SP-A and SP-D: Dual Functioning Immune Molecules With Antiviral and Immunomodulatory Properties

Abstract

Surfactant proteins A (SP-A) and D (SP-D) are soluble innate immune molecules which maintain lung homeostasis through their dual roles as anti-infectious and immunomodulatory agents. SP-A and SP-D bind numerous viruses including influenza A virus, respiratory syncytial virus (RSV) and human immunodeficiency virus (HIV), enhancing their clearance from mucosal points of entry and modulating the inflammatory response. They also have diverse roles in mediating innate and adaptive cell functions and in clearing apoptotic cells, allergens and other noxious particles. Here, we review how the properties of these first line defense molecules modulate inflammatory responses, as well as host-mediated immunopathology in response to viral infections. Since SP-A and SP-D are known to offer protection from viral and other infections, if their levels are decreased in some disease states as they are in severe asthma and chronic obstructive pulmonary disease (COPD), this may confer an increased risk of viral infection and exacerbations of disease. Recombinant molecules of SP-A and SP-D could be useful in both blocking respiratory viral infection while also modulating the immune system to prevent excessive inflammatory responses seen in, for example, RSV or coronavirus disease 2019 (COVID-19). Recombinant SP-A and SP-D could have therapeutic potential in neutralizing both current and future strains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus as well as modulating the inflammation-mediated pathology associated with COVID-19. A recombinant fragment of human (rfh)SP-D has recently been shown to neutralize SARS-CoV-2. Further work investigating the potential therapeutic role of SP-A and SP-D in COVID-19 and other infectious and inflammatory diseases is indicated.

Dysregulation of COVID-19 related gene expression in the COPD lung

“…Viral infection alone is not the only aspect of the development of severe COVID-19 as the majority of infected cases are asymptomatic or mild [ 2 , 58 ]. Whilst increased infection of the lower airway may be an important factor, it is the development of excessive inflammation which is key and targets of current and potential future COVID-19 therapeutics [ 59 – 64 ]. This involves cytokine production [ 65 ], influx of immature monocytes [ 66 ], and T cell activation [ 67 ].…”

Pattern recognition receptors in health and diseases

“…The biological significance is that they can selectively identify microbial carbohydrate structures that are harmful to themselves. 244 , 245 …”

Pattern Recognition Proteins: First Line of Defense Against Coronaviruses

“…The ability of SP-D and recombinant fragment of human SP-D to bind SARS-CoV-2 S-protein suggest that they are capable of dampening the “cytokine storm” by rapid clearance of the virus-infected cells and strengthening the lung capacity by restoring homeostasis. Both, SP-A and SP-D have antiviral and immunomodulatory properties against SARS-CoV-2 ( 70 , 71 ). SP-D participates in pulmonary viral neutralization, agglutination and clearance; reduction of the inflammatory response upon infection; enhancement of dendritic cell phagocytosis; enhancement of macrophage-mediated pathogen killing, inflammatory cytokine modulation and chemotaxis; modulation of intrapulmonary T-cell response; promotion of clearance of apoptotic cells to prevent necrosis and inflammation; and binding of neutrophil/eosinophil extracellular traps preventing degranulation and modulating cytokine production ( 70 ).…”

“…Both, SP-A and SP-D have antiviral and immunomodulatory properties against SARS-CoV-2 ( 70 , 71 ). SP-D participates in pulmonary viral neutralization, agglutination and clearance; reduction of the inflammatory response upon infection; enhancement of dendritic cell phagocytosis; enhancement of macrophage-mediated pathogen killing, inflammatory cytokine modulation and chemotaxis; modulation of intrapulmonary T-cell response; promotion of clearance of apoptotic cells to prevent necrosis and inflammation; and binding of neutrophil/eosinophil extracellular traps preventing degranulation and modulating cytokine production ( 70 ). SP-D recognizes SARS-CoV-2 S-protein, and recombinant SP-D bound to S-protein has been shown to inhibit interaction of the S-protein with ACE2 receptors ( 71 ).…”

“…SP-A and SP-D interact with foreign organisms, like SARS-CoV-2, apoptotic cells or cell debris through LRP1/CRT-mediated macrophage phagocytosis and modulation of the inflammatory response in lungs and atherosclerotic plaques ( 57 , 68 , 95 ). The ability of CRT/CD91 to scavenge microbial membrane lipoproteins and to digest apoptotic cells favors the control of local inflammation by preventing an overwhelming inflammatory response causing further injury, as found during SARS-CoV-2 infection-associated hyperinflammation and cytokine storm ( 70 , 96 ).…”