Many questions remain about the interactions between and the complement system, including how capsule structure alters complement recognition, the exact functions during infection of the multiple non-capsular factors thought to inhibit complement activity, and the importance of complement for inflammatory and other non-phagocytic mechanisms of immunity to and how evades these will provide a clearer understanding of disease pathogenesis, and more broadly potentially clarify why some bacterial commensal species are common pathogens as well as others rarely cause severe infections

Many questions remain about the interactions between and the complement system, including how capsule structure alters complement recognition, the exact functions during infection of the multiple non-capsular factors thought to inhibit complement activity, and the importance of complement for inflammatory and other non-phagocytic mechanisms of immunity to and how evades these will provide a clearer understanding of disease pathogenesis, and more broadly potentially clarify why some bacterial commensal species are common pathogens as well as others rarely cause severe infections. Author contributions EG, JB and MN conceived the manuscript. ability to cause invasive infections. However, at present we only have a limited understanding of the main mechanisms causing variations in match sensitivity between strains and to non-pathogenic streptococci. colonises the nasopharynx of a high proportion of infants and up to 10% of adults. can spread from your nasopharynx to the lungs to cause pneumonia, the blood to cause septicaemia (often associated with pneumonia), or to the meninges to cause meningitis and is a common cause of severe infections worldwide (Troeger et?al., 2018). Acumapimod Much like other mainly extracellular bacterial pathogens, host immunity to is usually critically dependent on phagocytosis and therefore opsonisation by circulating soluble host immune mediators, particularly complement. The importance of match for prevention of infection is usually demonstrated by the high incidence of invasive infections people with match deficiencies (Sj?holm et?al., 2006; Skattum et?al., 2011; Woehrl et?al., 2011). For example, around 50% of subjects with inherited deficiency of the classical match pathway component C2 have had an episode of pneumonia, septicaemia, or meningitis, the majority of which were caused by (J?nsson et?al., 2005). Genome wide association studies showing an association between genotypic match variants and poor outcomes in meningitis provide additional evidence of the importance of match for immunity to (Weiss et?al., 1998; Biesma et?al., 2001). Furthermore, human infections with are associated with significant reductions in circulating levels of match factors (Coonrod and Rylko-Bauer, 1977) suggesting match activation and consumption. Match activation by by neutrophils, and increased target organ CFU and disease severity in mouse models of pneumonia, septicaemia and meningitis (Brown et?al., 2002; Rupprecht et?al., 2007; Yuste et?al., 2008). Even though classical pathway was previously considered to be activated by antibody and therefore mediate adaptive immunity, mouse data have demonstrated an essential role for the classical pathway for innate complement-mediated immunity to (Brown et?al., 2002). Further work has exhibited that multiple pathways activate classical pathway acknowledgement of impartial of acquired antibody, including direct binding of C1q (the first match of the classical pathway), natural antibody acknowledgement (mainly of cell wall phosphocholine), binding of the serum components C-reactive protein (CRP) and Acumapimod serum amyloid P (SAP) protein, and activation on splenic macrophage cell surfaces through SIGN-R1 acknowledgement of the capsule (Physique?1) (Brown et?al., Acumapimod 2002; Kang et?al., 2004; Rupprecht et?al., 2007; IL23R Suresh et?al., 2007; Yuste et?al., 2007; Agrawal et?al., 2008) Open in a separate window Physique?1 Mechanisms of activation of complement pathways Acumapimod by and the downstream potential effects on the immune response. The alternative pathway amplifies match activation by initiated by the classical and lectin pathways (Xu et?al., 2001; Brown et?al., 2002) and is also activated directly through acknowledgement of cell wall phosphocholine (Winkelstein and Tomasz, 1978; Hummell et?al., 1981; Brown et?al., 1983b; Hummell et?al., 1985; Hyams et?al., 2010). Mice with deficiencies in components Acumapimod of the alternative pathway show impaired opsonophagocytosis of and increased susceptibility to contamination (Xu et?al., 2001; Brown et?al., 2002; Li et?al., 2011). In humans, hereditary deficiency of the alternative pathway component factor D is associated with severe pneumococcal disease (Weiss et?al., 1998; Biesma et?al., 2001). The role of the lectin match pathway for protection against infection is usually less obvious. The lectin pathway is usually activated by the binding to microbial carbohydrates of mannose-binding lectin (MBL) and the ficolins (Krarup et?al., 2005). Meta-analysis has suggested MBL deficiency in humans is usually associated with an increased susceptibility to invasive infections (Eisen et?al., 2008; Brouwer et?al., 2009) and L-ficolin binds to at least some capsular serotypes of (Krarup et?al., 2005). However, data from genetically altered mice is usually contradictory with some data showing the lectin pathway only has a small role in match acknowledgement of (Neth.