Recognition of Peptidoglycan from the Microbiota by Nod1 Enhances Systemic Innate Immunity

By Thomas B. Clarke, K. M. Davis, E. Lysenko, A. Zhou, Yimin Yu, J. Weiser. Nature Medicine, 2010

1,134 citations recorded by the source corpus.

Humans are colonized by a large and diverse bacterial flora (the microbiota) essential for the development of the gut immune system. A broader role for the microbiota as a major modulator of systemic immunity has been proposed; however, evidence and a mechanism for this role have remained elusive. We show that the microbiota are a source of peptidoglycan that systemically primes the innate immune system, enhancing killing by bone marrow–derived neutrophils of two major pathogens: Streptococcus pneumoniae and Staphylococcus aureus. This requires signaling via the pattern recognition receptor nucleotide-binding, oligomerization domain–containing protein-1 (Nod1, which recognizes meso-diaminopimelic acid (mesoDAP)-containing peptidoglycan found predominantly in Gram-negative bacteria), but not Nod2 (which detects peptidoglycan found in Gram-positive and Gram-negative bacteria) or Toll-like receptor 4 (Tlr4, which recognizes lipopolysaccharide). We show translocation of peptidoglycan from the gut to neutrophils in the bone marrow and show that peptidoglycan concentrations in sera correlate with neutrophil function. In vivo administration of Nod1 ligands is sufficient to restore neutrophil function after microbiota depletion. Nod1−/− mice are more susceptible than wild-type mice to early pneumococcal sepsis, demonstrating a role for Nod1 in priming innate defenses facilitating a rapid response to infection. These data establish a mechanism for systemic immunomodulation by the microbiota and highlight potential adverse consequences of microbiota disruption by broad-spectrum antibiotics on innate immune defense to infection.

Subfields: Emergency Medical Services, Immunology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/c7e05a7faaa5b804c2ed378c5dadbae5b39c42ea

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Citations in the corpus

The microbiome and human cancer (2021, background): “Microbiota-derived compounds can protect against irradiation-induced hematopoietic injury (60–62) through production of propionate and tryptophan metabolites (63) or by releasing microorganism-associated molecular patterns (MAMPs) known to maintain BM-derivedmyeloid cells and neutrophil function (64”
Role of the Microbiota in Immunity and inflammation (2014, background): “and Staphylococcus aureus by bone-marrow-derived neutrophils in a NOD1-dependent manner (Clarke et al., 2010).”
The role of gut microbiota in immune homeostasis and autoimmunity (2012, background): “This data elegantly demonstrated how systemic immunomodulation by intestinal microbiota could be achieved.(32) Other innate cell types.”
The microbiota of the respiratory tract: gatekeeper to respiratory health (2017, background): “In addition, gut microbiota-induced priming of innate immune cells at the intestinal mucosa was shown to affect respiratory health; for example, through NOD1 receptor-mediated activation of the neutrophils that are required for the clearance of Streptococcus pneumoniae in the URT 72, 166 .”
Antibiotic-Induced Changes in the Intestinal Microbiota and Disease. (2016, background): “NOD1-mediated sensing of meso-diaminopimelic acid (DAP) promotes neutrophil-mediated killing of pathogens such as Staphylococcus aureus and Streptococcus pneumoniae [22,23].”
Antibiotics and the Human Gut Microbiome: Dysbioses and Accumulation of Resistances (2016, background): “…mice have shown that antibiotic treatment can reduce the capacity to fight infections by Gram-positive organisms by decreasing the expression of bactericidal compounds and diminishing neutrophil-mediated killing (Brandl et al., 2008; Vaishnava et al., 2008; Clarke et al., 2010; Ubeda et al., 2010).”
Neutrophils: Between Host Defence, Immune Modulation, and Tissue Injury (2015, background): “While our understanding of cellular and molecular mechanisms remains incomplete, the regulation of neutrophil homeostasis by the microbiome seems to be mediated by structural features of bacteria that can activate innate pattern recognition receptors, leading to increased neutrophil production [93–9”
B–helper neutrophils stimulate immunoglobulin diversification and production in the marginal zone of the spleen (2011, background): “Although some MZ B cell responses may occur after translocation of commensal antigens across intact mucosal surface”
Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? (2018, background): “, 2016) and prime neutrophils for improved antimicrobial function (Clarke et al., 2010).”