbreak of coronavirus disease (COVID-19), and the pandemic has unfolded into a severe global public health crisis. (1,2) Remdesivir is currently the most advanced antiviral drug for COVID-19 treatment, which received an emergency-use authorization in the United States for patients with severe disease, but the mortality benefit is unproven. (3) The search for new drugs requires a clear understanding of the underlying molecular mechanisms of viral infection, which is a particular challenge with emerging viruses such as SARS-CoV-2. (4,5) Moreover, antiviral medicine often targets a specific viral species that cannot be deployed across different species or families of viruses and may be rendered ineffective as the virus accumulates mutations and escapes treatments. (6) Therefore, an effective therapeutic agent to inhibit SARS-CoV-2 infectivity, as well as its potential mutated species, would be a significant game changer in the battle against this public health crisis.

Early understanding of the clinical manifestation of COVID-19 is severe viral pneumonia. Emerging data are clear that SARS-CoV-2 elicits significant damage on other organ systems either directly or indirectly through downstream immunological effects. (7) Up to 75% of COVID-19 patients present with some renal involvement, with a significant portion of patients developing acute kidney injury. (8) Acute respiratory distress syndrome (ARDS) is a common and deadly manifestation of COVID-19 and is associated with prolonged intubation and high mortality. (9) Typically, COVID-19 patients initially present mild symptoms, yet a subset of patients rapidly develop complications such as ARDS and multiorgan failure and ultimately death. The rapid clinical deterioration is thought to be closely related to the cytokine storm. (10) Recently, coagulopathy has been described as a critical morbidity in COVID-19 patients and is associated with worse outcomes. (11) All of these clinical complications speak to the complexity of this disease and that the consequence of immune response to the viral infection may be the main driver of morbidity and mortality of COVID-19.

A novel approach to drug development is to place the focus on the affected host cells instead of targeting the causative agent. Inspired by the fact that the infectivity of SARS-CoV-2 relies on its binding with the protein receptors, either known or unknown, on the target cells, we create cellular nanosponges as a medical countermeasure to the coronavirus. These nanosponges are made of human-cell-derived membranes, which are sourced from cells that are naturally targeted by SARS-CoV-2 (Figure 1A). The nanosponges display the same receptors that the viruses depend on for cellular entry. We hypothesize that, upon binding with nanosponges, the coronaviruses are unable to infect their usual cellular targets. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) and CD147 expressed on the host cells, such as human alveolar epithelial type II cells, as receptors for cellular entry. (12) Human macrophages both express CD147 and have been reported to play a significant role in the infection by frequent interactions with virus-targeted cells through chemokines and phagocytosis signaling pathways. (13)

Figure 1

Figure 1. Fabrication and characterization of cellular nanosponges. (A) Schematic mechanism of cellular nanosponges inhibiting SARS-CoV-2 infectivity. The nanosponges were constructed by wrapping polymeric nanoparticle (NP) cores with natural cell membranes from target cells such as lung epithelial cells and macrophages (MΦs). The resulting nanosponges (denoted “Epithelial-NS” and “MΦ-NS”, respectively) inherit the surface antigen profiles of the source cells and serve as decoys to bind with SARS-CoV-2. Such binding interaction blocks viral entry and inhibits viral infectivity. (B) Dynamic light scattering measurements of hydrodynamic size (diameter, nm) and surface zeta-potential (ζ, mV) of polymeric NP cores before and after coating with cell membranes (n = 3; mean + standard deviation). (C) Selective protein bands of cell lysate, cell membrane vesicles, and cellular nanosponges resolved with Western blotting analysis. (D) Comparison of the fluorescence intensity measured from cellular nanosponges (100 μL, 0.5 mg/mL membrane protein concentration) or source cells (100 μL, approximately 2.5 × 106 cells) containing equal amounts of membrane content and stained with fluorescently labeled antibodies (n = 3; mean + standard deviation; n.s.: not significant; statistical analysis was performed with paired two-tailed t-test). (E) Stability of cellular nanosponges in 1× phosphate-buffered saline determined by monitoring particle size (diameter, nm) over a span of 7 days (n = 3; mean ± standard deviation).

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Based upon the current knowledge of SARS-CoV-2, we fabricated two types of cellular nanosponges, human lung epithelial type II cell nanosponge (denoted “Epithelial-NS”) and human macrophage nanosponge (denoted “MΦ-NS”). The resulting cellular nanosponges were thoroughly characterized for their physicochemical and biological properties, followed by in vivo evaluation of their safety in the lungs. Then, these samples were independently tested in a biosafety level 4 (BSL-4) laboratory for inhibitory effects on human SARS-CoV-2 virus and demonstrated clear antiviral efficacy in vitro.

