Host Immune Response to Bacterial Lipopolysaccharides

Bacterial lipopolysaccharides (LPS), components of the outer membrane of Gram-negative bacteria, are recognised as potent microbial-associated molecular patterns that drive innate immunity. Detection of LPS occurs primarily through the MD-2–TLR4 receptor complex on myeloid cells, triggering MyD88- and TRIF-dependent pathways that culminate in NF-κB activation and rapid production of pro-inflammatory cytokines such as tumour necrosis factor, interleukin-6 and interleukin-1β. Concurrently, interferon regulatory factors induce type I interferons and chemokines that recruit neutrophils and monocytes to sites of infection. Neutrophils engage in phagocytosis and degranulation, whereas macrophages orchestrate both microbial clearance and resolution by shifting from a pro-inflammatory to repair-promoting phenotype. Repeated or high-dose LPS exposure can induce tolerance, characterised by attenuated cytokine production, whereas low-dose priming elicits trained immunity with enhanced microbial killing. Host lipases, notably acyloxyacyl hydrolase, deacylate and detoxify LPS, facilitating the resolution of inflammation and preventing chronic tissue injury. Dysregulation of these processes underlies sepsis, acute respiratory distress and endotoxin shock. Advances in understanding the balance between activation, training and detoxification of LPS responses offer new avenues for therapeutic modulation in infectious and inflammatory disorders.

Research from Nature Portfolio

Recent studies have demonstrated that a single low-dose LPS exposure primes the innate immune system through expansion of neutrophil and interstitial macrophage subsets enriched for phagocytic and bactericidal gene programmes. A distinctive upregulation of the gene encoding galectin-3 in neutrophils underpins enhanced bacterial phagocytosis and killing. Intravital imaging confirmed increased galectin-3 protein at phagosomes, and galectin-3 deficiency abrogated the protective effect. Clinical samples from patients with acute respiratory failure revealed that higher galectin-3 levels in airway secretions correlate with neutrophil signatures and favourable outcomes, suggesting translational potential for harnessing galectin-3-mediated innate training against lethal bacterial infections.

Host Immune Response to Bacterial Lipopolysaccharides publication trend

The graph below shows the total number of articles in host immune response to bacterial lipopolysaccharides across all publications each year (not limited to Nature Index journals).

Technical terms

Lipopolysaccharide (LPS): A complex glycolipid in the outer membrane of Gram-negative bacteria that activates innate immune receptors.

Toll-like receptor 4 (TLR4): A membrane-bound receptor that, in association with MD-2, recognises LPS and initiates inflammatory signalling.

MyD88/TRIF pathways: Intracellular adaptor cascades downstream of TLR4 that lead to cytokine production and antiviral responses.

Galectin-3: A β-galactoside-binding lectin produced by neutrophils and macrophages that enhances microbial phagocytosis and killing.

Acyloxyacyl hydrolase (AOAH): A host lipase that removes secondary acyl chains from LPS, reducing its endotoxic activity and promoting inflammation resolution.

Innate immune training: A heightened state of innate responsiveness induced by subthreshold microbial exposures leading to enhanced subsequent defence.

Innate immune tolerance: A transient refractory state following strong or repeated microbial stimulation, marked by reduced cytokine output.

References

1. Neutrophils and galectin-3 defend mice from lethal bacterial infection and humans from acute respiratory failure. Nature Communications (2024).
2. In Situ Neutralization and Detoxification of LPS to Attenuate Hyperinflammation. Advanced Science (2023).
3. Acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance. PLOS Pathogens (2023).