Cytosolic recognition of flagellin by mouse macrophages restricts Legionella pneumophila infection

Abstract

Macrophages are the guardians of the innate immune system, recognizing a broad array of pathogen-associated molecular patterns (PAMPs) to initiate immediate defenses and to recruit the adaptive branch of the immune system. Toll-like receptors (TLRs) detect extracellular microbial products, such as lipopolysaccharide, peptidoglycan, lipotechoic acid, and fl agellin (1), whereas surveillance of the cytosol is the task of nucleotide-binding oligomerization domain (NOD) leucine-rich repeat (LRR) proteins. The best-characterized members of the NOD-LRR family are NOD1 and NOD2, which recognize distinct elements of bacterial cell wall peptidoglycan in the cytosol to mount or modulate a proinfl ammatory immune response or to promote apoptosis (2). In mouse macrophages, the NOD-LRR protein Naip5 (Birc1e) restricts intracellular replication of the opportunistic human pathogen Legionella pneumophila (3-5). Naip5 is comprised of three modules: NH 2-terminal baculoviral inhibitor of apoptosis repeats, a central NOD domain, and COOH-terminal LRRs (2). By analogy to other NOD-LRR proteins, the LRR region is thought to recognize microbial products, triggering oligomerization via the NOD domain and activation of a cellular response that is governed by various NH 2terminal eff ector-binding domains (2). Whereas virtually all mice are resistant to L. pneumophila, the A/J strain encodes a naip5 allele that confers susceptibility to infection (3). Whether the

Legionella pneumophila — a human pathogen that co-evolved with fresh water protozoa

“…Furthermore, flagellin is responsible for growth restriction of L. pneumophila in mouse macrophages, as cytosolic flagellin is recognized by the macrophages that responds by a Naip5 and a caspase 1-dependent mechanism to restrict bacterial replication and release proinflammatory cytokines. In agreement, flagellindeficient Legionella mutants are able to evade caspase-1-and Naip5-mediated macrophage immunity [53,54]. Moreover, other virulence-associated traits might be regulated by the different regulators involved in the flagella regulatory cascade, given that mutants not expressing flagella have lower virulence [50,52,55].…”

Characterization of a spontaneous avirulent mutant of Legionella pneumophila Serogroup 6: Evidence of DotA and flagellin involvement in the loss of virulence

“…Legionella modulates the expression of host cell apoptotic and anti-apoptotic genes to prevent the premature termination of its intracellular replication. In particular, the presence of flagellin and a competent Dot/Icm secretion system are critical for Legionella to regulate the apoptotic process (Amer et al, 2006;Molofsky et al, 2006;Abu-Zant et al, 2007;Santic et al, 2007;Shin and Roy, 2008). In this context, the loss of virulence of Virstrain should give an explanation on how severely damaged the type IV secretion system was, and the absence of flagellin signal could determine the de-regulation of the apoptotic process.…”

Legionella pathogenicity: Genome structure, regulatory networks and the host cell response

“…Naip5 belongs to the NACHT-LRR (NLR) protein family, a group of cytoplasmic proteins involved in intracellular recognition of conserved structures shared by many pathogens, called pathogen-associated molecular patterns (PAMPs). It has been shown that Naip5 can activate caspase 1 following phagocytosis of L. pneumophila by macrophages (Molofsky et al, 2006;Ren et al, 2006). This process obviously antagonizes the ability of L. pneumophila to remodel its phagosome.…”