To prepare cellular nanosponges, cell membranes of human lung epithelial cells and macrophages were derived with a differential centrifugation method and verified for purity. The membranes were then coated onto polymeric nanoparticle cores made from poly(lactic-co-glycolic acid) (PLGA) with a sonication method to form Epithelial-NS and MΦ-NS, respectively. When examined with dynamic light scattering, both Epithelial-NS and MΦ-NS showed hydrodynamic diameters larger than that of the uncoated PLGA cores (Figure 1B). The surface zeta-potential of the nanosponges was less negative than that of the PLGA cores but comparable to that of the source cells (Table S1). These changes are consistent with the addition of a bilayer cell membrane. Cell membrane coating allows nanosponges to inherit the viral receptors related to coronavirus entry into the host cells. For verification, Western blot analysis showed the presence of viral receptors such as ACE2, transmembrane serine protease 2 (TMPRSS2), and dipeptidyl peptidase IV (DPP4) on the Epithelial-NS, and ACE2, C-type lectin domain family 10 (CLEC10), and CD147 on the MΦ-NS (Figure 1C). (12,13) The results also showed that the nanosponge preparation facilitated membrane protein retention and enrichment on the nanosponges, without contamination from intracellular proteins (Figure S1). For viral neutralization, right-side-out membrane orientation, driven by the asymmetric repulsion between the cores and the extracellular membrane versus the intracellular membrane, is essential. (14) To examine the membrane sidedness, we stained cellular nanosponges and their source cells containing equal amounts of membrane content using fluorescently labeled antibodies against select membrane antigens. After the removal of free antibodies, cellular nanosponge samples showed fluorescence intensities comparable with those of the cell samples (Figure 1D). This indicates that the nanosponges adopted a right-side-out membrane orientation because inside-out membrane coating would reduce antibody staining. (15) The membrane coating also provided cellular nanosponges with extended colloidal stability in 1× phosphate-buffered saline (Figure 1E).

After confirming the successful fabrication of Epithelial-NS and MΦ-NS, we sought to evaluate their acute toxicity after in vivo administration in mice. Given that our intended use is the deployment of cellular nanosponges for the treatment of coronavirus infections that predominantly affect the respiratory tract, (9) we elected to study the intratracheal route of administration using the highest feasible dose of Epithelial-NS or MΦ-NS (300 μg, based on membrane protein, in a suspension of 20 μL). Histopathological analysis of lung tissue 3 days after nanosponge administration revealed that immune infiltration was similar to baseline levels, and there was no evidence of lesion formation or tissue damage (Figure 2A). Furthermore, we examined multiple blood parameters, including a comprehensive serum chemistry panel and blood cell counts, 3 days after nanosponge administration (Figure 2B,C). All of the blood markers that were studied, in addition to red blood cells, platelets, and white blood cell counts, were consistent with baseline levels, confirming the short-term safety of the cellular nanosponges.

Figure 2

Figure 2. In vivo safety of cellular nanosponges. (A) Hematoxylin and eosin (H&E) staining of representative lung sections taken 3 days after intratracheal administration of the cellular nanosponges (scale bar: 250 μm). (B) Comprehensive serum chemistry panel performed 3 days after intratracheal administration of the cellular nanosponges (n = 3; mean + standard deviation). ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMY, amylase; BUN, urea nitrogen; CA, calcium; CRE, creatinine; GLOB, globulin (calculated); GLU, glucose; K+, potassium; NA+, sodium; PHOS, phosphorus; TBIL, total bilirubin; TP, total protein. (C) Blood cell counts 3 days after intratracheal administration of cellular nanosponges (n = 3; mean + standard deviation).

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We next evaluated the neutralization of infectivity by authentic SARS-CoV-2 with a plaque reduction neutralization test. In the study, a low passage sample of SARS-CoV-2 (USA-WA1/2020, World Reference Center for Emerging Viruses and Arboviruses) (16) was amplified in Vero E6 cells to make a working stock of the virus. Vero E6 cells were seeded at 8 × 105 cells per well in 6-well plates the day prior to the experiment. Serial quarter-log dilutions of the nanosponges were mixed with 200 plaque-forming units (PFU) of SARS-CoV-2. The mixture was incubated at 37 °C for 1 h and then added to the cell monolayers followed by an additional 1 h of incubation. Mock-infected and diluent-only infected wells served as negative and positive controls, respectively. Monolayers were overlaid and incubated for 2 days followed by viral plaque enumeration. Following the incubation, cultures without adding Epithelial-NS showed a viral count comparable to that in the negative control, confirming viral entry and infection of the host cells. Inhibition of the infectivity increased as the concentration of Epithelial-NS increased, suggesting a dose-dependent neutralization effect (Figure 3A). Based on the results, a half-maximal inhibitory concentration (IC50) value of 827.1 μg/mL for Epithelial-NS was obtained. In parallel, a similar dose-dependent inhibition of the viral infectivity was observed with MΦ-NS (Figure 3B). In this case, an IC50 value of 882.7 μg/mL was obtained. These results indicate that the Epithelial-NS and MΦ-NS have comparable ability to inhibit viral infectivity of SARS-CoV-2. To further verify that the inhibition was indeed due to epithelial cell or macrophage membrane coating, control nanosponges made from membranes of red blood cells (denoted “RBC-NS”) were also tested in parallel for viral inhibition but were not effective in neutralizing SARS-CoV-2 infection of Vero E6 cells (Figure 3C).

Figure 3

Figure 3. Cellular nanosponges neutralize SARS-CoV-2 infectivity. The neutralization against SARS-CoV-2 infection by (A) Epithelial-NS, (B) MΦ-NS, and (C) nanosponges made from red blood cell membranes (RBC-NS, used as a control) was tested using live SARS-CoV-2 viruses on Vero E6 cells. The IC50 values for Epithelial-NS and MΦ-NS were found to be 827.1 and 882.7 μg/mL (membrane protein concentration), respectively. In all data sets, n = 3. Data are presented as mean + standard deviation. Horizontal dashed lines mark the zero levels. IC50 values were derived from the variable slope model using Graphpad Prism 8.

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As a novel virus causing the current global pandemic, new information regarding SARS-CoV-2 is emerging on a daily basis. Since the first case that was reported at the end of 2019, it has been shown that the virus is mutating at a rapid rate. (17) This rapid rate of mutation will pose a major challenge to the development of therapeutics and preventive measures. (18) Both Epithelial-NS and MΦ-NS demonstrated the ability to neutralize SARS-CoV-2 in a concentration-dependent manner. The nanosponge platform offers a unique benefit over other therapies currently in development for COVID-19 in that the nanosponges are mutation and potentially virus agnostic. In principle, as long as the target of the virus remains the identified host cell, the nanosponges will be able to neutralize the infection, providing a broad-acting countermeasure resistant to mutations and protection against this and other emerging coronaviruses. The utility of the cellular nanosponges for the treatment of SARS-CoV-2 infection requires further validation in appropriate animal models, which is currently underway, and this will pave the way for human clinical trials in the future. Moreover, optimization of the lead formulation may further improve the antiviral efficacy of these nanosponges.

For the treatment of COVID-19, MΦ-NS may have some significant advantages over Epithelial-NS. The clinical manifestation of COVID-19 is partially driven by direct viral damage but primarily by the immune response to the infection. Previous studies on SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) demonstrated that macrophages play a significant role in the pathogenesis of those infections. Emerging data from SARS-CoV-2 also paint a similar picture, where macrophages play a central role either through direct viral entry via CD147 or downstream hyperinflammatory response to SARS-CoV-2. (19) Our previous work has demonstrated that MΦ-NS has a broad-spectrum neutralization capability, including against bacterial toxins and inflammatory cytokines. (20) Specific to COVID-19, MΦ-NS can neutralize the viral activity not only early on to reduce the viral load in the body but also even late in disease, and it will be able to address the fulminant inflammation associated with COVID-19. Given the central role that macrophages play in the immune system, the application of MΦ-NS extends beyond infections such as SARS-CoV-2 and may have significant roles in treating inflammatory diseases such as sepsis and other autoimmune diseases.

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.nanolett.0c02278.

  • Materials and methods, Figure S1, and Table S1 (PDF)

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  • Corresponding Authors
    • Anthony Griffiths - Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, Massachusetts 02118, United States;  Email: [email protected]
    • Liangfang Zhang - Department of NanoEngineering, Chemical Engineering Program and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, United States;  Orcidhttp://orcid.org/0000-0003-0637-0654;  Email: [email protected]
  • Authors
    • Qiangzhe Zhang - Department of NanoEngineering, Chemical Engineering Program and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, United States
    • Anna Honko - Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, Massachusetts 02118, United States
    • Jiarong Zhou - Department of NanoEngineering, Chemical Engineering Program and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, United States
    • Hua Gong - Department of NanoEngineering, Chemical Engineering Program and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, United States
    • Sierra N. Downs - Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, Massachusetts 02118, United States
    • Jhonatan Henao Vasquez - Department of Microbiology and National Emerging Infectious Diseases Laboratories, Boston University School of Medicine, Boston, Massachusetts 02118, United States
    • Ronnie H. Fang - Department of NanoEngineering, Chemical Engineering Program and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, United States
    • Weiwei Gao - Department of NanoEngineering, Chemical Engineering Program and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, United States
  • Author Contributions

    Q.Z., A.H., and J.Z. contributed equally to this work. Q.Z., A.H., R.H.F., W.G., A.G., and L.Z. designed the study. Q.Z., A.H., J.Z., H.G., S.N.D., and J.H.V. performed the experiments. Q.Z., A.H., J.Z., R.H.F., and W.G. analyzed the data. Q.Z., A.H., R.H.F., W.G., A.G., and L.Z. wrote the paper.

  • Notes
    The authors declare the following competing financial interest(s): L.Z. discloses financial interest in Cellics Therapeutics.

Acknowledgments

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This work is supported by the Defense Threat Reduction Agency Joint Science and Technology Office for Chemical and Biological Defense under Grant No. HDTRA1-18-1-0014. The following reagent was obtained through BEI Resources, NIAID, NIH: VERO C1008 (E6), Kidney (African green monkey), Working Cell Bank, NR-596. The SARS-CoV-2 starting material was provided by the World Reference Center for Emerging Viruses and Arboviruses (WRCEVA), with Natalie Thornburg ([email protected]) as the CDC Principal Investigator. Avicel RC-591 was kindly provided by DuPont Nutrition & Health.

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    To date, no vaccines or effective drugs have been approved to prevent or treat COVID-19 and the current standard care relies on supportive treatments. Therefore, based on the fast and global spread of the virus, urgent investigations are warranted in order to develop preventive and therapeutic drugs. In this regard, treatments addressing the immunopathology of SARS-CoV-2 infection have become a major focus. Notably, while a rapid and well-coordinated immune response represents the first line of defense against viral infection, excessive inflammatory innate response and impaired adaptive host immune defense may lead to tissue damage both at the site of virus entry and at systemic level. Several studies highlight relevant changes occurring both in innate and adaptive immune system in COVID-19 patients. In particular, the massive cytokine and chemokine release, the so-called "cytokine storm", clearly reflects a widespread uncontrolled dysregulation of the host immune defense. Although the prospective of counteracting cytokine storm is compelling, a major limitation relies on the limited understanding of the immune signaling pathways triggered by SARS-CoV-2 infection. The identification of signaling pathways altered during viral infections may help to unravel the most relevant molecular cascades implicated in biological processes mediating viral infections and to unveil key molecular players that may be targeted. Thus, given the key role of the immune system in COVID-19, a deeper understanding of the mechanism behind the immune dysregulation might give us clues for the clinical management of the severe cases and for preventing the transition from mild to severe stages.
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    Nature Reviews Drug Discovery (2016), 15 (5), 327-347CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)
    A review. In humans, infections with the human coronavirus (HCoV) strains HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 usually result in mild, self-limiting upper respiratory tract infections, such as the common cold. By contrast, the CoVs responsible for severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which were discovered in Hong Kong, China, in 2003, and in Saudi Arabia in 2012, resp., have received global attention over the past 12 years owing to their ability to cause community and health-care-assocd. outbreaks of severe infections in human populations. These two viruses pose major challenges to clin. management because there are no specific antiviral drugs available. In this Review, we summarize the epidemiol., virol., clin. features and current treatment strategies of SARS and MERS, and discuss the discovery and development of new virus-based and host-based therapeutic options for CoV infections.
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    Tay, M. Z.; Poh, C. M.; Renia, L.; MacAry, P. A.; Ng, L. F. P. The trinity of COVID-19: Immunity, inflammation and intervention. Nat. Rev. Immunol. 2020, 20, 363– 374,  DOI: 10.1038/s41577-020-0311-8
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    Nature Reviews Immunology (2020), 20 (6), 363-374CODEN: NRIABX; ISSN:1474-1733. (Nature Research)
    A review. A review. Abstr.: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Alongside investigations into the virol. of SARS-CoV-2, understanding the fundamental physiol. and immunol. processes underlying the clin. manifestations of COVID-19 is vital for the identification and rational design of effective therapies. Here, we provide an overview of the pathophysiol. of SARS-CoV-2 infection. We describe the interaction of SARS-CoV-2 with the immune system and the subsequent contribution of dysfunctional immune responses to disease progression. From nascent reports describing SARS-CoV-2, we make inferences on the basis of the parallel pathophysiol. and immunol. features of the other human coronaviruses targeting the lower respiratory tract - severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Finally, we highlight the implications of these approaches for potential therapeutic interventions that target viral infection and/or immunoregulation.
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    Pei, G.; Zhang, Z.; Peng, J.; Liu, L.; Zhang, C.; Yu, C.; Ma, Z.; Huang, Y.; Liu, W.; Yao, Y.; Zeng, R.; Xu, G. Renal involvement and early prognosis in patients with COVID-19 pneumonia. J. Am. Soc. Nephrol. 2020, 31, 1157– 1165,  DOI: 10.1681/ASN.2020030276
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    Pei Guangchang; Liu Liu; Zhang Chunxiu; Yu Chong; Ma Zufu; Huang Yi; Liu Wei; Yao Ying; Zeng Rui; Xu Gang; Zhang Zhiguo; Zhang Zhiguo; Peng Jing
    Journal of the American Society of Nephrology : JASN (2020), 31 (6), 1157-1165 ISSN:.
    BACKGROUND: Some patients with COVID-19 pneumonia also present with kidney injury, and autopsy findings of patients who died from the illness sometimes show renal damage. However, little is known about the clinical characteristics of kidney-related complications, including hematuria, proteinuria, and AKI. METHODS: In this retrospective, single-center study in China, we analyzed data from electronic medical records of 333 hospitalized patients with COVID-19 pneumonia, including information about clinical, laboratory, radiologic, and other characteristics, as well as information about renal outcomes. RESULTS: We found that 251 of the 333 patients (75.4%) had abnormal urine dipstick tests or AKI. Of 198 patients with renal involvement for the median duration of 12 days, 118 (59.6%) experienced remission of pneumonia during this period, and 111 of 162 (68.5%) patients experienced remission of proteinuria. Among 35 patients who developed AKI (with AKI identified by criteria expanded somewhat beyond the 2012 Kidney Disease: Improving Global Outcomes definition), 16 (45.7%) experienced complete recovery of kidney function. We suspect that most AKI cases were intrinsic AKI. Patients with renal involvement had higher overall mortality compared with those without renal involvement (28 of 251 [11.2%] versus one of 82 [1.2%], respectively). Stepwise multivariate binary logistic regression analyses showed that severity of pneumonia was the risk factor most commonly associated with lower odds of proteinuric or hematuric remission and recovery from AKI. CONCLUSIONS: Renal abnormalities occurred in the majority of patients with COVID-19 pneumonia. Although proteinuria, hematuria, and AKI often resolved in such patients within 3 weeks after the onset of symptoms, renal complications in COVID-19 were associated with higher mortality.
