Abstract
ABSTRACTThe complement system is pivotal in the defense against invasive disease caused by Neisseria meningitidis (Nme, meningococcus), particularly via the membrane attack complex. Complement activation liberates the anaphylatoxins C3a and C5a, which activate three distinct G-protein coupled receptors, C3aR, C5aR1 and C5aR2 (anaphylatoxin receptors, ATRs). We recently discovered that C5aR1 exacerbates the course of the disease, revealing a downside of complement in Nme sepsis. Here, we compared the roles of all three ATRs during mouse nasal colonization, intraperitoneal infection and human whole blood infection with Nme. Deficiency of complement or ATRs did not alter nasal colonization, but significantly affected invasive disease: Compared to WT mice, the disease was aggravated in C3ar−/- mice, whereas C5ar1−/- and C5ar2−/- mice showed increased resistance to meningococcal sepsis. Surprisingly, deletion of either of the ATRs resulted in lower cytokine/chemokine responses, irrespective of the different susceptibilities of the mice. This was similar in ex vivo human whole blood infection using ATR inhibitors. Neutrophil responses to Nme were reduced in C5ar1−/- mouse blood. Upon stimulation with C5a plus Nme, mouse macrophages displayed reduced phosphorylation of ERK1/2, when C5aR1 or C5aR2 were ablated or inhibited, suggesting that both C5a-receptors prime an initial macrophage response to Nme. Finally, in vivo blockade of C5aR1 alone (PMX205) or along with C5aR2 (A8Δ71−73) resulted in ameliorated disease, whereas neither antagonizing C3aR (SB290157) nor its activation with a “super-agonist” peptide (WWGKKYRASKLGLAR) demonstrated a benefit. Thus, C5aR1 and C5aR2 augment disease pathology and are interesting targets for treatment, whereas C3aR is protective in experimental meningococcal sepsis.
Highlights
Usually a harmless colonizer of the upper respiratory tract, the Gram-negative bacterium Neisseria meningitidis (Nme, meningococcus) is feared for its potential to cause rapidly progressing invasive diseases such as meningitis and septicemia [1]
While we found no significant contribution of complement in general (C3, C5), or of the anaphylatoxin receptors” (ATRs) during asymptomatic Nme nasal colonization, we identified a significant contribution of the ATRs to the course of Nme sepsis in mice
We expanded upon our recent observation that C5aR1 aggravates Nme sepsis pathophysiology [41] in showing that C3aR is protective, whereas C5aR2, like C5aR1, is detrimental in the mouse Nme sepsis model
Summary
Usually a harmless colonizer of the upper respiratory tract, the Gram-negative bacterium Neisseria meningitidis (Nme, meningococcus) is feared for its potential to cause rapidly progressing invasive diseases such as meningitis and septicemia [1]. Initial symptoms of invasive meningococcal diseases (IMD) are often not timely recognized before the disease rapidly progresses, thereby limiting the time window for successful treatment; most deaths caused by meningococcal septicemia occur within 24 h after hospital admission [2]. The major virulence factor of Nme in protecting against complement is a polysaccharide capsule, by which 12 different serogroups can be distinguished [4]. Nme sequester the complement regulator fH via the outer membrane proteins fHbp [5] and NspA [6]. Capsule and fHbp are used as antigens in meningococcal vaccines [7,8]
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