The Sialic Acid Binding Activity of Human Parainfluenza Virus 3 and Mumps Virus Glycoproteins Enhances the Adherence of Group B Streptococci to HEp-2 Cells

ORIGINAL RESEARCH published: 17 August 2018 doi: 10.3389/fcimb.2018.00280 The Sialic Acid Binding Activity of Human Parainfluenza Virus 3 and Mumps Virus Glycoproteins Enhances the Adherence of Group B Streptococci to HEp-2 Cells Jie Tong 1† , Yuguang Fu 1† , Fandan Meng 1,2 , Nadine Krüger 1 , Peter Valentin-Weigand 3* and Georg Herrler 1* 1 Institute of Virology, University of Veterinary Medicine Hannover, Hanover, Germany, 2 State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China, 3 Institute of Microbiology, University of Veterinary Medicine Hannover, Hanover, Germany Edited by: Jianming Qiu, University of Kansas Medical Center, United States Reviewed by: Jodi L. McGill, Iowa State University, United States Yu Zhang, University of Pittsburgh, United States *Correspondence: Peter Valentin-Weigand Georg Herrler † These authors have contributed equally to this work Received: 08 February 2018 Accepted: 25 July 2018 Published: 17 August 2018 Citation: Tong J, Fu Y, Meng F, Krüger N, Valentin-Weigand P and Herrler G (2018) The Sialic Acid Binding Activity of Human Parainfluenza Virus 3 and Mumps Virus Glycoproteins Enhances the Adherence of Group B Streptococci to HEp-2 Cells. Front. Cell. Infect. Microbiol. 8:280. doi: 10.3389/fcimb.2018.00280 In the complex microenvironment of the human respiratory tract, different kinds of microorganisms may synergistically interact with each other resulting in viral-bacterial co-infections that are often associated with more severe diseases than the respective mono-infections. Human respiratory paramyxoviruses, for example parainfluenza virus type 3 (HPIV3), are common causes of respiratory diseases both in infants and a subset of adults. HPIV3 recognizes sialic acid (SA)-containing receptors on host cells. In contrast to human influenza viruses which have a preference for α2,6-linked sialic acid, HPIV3 preferentially recognize α2,3-linked sialic acids. Group B streptococci (GBS) are colonizers in the human respiratory tract. They contain a capsular polysaccharide with terminal sialic acid residues in an α2,3-linkage. In the present study, we report that HPIV3 can recognize the α2,3-linked sialic acids present on GBS. The interaction was evident not only by the binding of virions to GBS in a co-sedimentation assay, but also in the GBS binding to HPIV3-infected cells. While co-infection by GBS and HPIV3 had a delaying effect on the virus replication, it enhanced GBS adherence to virus-infected cells. To show that other human paramyxoviruses are also able to recognize the capsular sialic acid of GBS we demonstrate that GBS attaches in a sialic acid-dependent way to transfected BHK cells expressing the HN protein of mumps virus (MuV) on their surface. Overall, our results reveal a new type of synergism in the co-infection by respiratory pathogens, which is based on the recognition of α2,3-linked sialic acids. This interaction between human paramyxoviruses and GBS enhances the bacterial adherence to airway cells and thus may result in more severe disease. Keywords: sialic acids, hemagglutinin-neuraminidase protein, parainfluenza virus, mumps virus, group B streptococci, co-infection Frontiers in Cellular and Infection Microbiology | www.frontiersin.org 1 August 2018 | Volume 8 | Article 280 Tong et al. Co-infection by Paramyxoviruses and Group B Streptococci INTRODUCTION on the surface of virus-infected cells enhances the bacterial adhesion and invasion properties (Tong et al., 2018). However, avian influenza viruses only occasionally infect humans (Stevens et al., 2006; Shi et al., 2013). In contrast to human influenza viruses which have a preference for α2,6-linked sialic acid, human paramyxoviruses recognize α2,3-linked sialic acid. Therefore we analyzed the interactions between GBS and a human paramyxovirus, HPIV3. Human parainfluenza viruses (HPIV) were first isolated in the late 1950s from children sick with lower respiratory diseases. The virus differed from influenza viruses of the family Orthomyxoviridae by a non-segmented genome (Numazaki et al., 1968) and therefore, was assigned to a different virus family, Paramyxoviridae. (Burton, 1964; Cooney et al., 1975), HPIV3 causes acute respiratory infections (ARI) worldwide that are associated with a mortality of nearly 20% in children under 5 years-old (Glezen et al., 1984). HPIV has become one of the most threatening childhood infectious agents around the world due to insufficient vaccines or treatments (Counihan et al., 2001; Moscona, 2005; Garg et al., 2017). HPIV3 and some other viruses of the family Paramyxoviridae share the common feature of recognizing sialic acid (SA)containing receptors on host cells (Suzuki et al., 2001, 2004). Two surface glycoproteins, the hemagglutinin-neuraminidase (HN) protein and the fusion (F) protein, are involved in the initial steps of viral-cell interactions (Moscona and Peluso, 1992; Porotto et al., 2007). For optimal infection conditions, a balanced interaction between the sialic acid binding activity and the neuraminidase activity of the HN protein is essential (Tappert et al., 2013). HPIV3, the clinically most prevalent HPIV subtype, recognizes α2,3-linked sialic acids in branched and unbranched oligosaccharides present on either glycoproteins or glycolipids (Suzuki et al., 2001). Most efficient binding was observed with a sialylated tetrasaccharide (Amonsen et al., 2007). Mumps virus (MuV), another paramyxovirus, has recently been reported to use a trisaccharide containing α2,3-linked sialic acid in unbranched sugar chains as a receptor determinant (Kubota et al., 2016). Some strains especially neurovirulent variants may show an increased binding activity for α2,6linked sialic acid (Reyes-Leyva et al., 2007). With respect to the sialic acid binding activity, the human paramyxoviruses HPIV3 and MuV differ from human influenza viruses which have a clear preference for the α2,6 linkage (Rogers and Paulson, 1983). In the complex microenvironment of the human respiratory tract, different kinds of microorganisms may synergistically interact with each other resulting in viral-bacterial co-infections that are often associated with more severe disease than the respective mono-infections (Beadling and Slifka, 2004; Franz et al., 2010). Apart from influenza A viruses, paramyxoviruses including HPIV also have been frequently implicated in the pathogenesis of bacterial pneumonia in humans (Korppi et al., 1990; Juvén et al., 2000). Among the bacterial pathogens involved in respiratory co-infections, streptococci play a prominent role and S. pneumonia being a well-known representative. Group B streptococci (GBS, Streptococcus agalactiae), the causative agent of infant meningitis and pneumonia in non-pregnant adults have been found to colonize the human airway epithelium (Fallon and Sonnenwirth, 1978; Christensen et al., 1983; Doran et al., 2002). In a (...truncated)