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    Zangrillo, A.; Beretta, L.; Scandroglio, A. M.; Monti, G.; Fominskiy, E.; Colombo, S.; Morselli, F.; Belletti, A.; Silvani, P.; Crivellari, M.; Monaco, F.; Azzolini, M. L.; Reineke, R.; Nardelli, P.; Sartorelli, M.; Votta, C. D.; Ruggeri, A.; Ciceri, F.; Cobelli, F. D.; Tresoldi, M.-n.; Dagna, L.; Rovere-Querini, P.; Neto, A. S.; Bellomo, R.; Landon, G. Characteristics, treatment, outcomes and cause of death of invasively ventilated patients with COVID-19 ARDS in Milan, Italy. Crit. Care Resusc. 2020; published online ahead of print.
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    Ye, Q.; Wang, B.; Mao, J. The pathogenesis and treatment of the ‘cytokine storm’ in COVID-19. J. Infect. 2020, 80, 607– 613,  DOI: 10.1016/j.jinf.2020.03.037
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    Journal of Infection (2020), 80 (6), 607-613CODEN: JINFD2; ISSN:0163-4453. (Elsevier B.V.)
    A review. Cytokine storm is a general term applied to maladaptive cytokine release in response to infection and other stimuli. The pathogenesis is complex but includes loss of regulatory control of proinflammatory cytokine prodn., both at local and systemic levels. The disease progresses rapidly, and the mortality is high. Some evidence shows that, during the coronavirus disease 2019 (COVID-19) epidemic, severe deterioration in some patients has been closely assocd. with dysregulated and excessive cytokine release. This article reviews what we know of the mechanism and treatment strategies of the COVID-19 virus-induced inflammatory storm in an attempt to provide some background to inform future guidance for clin. treatment.
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    Connors, J. M.; Levy, J. H. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020, 135, 2033– 2040,  DOI: 10.1182/blood.2020006000
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    COVID-19 and its implications for thrombosis and anticoagulation
    Connors Jean M; Levy Jerrold H; Levy Jerrold H; Levy Jerrold H
    Blood (2020), 135 (23), 2033-2040 ISSN:.
    Severe acute respiratory syndrome coronavirus 2, coronavirus disease 2019 (COVID-19)-induced infection can be associated with a coagulopathy, findings consistent with infection-induced inflammatory changes as observed in patients with disseminated intravascular coagulopathy (DIC). The lack of prior immunity to COVID-19 has resulted in large numbers of infected patients across the globe and uncertainty regarding management of the complications that arise in the course of this viral illness. The lungs are the target organ for COVID-19; patients develop acute lung injury that can progress to respiratory failure, although multiorgan failure can also occur. The initial coagulopathy of COVID-19 presents with prominent elevation of D-dimer and fibrin/fibrinogen-degradation products, whereas abnormalities in prothrombin time, partial thromboplastin time, and platelet counts are relatively uncommon in initial presentations. Coagulation test screening, including the measurement of D-dimer and fibrinogen levels, is suggested. COVID-19-associated coagulopathy should be managed as it would be for any critically ill patient, following the established practice of using thromboembolic prophylaxis for critically ill hospitalized patients, and standard supportive care measures for those with sepsis-induced coagulopathy or DIC. Although D-dimer, sepsis physiology, and consumptive coagulopathy are indicators of mortality, current data do not suggest the use of full-intensity anticoagulation doses unless otherwise clinically indicated. Even though there is an associated coagulopathy with COVID-19, bleeding manifestations, even in those with DIC, have not been reported. If bleeding does occur, standard guidelines for the management of DIC and bleeding should be followed.
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    Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2
    Yan, Renhong; Zhang, Yuanyuan; Li, Yaning; Xia, Lu; Guo, Yingying; Zhou, Qiang
    Science (Washington, DC, United States) (2020), 367 (6485), 1444-1448CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
    Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo-electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resoln. of 2.9 angstroms, with a local resoln. of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the mol. basis for coronavirus recognition and infection.
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    Biochemical and Biophysical Research Communications (2020), 526 (1), 135-140CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)
    The new coronavirus (SARS-CoV-2) outbreak from Dec. 2019 in Wuhan, Hubei, China, has been declared a global public health emergency. Angiotensin I converting enzyme 2 (ACE2), is the host receptor by SARS-CoV-2 to infect human cells. Although ACE2 is reported to be expressed in lung, liver, stomach, ileum, kidney and colon, its expressing levels are rather low, esp. in the lung. SARS-CoV-2 may use co-receptors/auxiliary proteins as ACE2 partner to facilitate the virus entry. To identify the potential candidates, we explored the single cell gene expression atlas including 119 cell types of 13 human tissues and analyzed the single cell co-expression spectrum of 51 reported RNA virus receptors and 400 other membrane proteins. Consistent with other recent reports, we confirmed that ACE2 was mainly expressed in lung AT2, liver cholangiocyte, colon colonocytes, esophagus keratinocytes, ileum ECs, rectum ECs, stomach epithelial cells, and kidney proximal tubules. Intriguingly, we found that the candidate co-receptors, manifesting the most similar expression patterns with ACE2 across 13 human tissues, are all peptidases, including ANPEP, DPP4 and ENPEP. Among them, ANPEP and DPP4 are the known receptors for human CoVs, suggesting ENPEP as another potential receptor for human CoVs. We also conducted "CellPhoneDB" anal. to understand the cell crosstalk between CoV-targets and their surrounding cells across different tissues. We found that macrophages frequently communicate with the CoVs targets through chemokine and phagocytosis signaling, highlighting the importance of tissue macrophages in immune defense and immune pathogenesis.
