Antiviral Activities of SP-A:
SP-A has been shown to have antiviral activity against a range of viruses, including influenza virus, respiratory syncytial virus (RSV), and coronaviruses. In the case of coronaviruses, studies have shown that SP-A can inhibit viral replication by binding to the viral surface proteins, such as the spike protein, and preventing their interaction with host cells. This binding activity is thought to be mediated by the carbohydrate recognition domain (CRD) of SP-A, which recognizes and binds to specific carbohydrates on the viral surface.
Immunomodulatory Activities of SP-A:
In addition to its antiviral activity, SP-A also has immunomodulatory activities that can help to regulate the immune response to viral infections. Specifically, SP-A has been shown to modulate the production of cytokines, which are signaling molecules that play a critical role in the immune response to viral infections.
Studies have shown that SP-A can inhibit the production of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), which are associated with the severe inflammatory response observed in some coronavirus infections. At the same time, SP-A can promote the production of anti-inflammatory cytokines, such as interleukin-10 (IL-10), which can help to resolve inflammation and promote tissue repair.
Furthermore, SP-A has been shown to promote the development of regulatory T cells (Tregs), which are a type of immune cell that play a critical role in regulating the immune response to viral infections. Specifically, Tregs can suppress the activity of other immune cells, such as T helper cells, that can contribute to the excessive inflammation observed in some coronavirus infections.
One study conducted by researchers from the University of California, San Francisco, measured the levels of SP-A in the blood of 54 COVID-19 patients who were admitted to the ICU. They found that the patients who had more severe disease had significantly lower levels of SP-A than those with milder disease.
The researchers also found that the levels of SP-A were inversely correlated with the levels of inflammatory cytokines, such as interleukin-6 (IL-6), in the blood. This suggests that the lower levels of SP-A may be due to the increased inflammation associated with severe COVID-19.
Another study conducted by researchers from the University of Virginia School of Medicine and published in the Journal of Clinical Investigation Insight also found that severe COVID-19 patients had relatively lower levels of SP-A in their lungs compared to patients with mild disease.
The researchers measured the levels of SP-A in lung fluid samples from 83 COVID-19 patients and found that the patients who required mechanical ventilation had significantly lower levels of SP-A than those who did not. They also found that the levels of SP-A were inversely correlated with the levels of inflammatory cytokines in the lung fluid, further supporting the hypothesis that the lower levels of SP-A may be due to the increased inflammation associated with severe COVID-19.
The exact mechanism by which the lower levels of SP-A contribute to the severity of COVID-19 is not yet clear. However, it has been suggested that the reduced levels of SP-A may compromise the ability of the lungs to clear viral particles and other pathogens, which could exacerbate the inflammatory response and lead to more severe disease. Additionally, SP-A is known to have anti-inflammatory properties and may help to dampen the cytokine storm that is associated with severe COVID-19.
A new study study examined the mechanistic role of human SP-A in SARS-CoV-2 infectivity.
reference link: https://www.biorxiv.org/content/10.1101/2023.04.03.535215v1
Previous studies have shown that high morbidity and mortality following SARS-CoV-2 infection are predominantly due to a robust influx of inflammatory cells and cytokines into the lungs resulting in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)(2).
SARS-CoV-2, like other coronaviruses, is an enveloped virus with several structural and non-structural proteins that facilitate its infectivity and pathogenicity in humans (3). Most important among the structural proteins for viral infectivity is the spike protein (S protein) which associates as a trimer on the viral envelope and is the basic unit through which the virus attaches to the host cellular receptor, human angiotensin-converting enzyme receptor 2 (hACE2), predominantly expressed on epithelial cells, including alveolar type II cells (ATII) in the lungs and in several other tissues (4).
Each monomer of the S protein is composed of the S1 and S2 subunits. The S1 subunit contains the receptor-binding domain (RBD) which primarily binds to hACE2 while the S2 domain mediates the fusion of the viral and host cell membrane upon cleavage of the S protein subunit by the host transmembrane protease serine 2 (TMPRSS2) (5).
Interestingly, as observed in most viral glycoproteins, the SARS-CoV-2 S protein is decorated with several N- and O- linked carbohydrate structures that have been demonstrated to protect it from antibody recognition (5, 6).
While the presence of sugars on viral S protein can enable immune evasion, it may also enhance recognition by host innate immune carbohydrate-binding proteins (lectins), such as the human surfactant protein A (SP-A).
Human SP-A is a hydrophilic protein and belongs to the C-type lectin family of proteins (collectins) that surveys mucosal epithelial surfaces of the lungs, regions of the upper airway including laryngeal tissues, salivary glands, oral gingiva, and nasal mucosa, and bind to pathogen-associated molecular patterns (PAMPs) of most invading microbes (4, 7).
Like other collectins, SP-A is composed of four functional domains among which is a carbohydrate recognition domain (CRD) that mediates Ca2+-dependent binding to sugars on microbial glycoproteins (7). As a pattern recognition molecule (PRM), SP-A, alongside a related human lung-associated collectin (SP-D), has been demonstrated to bind sugar moieties on viral surfaces and inhibit their infectivity (7).
Furthermore, SP-A enhances viral aggregation, opsonization, and lysis while modulating inflammation by interacting with various types of receptors on innate immune cells (7, 8). Several studies have described the antiviral and immunomodulatory activities of SP-A in the context of respiratory syncytial virus (RSV), Influenza A virus (IAV), human coronavirus 229E (HCoV-229E), and HIV (9-12).
Interestingly, a recent in silico analysis showed that SP-A could ligate the S protein with an affinity similar to the ACE2-spike interaction (13), suggesting that SP-A may have an implication in the pathogenesis of SARS- CoV-2 infection. Given that the effectiveness of the newly developed vaccines and therapeutics for COVID-19 is continuously being threatened by the frequent emergence of SARS-CoV-2 variants with unique changes in the spike epitope that facilitate immune escape, there is a considerable ongoing global effort to develop and improve antivirals and immunomodulatory agents (14-16).
In this study, we explored whether SP-A can bind SARS-CoV-2 S protein, RBD and hACE2, and inhibit viral entry in susceptible host cells. Our results revealed important information about the inhibitory role of human SP-A on SARS-CoV-2 infectivity and its mucosal innate immune response following SARS-CoV-2 infection.
Moreover, the level of SP-A in the saliva of COVID-19 patients was also assessed. These findings contribute to our understanding of the role of human SP-A in SARS-CoV-2 induced pathogenesis and highlight SP-A as an important host protein that could serve as a biomarker for COVID-19 severity as well as a potential therapeutic component.
