[PMC free content] [PubMed] [Google Scholar]Stoermer KA, Morrison TE. preliminary antibody response to parainfluenza infections, with implications for understanding infant immune design and replies of vaccine approaches for these pediatric pathogens. INTRODUCTION The supplement system can be an important element of the innate immune system response to infections. Supplement (C) antiviral features add a large numbers of actions, including identification of infections and virus-infected cells, immediate neutralization of trojan infectivity, arousal and recruitment of leukocytes at sites of an infection, phagocytosis by immune system cells, and activation of antiviral T and B cells (Blue et al., 2004; Gasque, 2004; Atkinson and Kemper, 2007). Likewise, infections employ systems to limit C features (e.g., Blue et al., 2004; Johnson et al. 2012). The total amount between C efficiency and trojan inhibition of C can possess essential implications for viral pathogenesis and dissemination (Delgado and Polack, 2004; Morrison et al., 2007, Morrison and Stoermer, 2011). C may also straight impact adaptive immunity (Carroll, 2004; Kemper and Atkinson, 2007) and can influence the quality of anti-viral antibody responses (Pierson et al., 2008). The overall goal of the work described here was to determine the contribution of C to the neutralizing PKI-402 capacity of antibodies elicited by respiratory tract infection of nonhuman primates with parainfluenza virus. The C proteolytic cascade can be initiated through three main pathways: the classical pathway, lectin pathway and alternative pathway (Gasque, 2004; Roozendaal and Carroll, 2006). Activation of the classical pathway typically involves binding of the C1q component to virus-antibody complexes. Human Immunodeficiency Virus (HIV; Ebenbichler et al., 1991) and vesicular stomatitis virus (VSV; Beebe and Cooper, 1981) are known to activate the classical pathway. The lectin pathway is activated through recognition of carbohydrate signatures on viral glycoproteins by the cellular mannan-binding lectin (MBL). This is an important pathway in the pathogenesis of Ross River Virus (Gunn et al., 2012) and in the opsonization of influenza virus (Hartshorn et al., 1993). Compared PKI-402 to activation of the classical and lectin PKI-402 pathways, the signals that activate the alternative pathway are less well understood, but they are thought to involve recognition of foreign surfaces by an antibody-independent mechanism (Gasque, 2004; Pangburn et al., 1981). Parainfluenza virus 5 (PIV5), human parainfluenza virus 2 (HPIV2) and mumps virus (MuV) are closely-related negative strand RNA viruses belonging to the rubulavirus genus of the paramyxovirus family (Lamb and Parks, 2013; Parks PKI-402 et al. 2011). Prior work has shown that the rubulavirus attachment protein (Hemagglutinin-Neuraminidase; HN) and the fusion protein (F) can both contribute to activation of the alternative pathway (McSharry et al., 1981; Hirsch et al., 1986; Johnson et al., 2008; 2013). For PIV5 and MuV, the extent of alternative pathway activation is directly related to the loss of sialic acid on particles due to the presence of neuraminidase activity in the HN protein (McSharry et al., 1981; Hirsch et al., 1986). Furthermore, the rubulavirus F protein can dictate which arm of the C pathway is activated. This was evident by our recent finding that a single point mutation in the ectodomain of the PIV5 F protein led to increased fusion activity, but also Keratin 18 (phospho-Ser33) antibody led to enhanced binding of IgG contained in normal human sera (NHS) and a subsequent shift in C activation from the alternative to the classical pathway (Johnson et al., 2013). Once activated, C components are capable of direct neutralization of viruses, through mechanisms that can include aggregation or virion lysis (Blue et al., 2004; Stoermer and Morrison, 2011). In addition, C can enhance the neutralizing capacity of antibodies (Mehlop et al., 2009). For HPIV2, our prior results demonstrated very high levels of neutralizing antibody in NHS (Johnson et al, 2008), making the contribution of C to neutralization difficult to analyze. In addition, repeated exposure to parainfluenza virus as PKI-402 infants (Karron and Collins, 2013) and the use of adult NHS in neutralization assays makes it difficult to determine the role of C in the antibody function following the very first exposure at an early age to human parainfluenza.