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    Nanoscale (2014), 6 (5), 2730-2737CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
    The unique structural features and stealth properties of a recently developed red blood cell membrane-cloaked nanoparticle (RBC-NP) platform raise curiosity over the interfacial interactions between natural cellular membranes and polymeric nanoparticle substrates. Herein, several interfacial aspects of the RBC-NPs are examd., including completeness of membrane coverage, membrane sidedness upon coating, and the effects of polymeric particles' surface charge and surface curvature on the membrane cloaking process. The study shows that RBC membranes completely cover neg. charged polymeric nanoparticles in a right-side-out manner and enhance the particles' colloidal stability. The membrane cloaking process is applicable to particle substrates with a diam. ranging from 65 to 340 nm. Addnl., the study reveals that both surface glycans on RBC membranes and the substrate properties play a significant role in driving and directing the membrane-particle assembly. These findings further the understanding of the dynamics between cellular membranes and nanoscale substrates and provide valuable information toward future development and characterization of cellular membrane-cloaked nanodevices.
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    Severe acute respiratory syndrome coronavirus 2 from patient with coronavirus disease, United States
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    Emerging Infectious Diseases (2020), 26 (6), 1266-1273CODEN: EIDIFA; ISSN:1080-6059. (Centers for Disease Control and Prevention)
    The etiol. agent of an outbreak of pneumonia in Wuhan, China, was identified as severe acute respiratory syndrome coronavirus 2 in Jan. 2020. A patient in the United States was given a diagnosis of infection with this virus by the state of Washington and the US Centers for Disease Control and Prevention on Jan. 20, 2020. We isolated virus from nasopharyngeal and oropharyngeal specimens from this patient and characterized the viral sequence, replication properties, and cell culture tropism. The virus replicates to high titer in Vero-CCL81 cells and Vero E6 cells in the absence of trypsin. We also deposited the virus into 2 virus repositories, making it broadly available to the public health and research communities. We hope that open access to this reagent will expedite development of medical countermeasures.
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    Profile of a killer: the complex biology powering the coronavirus pandemic
    Cyranoski, David
    Nature (London, United Kingdom) (2020), 581 (7806), 22-26CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    Scientists are piecing together how SARS-CoV-2 operates, where it came from and what it might do next - but pressing questions remain about the source of COVID-19.
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    Merad, M.; Martin, J. C. Pathological inflammation in patients with COVID-19: A key role for monocytes and macrophages. Nat. Rev. Immunol. 2020, 20, 355– 362,  DOI: 10.1038/s41577-020-0331-4
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    Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages
    Merad, Miriam; Martin, Jerome C.
    Nature Reviews Immunology (2020), 20 (6), 355-362CODEN: NRIABX; ISSN:1474-1733. (Nature Research)
    A review. Abstr.: The COVID-19 pandemic caused by infection with SARS-CoV-2 has led to more than 200,000 deaths worldwide. Several studies have now established that the hyperinflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. Macrophages are a population of innate immune cells that sense and respond to microbial threats by producing inflammatory mols. that eliminate pathogens and promote tissue repair. However, a dysregulated macrophage response can be damaging to the host, as is seen in the macrophage activation syndrome induced by severe infections, including in infections with the related virus SARS-CoV. Here we describe the potentially pathol. roles of macrophages during SARS-CoV-2 infection and discuss ongoing and prospective therapeutic strategies to modulate macrophage activation in patients with COVID-19.
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    Thamphiwatana, S.; Angsantikul, P.; Escajadillo, T.; Zhang, Q. Z.; Olson, J.; Luk, B. T.; Zhang, S.; Fang, R. H.; Gao, W.; Nizet, V.; Zhang, L. Macrophage-like nanoparticles concurrently absorbing endotoxins and proinflammatory cytokines for sepsis management. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 11488– 11493,  DOI: 10.1073/pnas.1714267114
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    Macrophage-like nanoparticles concurrently absorbing endotoxins and proinflammatory cytokines for sepsis management
    Thamphiwatana, Soracha; Angsantikul, Pavimol; Escajadillo, Tamara; Zhang, Qiangzhe; Olson, Joshua; Luk, Brian T.; Zhang, Sophia; Fang, Ronnie H.; Gao, Weiwei; Nizet, Victor; Zhang, Liangfang
    Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (43), 11488-11493CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Sepsis, resulting from uncontrolled inflammatory responses to bacterial infections, continues to cause high morbidity and mortality worldwide. Currently, effective sepsis treatments are lacking in the clinic, and care remains primarily supportive. Here we report the development of macrophage biomimetic nanoparticles for the management of sepsis. The nanoparticles, made by wrapping polymeric cores with cell membrane derived from macrophages, possess an antigenic exterior the same as the source cells. By acting as macrophage decoys, these nanoparticles bind and neutralize endotoxins that would otherwise trigger immune activation. In addn., these macrophage-like nanoparticles sequester proinflammatory cytokines and inhibit their ability to potentiate the sepsis cascade. In a mouse Escherichia coli bacteremia model, treatment with macrophage mimicking nanoparticles, termed MΦ-NPs, reduced proinflammatory cytokine levels, inhibited bacterial dissemination, and ultimately conferred a significant survival advantage to infected mice. Employing MΦ-NPs as a biomimetic detoxification strategy shows promise for improving patient outcomes, potentially shifting the current paradigm of sepsis management.
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  • Abstract

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    Figure 1

    Figure 1. Fabrication and characterization of cellular nanosponges. (A) Schematic mechanism of cellular nanosponges inhibiting SARS-CoV-2 infectivity. The nanosponges were constructed by wrapping polymeric nanoparticle (NP) cores with natural cell membranes from target cells such as lung epithelial cells and macrophages (MΦs). The resulting nanosponges (denoted “Epithelial-NS” and “MΦ-NS”, respectively) inherit the surface antigen profiles of the source cells and serve as decoys to bind with SARS-CoV-2. Such binding interaction blocks viral entry and inhibits viral infectivity. (B) Dynamic light scattering measurements of hydrodynamic size (diameter, nm) and surface zeta-potential (ζ, mV) of polymeric NP cores before and after coating with cell membranes (n = 3; mean + standard deviation). (C) Selective protein bands of cell lysate, cell membrane vesicles, and cellular nanosponges resolved with Western blotting analysis. (D) Comparison of the fluorescence intensity measured from cellular nanosponges (100 μL, 0.5 mg/mL membrane protein concentration) or source cells (100 μL, approximately 2.5 × 106 cells) containing equal amounts of membrane content and stained with fluorescently labeled antibodies (n = 3; mean + standard deviation; n.s.: not significant; statistical analysis was performed with paired two-tailed t-test). (E) Stability of cellular nanosponges in 1× phosphate-buffered saline determined by monitoring particle size (diameter, nm) over a span of 7 days (n = 3; mean ± standard deviation).

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    Figure 2

    Figure 2. In vivo safety of cellular nanosponges. (A) Hematoxylin and eosin (H&E) staining of representative lung sections taken 3 days after intratracheal administration of the cellular nanosponges (scale bar: 250 μm). (B) Comprehensive serum chemistry panel performed 3 days after intratracheal administration of the cellular nanosponges (n = 3; mean + standard deviation). ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AMY, amylase; BUN, urea nitrogen; CA, calcium; CRE, creatinine; GLOB, globulin (calculated); GLU, glucose; K+, potassium; NA+, sodium; PHOS, phosphorus; TBIL, total bilirubin; TP, total protein. (C) Blood cell counts 3 days after intratracheal administration of cellular nanosponges (n = 3; mean + standard deviation).

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    Figure 3

    Figure 3. Cellular nanosponges neutralize SARS-CoV-2 infectivity. The neutralization against SARS-CoV-2 infection by (A) Epithelial-NS, (B) MΦ-NS, and (C) nanosponges made from red blood cell membranes (RBC-NS, used as a control) was tested using live SARS-CoV-2 viruses on Vero E6 cells. The IC50 values for Epithelial-NS and MΦ-NS were found to be 827.1 and 882.7 μg/mL (membrane protein concentration), respectively. In all data sets, n = 3. Data are presented as mean + standard deviation. Horizontal dashed lines mark the zero levels. IC50 values were derived from the variable slope model using Graphpad Prism 8.

