Abstract
SummaryInteractions between microbes and hosts can be a benign, deleterious, or even fatal, resulting in death of the host, the microbe, or both. Sialic acid-binding immunoglobulin-like lectins (Siglecs) suppress infection responses to sialylated pathogens. However, most pathogens are nonsialylated. Here we determined Siglecs respond to nonsialylated Gram-negative bacteria (Escherichia coli 25922 and DH5α) and Gram-positive bacteria (Staphylococcus aureus and Listeria monocytogenes). We found that Siglece−/− mice had higher mortality than wild-type mice following Gram-negative but not Gram-positive bacterial infection. Better survival in wild-type mice depended on more efficient clearance of Gram-negative than Gram-positive bacteria. Gram-negative bacteria upregulated Siglec-E, thus increasing reactive oxygen species (ROS); Tyr432 in the ITIM domain of Siglec-E was required to increase ROS. Moreover, Gram-negative bacteria upregulated Siglec-E via TLR4/MyD88/JNK/NF-κB/AP-1, whereas Gram-positive bacteria downregulated Siglec-E via TLR2/RANKL/TRAF6/Syk. Thus, our study describes a fundamentally new role for Siglec-E during infection.
Highlights
Interactions between host molecules and bacterial antigens are dynamic and can be benign, deleterious, or even fatal, resulting in the death of the host, microbe, or both (Merrell and Falkow, 2004; Ottemann and Kenney, 2019; Medzhitov, 2007; Bhavsar et al, 2007; Casadevall and Pirofski, 2000)
SigleceÀ/À Mice Are less Resistant to E. coli 25922 and DH5a but Not S. aureus and L. monocytogenes Infection Than Siglece+/+ Mice Recent studies indicated Siglec-E represses the immune response by direct binding to heavily sialylated Group B streptococcus via a2-3-linked sialyllactosamine capsular polysaccharide (Chang et al, 2014; Saito et al, 2016; Chang and Nizet, 2014)
Siglec-E-deficient and wild-type littermates were infected intraperitoneally (i.p.) with Gram-negative E. coli 25922 or DH5a or Gram-positive S. aureus or L. monocytogenes. These bacteria are nonsialylated as revealed by staining with Sambucus nigra lectin (SNA) and Maackia amurensis lectin (MAA) (Figure S2) and showed no binding activity to soluble SiglecE IgG Fc fusion protein (Figure S3)
Summary
Interactions between host molecules and bacterial antigens are dynamic and can be benign, deleterious, or even fatal, resulting in the death of the host, microbe, or both (Merrell and Falkow, 2004; Ottemann and Kenney, 2019; Medzhitov, 2007; Bhavsar et al, 2007; Casadevall and Pirofski, 2000). Many microbial pathogens avoid host recognition or dampen subsequent immune activation through interactions with host responses, but some pathogens benefit from stimulating inflammatory responses (Vimr and Lichtensteiger, 2002). Sialic acids are a family of nine-carbon sugars, and N-Glycolylneuraminic acid (Neu5Gc) and N-acetylneuraminic acid (Neu5Ac) are major sialic acids (Chen et al, 2014b). Some oropharyngeal pathogens express sialic acid units on their surfaces, mimicking the sialyl-rich mucin layer coating host epithelial cells to masquerade as ‘‘self’’ while eluding host immune mechanisms, most microbes do not express sialic acid on their surface (Vimr and Lichtensteiger, 2002). How hosts respond to nonsialylated microbial pathogens is poorly understood
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