Pulmonary surfactant as a versatile biomaterial to fight COVID-19

Abstract

The COVID-19 pandemic has wielded an enormous pressure on global health care systems, economics and politics. Ongoing vaccination campaigns effectively attenuate viral spreading, leading to a reduction of infected individuals, hospitalizations and mortality. Nevertheless, the development of safe and effective vaccines as well as their global deployment is time-consuming and challenging. In addition, such preventive measures have no effect on already infected individuals and can show reduced efficacy against SARS-CoV-2 variants that escape vaccine-induced host immune responses. Therefore, it is crucial to continue the development of specific COVID-19 targeting therapeutics, including small molecular drugs, antibodies and nucleic acids. However, despite clear advantages of local drug delivery to the lung, inhalation therapy of such antivirals remains difficult. This review aims to highlight the potential of pulmonary surfactant (PS) in the treatment of COVID-19. Since SARS-CoV-2 infection can progress to COVID-19-related acute respiratory distress syndrome (CARDS), which is associated with PS deficiency and inflammation, replacement therapy with exogenous surfactant can be considered to counter lung dysfunction. In addition, due to its surface-active properties and membrane-interacting potential, PS can be repurposed to enhance drug spreading along the respiratory epithelium and to promote intracellular drug delivery. By merging these beneficial features, PS can be regarded as a versatile biomaterial to combat respiratory infections, in particular COVID-19.

Keywords: Antiviral drugs; Coronavirus disease-19; Inhalation therapy; Lung delivery; Nanomedicine; Pulmonary surfactant; Severe acute respiratory syndrome coronavirus-2; Small-interfering RNA.

Graphical abstract

Fig. 1

SARS-CoV-2 structure and host cell entry mechanisms. The single stranded (ss) RNA viral genome encodes four structural proteins including the nucleocapsid, membrane, envelope and spike protein (A). Binding of S1 of the viral spike protein to the ACE-2 receptor on host cells induces 1) spike protein cleavage by TMPRSS2, followed by activation of S2 and viral internalization via direct fusion of the viral envelope and the host cell plasma membrane or 2) viral internalization via endocytic entry, followed by fusion between the viral envelope and the endosomal membrane (B). Abbreviations: SARS-CoV-2; severe acute respiratory syndrome coronavirus-2, ACE-2; angiotensin-converting enzyme-2, TMPRSS2; transmembrane protease serine 2, S1; subunit 1, S2; subunit 2. Adapted from ‘Mechanisms of SARS-CoV-2 Viral Entry’, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates

Fig. 2

Schematic representation of the alveolar compartment, including the alveolar epithelium (i.e. type I- and type II pneumocytes), alveolar macrophages and pulmonary surfactant (A). Proteolipid composition of pulmonary surfactant (wt%) (B). Organization of pulmonary surfactant and lipid-protein interactions during expiration, according to the squeeze-out model. Grey, orange and purple lipids represent saturated lipids, unsaturated lipids and cholesterol, respectively (C). Abbreviations: DPPC; dipalmitoylphosphatidylcholine, PC; phosphatidylcholine, PG; phosphatidylglycerol, PL; phospholipid, NL; neutral lipid, SPs; surfactant proteins, SP-A; surfactant protein-A, SP-B; surfactant protein-B, SP-C; surfactant protein-C, SP-D; surfactant protein-D. Created with BioRender.com (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Interaction of endogenous pulmonary surfactant with pulmonary cells, cellular membranes and the immune system. Pulmonary surfactant is produced by type II pneumocytes in concentrically organized lamellar bodies, which are partly converted into tubular myelin upon secretion into the alveolar lumen. The presence of SP-B and SP-C in tubular myelin drives the adsorption of surfactant membranes towards the air-liquid interface (1). Binding of SP-A to the P63/CKAP4 receptor expressed by type II pneumocytes induces the uptake and recycling of used surfactant components (2). Degradation of used surfactant components occurs via uptake and phagocytosis by alveolar macrophages (3). SP-A and SP-D are involved in the pulmonary innate immune system via opsonization of aerial pathogens, followed by phagocytosis by alveolar macrophages (4). SP-A and SP-D modulate inflammatory responses via interactions with immune cells, thereby reducing cytokine production, as well as via direct binding and inactivation of soluble cytokines (5). Grey, orange and purple lines represent saturated, unsaturated and cholesterol-rich domains, respectively. Abbreviations: SP-A; surfactant protein-A, SP-B; surfactant protein-B, SP-C; surfactant protein-C, SP-D; surfactant protein-D. Created with BioRender.com (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Non-treated (A)versus pulmonary surfactant-treated COVID-19-related acute respiratory distress syndrome (B). Infection with SARS-CoV-2 results in the recruitment of alveolar macrophages, which produce high levels of cytokines, also referred to as a cytokine storm (1). Subsequent neutrophil recruitment and degranulation (2) leads to the destruction of type II pneumocytes and endothelial cells, resulting in reduced surfactant production and secretion, serum leakage in the alveolar spaces and surfactant inactivation by surface-active cytokines and serum proteins that adsorb to the air-liquid interface, thereby excluding endogenous PS components (3). Improper surfactant function leads to collapsed alveoli, aberrant gas exchange and respiratory failure. The administration of exogenous surfactant can supplement the affected endogenous PS pool (1), as well as dampen the inflammatory response via interactions with immune cells, cytokines and SARS-CoV-2 (2). Exogenous SP-A and SP-D can prevent viral infection via binding and neutralization of the spike protein, thereby preventing its interaction with the ACE-2 receptor on type II pneumocytes (3). Exogenous SP-A and SP-D grants more resistance towards surfactant inactivation (4). Recovery of the surfactant layer as well as reduced inflammation leads to less cellular damage, reduced serum leakage in the alveolar spaces, enhanced gas exchange and thus the prevention of respiratory failure. Abbreviations: COVID-19; coronavirus disease-19, SARS-CoV-2; severe acute respiratory syndrome coronavirus-2, ACE-2; angiotensin-converting enzyme-2, SP-A; surfactant protein-A, SP-D; surfactant protein-D. Created with BioRender.com

Fig. 5

Exogenous pulmonary surfactant as a vehicle or liposomal carrier for COVID-19-targeting drugs. Encapsulation of drugs inside exogenous PS can improve drug spreading and adsorption along the entire pulmonary epithelium (1). The administration of exogenous surfactant can supplement the reduced or inactivated endogenous surfactant pool, which prevents alveolar collapse and facilitates the delivery and deposition of inhaled drugs in deeper lung regions (2). SP-A-mediated uptake in type II pneumocytes induces drug- and surfactant recycling, which allows further drug spreading along the alveolar interface (3). SP-A- and SP-D-mediated drug internalization by alveolar macrophages allows anti-inflammatory drugs (e.g. corticosteroids) to interfere with the production of pro-inflammatory cytokines (4). SP-A-mediated uptake of antivirals in type II pneumocytes results in the reduction of viral replication processes and/or viral infectivity via various mechanisms of action (5). PS-assisted delivery of monoclonal-antibody based products (e.g. heavy chain-only antibodies) allows them to bind to viral components (e.g. the spike protein), thereby preventing interactions with the ACE-2 receptor thus reducing their infectivity (6). Abbreviations: SP-A; surfactant protein-A, SP-B; surfactant protein-B, SP-C; surfactant protein-C, SP-D; surfactant protein-D, ACE-2; angiotensin-converting enzyme-2, SARS-CoV-2. severe acute respiratory syndrome coronavirus-2, PL; phospholipid, PS; pulmonary surfactant. Created with BioRender.com

Fig. 6

Schematic overview of relative TNFα silencing in a murine, LPS-induced acute lung injury (ALI) model. Intratracheal administration of anti-TNFα siRNA was performed using uncoated nanogels (siNGs) or nanogels coated with a surfactant-inspired proteolipid composition (DPPC or DOPC:PG 85:15, LIP), with or without SP-B (siNGs LIP, siNGs LIP:SP-B), followed by LPS administration after 24 h. TNFα levels were quantified in BAL fluid, obtained 24 h after LPS stimulation. TNFα expression levels of mice treated with anti-TNFα siRNA are normalized to mice treated with control siRNA (siCTRL). Only siRNA delivery using siNGs coated with DPPC:PG and supplemented with SP-B leads to substantial gene silencing. All values are a mean ± standard deviation (SD) from four independent repeats (n = 4). Statistical analysis was performed via One-Way ANOVA followed by a Tukey's multiple comparison test. Abbreviations: TNFα; tumor necrosis factor α, LPS; lipopolysaccharide, siNGs; siRNA-loaded nanogels, SP-B; surfactant protein-B, BAL; bronchoalveolar lavage. Data adopted from [49], with permission. Created with BioRender.com

Fig. 7

SP-B-mediated cytosolic delivery of siRNA molecules occurs via the promotion of fusion events. The surfactant-coated siNGs are internalized by endocytosis and reside in the late endosomal compartment upon endosomal maturation. The cationic SP-B can interact with anionic lipids in the membrane of late endosomes, followed by direct fusion of the surfactant-coated siNGs with the endosomal membrane, hydrolysis of the NGs and cytosolic delivery of the siRNA molecules (A). The cationic SP-B can interact with anionic lipids in intraluminal vesicles (ILVs), followed by fusion between surfactant-coated siNGs and ILVs, hydrolysis of the NGs, translocation of the siRNA molecules and cytosolic delivery upon back-fusion between the ILVs and the endosomal membrane (B). Abbreviations: RISC; RNA-induced silencing complex. Created with BioRender.com