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      Science (Washington, DC, United States) (2020), 367 (6485), 1444-1448CODEN: SCIEAS; ISSN:1095-9203. (American Association for the Advancement of Science)
      Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome coronavirus (SARS-CoV) and the new coronavirus (SARS-CoV-2) that is causing the serious coronavirus disease 2019 (COVID-19) epidemic. Here, we present cryo-electron microscopy structures of full-length human ACE2 in the presence of the neutral amino acid transporter B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resoln. of 2.9 angstroms, with a local resoln. of 3.5 angstroms at the ACE2-RBD interface. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues. These findings provide important insights into the mol. basis for coronavirus recognition and infection.
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      The new coronavirus (SARS-CoV-2) outbreak from Dec. 2019 in Wuhan, Hubei, China, has been declared a global public health emergency. Angiotensin I converting enzyme 2 (ACE2), is the host receptor by SARS-CoV-2 to infect human cells. Although ACE2 is reported to be expressed in lung, liver, stomach, ileum, kidney and colon, its expressing levels are rather low, esp. in the lung. SARS-CoV-2 may use co-receptors/auxiliary proteins as ACE2 partner to facilitate the virus entry. To identify the potential candidates, we explored the single cell gene expression atlas including 119 cell types of 13 human tissues and analyzed the single cell co-expression spectrum of 51 reported RNA virus receptors and 400 other membrane proteins. Consistent with other recent reports, we confirmed that ACE2 was mainly expressed in lung AT2, liver cholangiocyte, colon colonocytes, esophagus keratinocytes, ileum ECs, rectum ECs, stomach epithelial cells, and kidney proximal tubules. Intriguingly, we found that the candidate co-receptors, manifesting the most similar expression patterns with ACE2 across 13 human tissues, are all peptidases, including ANPEP, DPP4 and ENPEP. Among them, ANPEP and DPP4 are the known receptors for human CoVs, suggesting ENPEP as another potential receptor for human CoVs. We also conducted "CellPhoneDB" anal. to understand the cell crosstalk between CoV-targets and their surrounding cells across different tissues. We found that macrophages frequently communicate with the CoVs targets through chemokine and phagocytosis signaling, highlighting the importance of tissue macrophages in immune defense and immune pathogenesis.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlt1Wrt78%253D&md5=7f484d8f3654456f18e7a7ca9c5dd80a
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      Nanoscale (2014), 6 (5), 2730-2737CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
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      Emerging Infectious Diseases (2020), 26 (6), 1266-1273CODEN: EIDIFA; ISSN:1080-6059. (Centers for Disease Control and Prevention)
      The etiol. agent of an outbreak of pneumonia in Wuhan, China, was identified as severe acute respiratory syndrome coronavirus 2 in Jan. 2020. A patient in the United States was given a diagnosis of infection with this virus by the state of Washington and the US Centers for Disease Control and Prevention on Jan. 20, 2020. We isolated virus from nasopharyngeal and oropharyngeal specimens from this patient and characterized the viral sequence, replication properties, and cell culture tropism. The virus replicates to high titer in Vero-CCL81 cells and Vero E6 cells in the absence of trypsin. We also deposited the virus into 2 virus repositories, making it broadly available to the public health and research communities. We hope that open access to this reagent will expedite development of medical countermeasures.
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      Scientists are piecing together how SARS-CoV-2 operates, where it came from and what it might do next - but pressing questions remain about the source of COVID-19.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXosV2jurc%253D&md5=826e66de35a020886c414db4dbdd0ed0
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      Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages
      Merad, Miriam; Martin, Jerome C.
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      A review. Abstr.: The COVID-19 pandemic caused by infection with SARS-CoV-2 has led to more than 200,000 deaths worldwide. Several studies have now established that the hyperinflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. Macrophages are a population of innate immune cells that sense and respond to microbial threats by producing inflammatory mols. that eliminate pathogens and promote tissue repair. However, a dysregulated macrophage response can be damaging to the host, as is seen in the macrophage activation syndrome induced by severe infections, including in infections with the related virus SARS-CoV. Here we describe the potentially pathol. roles of macrophages during SARS-CoV-2 infection and discuss ongoing and prospective therapeutic strategies to modulate macrophage activation in patients with COVID-19.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXoslOqt7s%253D&md5=d38b037fed1fcc469e6c8caa23777fc7
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      Thamphiwatana, S.; Angsantikul, P.; Escajadillo, T.; Zhang, Q. Z.; Olson, J.; Luk, B. T.; Zhang, S.; Fang, R. H.; Gao, W.; Nizet, V.; Zhang, L. Macrophage-like nanoparticles concurrently absorbing endotoxins and proinflammatory cytokines for sepsis management. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 11488– 11493,  DOI: 10.1073/pnas.1714267114
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      Macrophage-like nanoparticles concurrently absorbing endotoxins and proinflammatory cytokines for sepsis management
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      Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (43), 11488-11493CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Sepsis, resulting from uncontrolled inflammatory responses to bacterial infections, continues to cause high morbidity and mortality worldwide. Currently, effective sepsis treatments are lacking in the clinic, and care remains primarily supportive. Here we report the development of macrophage biomimetic nanoparticles for the management of sepsis. The nanoparticles, made by wrapping polymeric cores with cell membrane derived from macrophages, possess an antigenic exterior the same as the source cells. By acting as macrophage decoys, these nanoparticles bind and neutralize endotoxins that would otherwise trigger immune activation. In addn., these macrophage-like nanoparticles sequester proinflammatory cytokines and inhibit their ability to potentiate the sepsis cascade. In a mouse Escherichia coli bacteremia model, treatment with macrophage mimicking nanoparticles, termed MΦ-NPs, reduced proinflammatory cytokine levels, inhibited bacterial dissemination, and ultimately conferred a significant survival advantage to infected mice. Employing MΦ-NPs as a biomimetic detoxification strategy shows promise for improving patient outcomes, potentially shifting the current paradigm of sepsis management.
      >> More from SciFinder ®
      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1aisr7J&md5=7d85b146ca874333f82bed02c57bdabd

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