Surfactant Proteins A and D: Trimerized Innate Immunity Proteins with an Affinity for Viral Fusion Proteins

Abstract

Innate recognition of viruses is an essential part of the immune response to viral pathogens. This is integral to the maintenance of healthy lungs, which are free from infection and efficient at gaseous exchange. An important component of innate immunity for identifying viruses is the family of C-type collagen-containing lectins, also known as collectins. These secreted, soluble proteins are pattern recognition receptors (PRRs) which recognise pathogen-associated molecular patterns (PAMPs), including viral glycoproteins. These innate immune proteins are composed of trimerized units which oligomerise into higher-order structures and facilitate the clearance of viral pathogens through multiple mechanisms. Similarly, many viral surface proteins form trimeric configurations, despite not showing primary protein sequence similarities across the virus classes and families to which they belong. In this review, we discuss the role of the lung collectins, i.e., surfactant proteins A and D (SP-A and SP-D) in viral recognition. We focus particularly on the structural similarity and complementarity of these trimeric collectins with the trimeric viral fusion proteins with which, we hypothesise, they have elegantly co-evolved. Recombinant versions of these innate immune proteins may have therapeutic potential in a range of infectious and inflammatory lung diseases including anti-viral therapeutics.

Keywords: Collectins; Fusion proteins; Innate immunity; Structure; Surfactant proteins; Trimeric proteins; Virus.

Fig. 1

Structure of the collectins. a The different oligomeric states of SP-A and SP-D: the carbohydrate recognition domains (CRDs) (orange), neck region (blue), collagenous region (green), and N-terminal domain (black). The box on the higher oligomerised SP-D shows the recombinant fragment of human SP-D (rfhSP-D), which entails 8 Gly-Xaa-Yaa repeats of the collagen-like region, the neck region, and the CRD [20] (this Figure is not to scale). b Three-dimensional structures of trimeric rfhSP-D. The 8 Gly-Xaa-Yaa repeats of the collagen-like region, which are part of rfhSP-D, are never identified in the crystallised structure [20, 21, 127]. Top and side view. The 3 calcium ions are shown as black spheres at the lectin-binding site. MOE2014 software with PBD 1PW9 was used to create these figures.

Fig. 2

The quaternary structure of the trimeric neck-CRD recombinant fragments of human SP-D (rfhSP-D) and rat SP-A (rfrSP-A). a The electrostatic potential of trimeric neck-CRD rfhSP-D (left) and rfrSP-A (right). Isovalues from red (–3.0) to blue (+3.0). PyMOL v1.6.0 and APBS v1.2 were used to create this Figure. b Three-dimensional structures of trimeric neck-CRD rfhSP-D (left) and rfrSP-A (right) showing the “Y” shape of SP-D and the “T” shape of SP-A. The 3 calcium ions found for SP-D and 1 for SP-A are shown as black spheres at the lectin-binding site. MOE2014 software was used to create this figure (PDB numbers appear in parentheses).

Fig. 3

Immune functions of SP-A and SP-D as collectins. They bind to and opsonize viruses, bacteria, worms, allergens, and apoptotic cells. They enhance microbial phagocytosis by aggregating bacteria and viruses. They also possess direct bactericidal effects and potentially bind to a variety of receptors to modulate the expression of immune cell cytokines and inflammatory mediators (adapted with permission from [128]).

Fig. 4

The trimeric configuration of viral fusion proteins and SP-A and SP-D (PDB numbers appear in parentheses). PyMOL v1.6.0 was used to create this figure.

Fig. 5

Binding of SP-D to influenza A H3 haemagglutinin. Circles show the lectin domain in 1 of the SP-D monomeric units and the N165 glycosylation site at the tip of 1 of the H3 haemagglutinin molecules shown to be involved in the binding to SP-D. The 3 calcium ions found for SP-D are shown as black spheres at the lectin-binding site (PDB numbers appear in parentheses). MOE2014 software was used to create this figure.