Abstract
Toll-like receptor 4 (TLR4) initiates immune response against Gram-negative bacteria upon specific recognition of lipid A moiety of lipopolysaccharide (LPS), the major component of their cell wall. Some natural differences between LPS variants in their ability to interact with TLR4 may lead to either insufficient activation that may not prevent bacterial growth, or excessive activation which may lead to septic shock. In this study we evaluated the biological activity of LPS isolated from pathogenic strain of Campylobacter jejuni, the most widespread bacterial cause of foodborne diarrhea in humans. With the help of hydrophobic chromatography and MALDI-TOF mass spectrometry we showed that LPS from a C. jejuni strain O2A consists of both hexaacyl and tetraacyl forms. Since such hypoacylation can result in a reduced immune response in humans, we assessed the activity of LPS from C. jejuni in mouse macrophages by measuring its capacity to activate TLR4-mediated proinflammatory cytokine and chemokine production, as well as NFκB-dependent reporter gene transcription. Our data support the hypothesis that LPS acylation correlates with its bioactivity.
Highlights
Toll-like receptors constitute a family of immune sensors that recognize conserved molecular patterns associated with bacteria and viruses, mediate interaction of the host immune system with commensal microbiota and initiate early responses to infection (Akira and Hemmi, 2003; RakoffNahoum et al, 2004)
We have previously assessed the bioactivity of LPS preparations from various pathogenic bacteria, such as Y. pestis, B. mallei, FIGURE 2 | LPS isolated from a C. jejuni O2A strain is a mild activator of mRNA expression of proinflammatory cytokines in bone marrow-derived macrophages (BMDM)
Lipid A from a C. jejuni O2A strain has on the average longer acyl groups (C14-16) as compared to LPS from E. coli (C14), but it demonstrates lower biological activity (Figures 2–5)
Summary
Toll-like receptors constitute a family of immune sensors that recognize conserved molecular patterns associated with bacteria and viruses, mediate interaction of the host immune system with commensal microbiota and initiate early responses to infection (Akira and Hemmi, 2003; RakoffNahoum et al, 2004). Activation of TLR4 signaling pathways and downstream transcription factors of NFκB and IRF families leads to production of proinflammatory cytokines and reactive oxygen species (Akira and Takeda, 2004; Lu et al, 2008). These agents can be harmful both to pathogens and to the host cells; TLR4 involvement has been reported for such pathologies as sepsis, autoimmune diseases and cancer (Cario and Podolsky, 2000; Bank et al, 2014; Korneev et al, 2017). Y. pestis produces highly active hexaacyl lipid A in fleas at 25◦C, but alters it to a less active tetraacyl form after infecting mammals with higher body temperature of 37◦C (Knirel et al, 2005)
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