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.

Keywords: coronavirus disease 2019; immunoregulation; inflammation; recombinant fragment of human SP-D (rfhSP-D); severe acute respiratory syndrome coronavirus 2 (2019-nCoV); surfactant protein A; surfactant protein D; therapeutic.

Figure 1

Structure of surfactant proteins A (SP-A) and SP-D. SP-A and SP-D contain four domains: the N-terminal domain (black), collagen-like domain (green), neck region (blue) and carbohydrate recognition domain (CRD) (red). SP-A and SP-D form functional trimers and can then further oligomerize into an octadecameric-like structure for SP-A and a dodecameric cruciform-like structure which can further assemble into ‘stellate multimers’ for SP-D. Also shown is the crystal structure of the recombinant fragment of human SP-D (rfhSP-D) (8). rfhSP-D is formed of the CRD, neck and 8x Gly Xaa Yaa repeats of the collagen-like region.

Figure 2

Maintenance of homeostasis in the lung by surfactant protein D (SP-D). Shown is an overview of the roles of SP-D in the lung. Indicated is the role SP-D plays in neutralizing, agglutinating and clearing viruses as well as reducing the inflammatory response upon infection with influenza A virus, respiratory syncytial virus (RSV), and human immunodeficiency virus (HIV). The role of SP-D in enhancing phagocytosis by dendritic cells (DCs) while simultaneously reducing antigen presentation and activation of co-stimulatory markers is indicated. Also shown is the role of SP-D in keeping T cells in a hyporesponsive state to increase CTLA4 expression, reduce T cell proliferation, reduce allergen induced Th2 cytokine production and modulate apoptosis. The role of SP-D in clearing and agglutinating noxious particles, pollen and pathogens is indicated. Similarly, the role of SP-D in enhancing macrophage-mediated pathogen killing, modulating inflammatory cytokine production by macrophages and macrophage chemotaxis and reducing antigen presentation is displayed. Also shown is the role of SP-D in clearing apoptotic and necrotic cells in the lung as well as its interaction with neutrophils in binding to neutrophil NETS, and eosinophil extracellular traps, preventing degranulation and modulating cytokine production. Finally, the role of SP-D and rfhSP-D in correcting the phenotype of the SP-D knockout mouse is indicated, specifically their role in decreasing emphysema, excessive phospholipid production, decreasing inflammatory cell and apoptotic and necrotic cell numbers, decreasing the level of reactive oxygen species (ROS), decreasing inflammatory cytokines including IL-6 and IL-12 and decreasing the susceptibility of SP-D knockout mice to pathology as a result of challenge with pathogens, allergens and noxious particles. Adapted from “Alveolar Epithelium (Comparison)”, by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates.

Figure 3

Mechanisms for reduction in surfactant proteins A (SP-A) and SP-D in the lung during infection and inflammation. Indicated is the degradation of SP-A and SP-D through their role as scavenger receptors to bind and enhance clearance of pathogens, noxious particles, apoptotic cells and cell debris (1); degradation of SP-A and SP-D through pathogen-derived proteases and elevated endogenous proteases secreted by recruited inflammatory cells or released from dying and damaged cells (2); damage to the alveolar epithelium leading to reduction of SP-A and SP-D production (3) and leakage into the blood (4). Adapted from “Cytokine Storm”, by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates.