Leukocyte Inflammatory Responses Provoked by Pneumococcal Sialidase

Abstract

Cell surface expression of sialic acid has been reported to decrease during immune cell activation, but the significance and regulation of this phenomenon are still being investigated. The major human bacterial pathogen Streptococcus pneumoniae causes pneumonia, sepsis and meningitis, often accompanied by strong inflammatory responses. S. pneumoniae expresses a sialidase (NanA) that contributes to mucosal colonization, platelet clearance, and blood-brain barrier penetration. Using wild-type and isogenic NanA-deficient mutant strains, we showed that S. pneumoniae NanA can desialylate the surface of human THP-1 monocytes, leading to increased ERK phosphorylation, NF-κB activation, and proinflammatory cytokine release. S. pneumoniae NanA expression also stimulates interleukin-8 release and extracellular trap formation from human neutrophils. A mechanistic contribution of unmasking of inhibitory Siglec-5 from cis sialic acid interactions to the proinflammatory effect of NanA is suggested by decreased SHP-2 recruitment to the Siglec-5 intracellular domain and RNA interference studies. Finally, NanA increased production of proinflammatory cytokines in a murine intranasal challenge model of S. pneumoniae pneumonia.Importance Sialic acids decorate the surface of all mammalian cells and play important roles in physiology, development, and evolution. Siglecs are sialic acid-binding receptors on the surface of immune cells, many of which engage in cis interactions with host sialoglycan ligands and dampen inflammatory responses through transduction of inhibitory signals. Recently, certain bacterial pathogens have been shown to suppress leukocyte innate immune responses by molecular mimicry of host sialic acid structures and engagement of inhibitory Siglecs. Our present work shows that the converse can be true, i.e., that a microbial sialic acid-cleaving enzyme can induce proinflammatory responses, which are in part mediated by unmasking of an inhibitory Siglec. We conclude that host leukocytes are poised to detect and respond to microbial sialidase activity with exaggerated inflammatory responses, which could be beneficial or detrimental to the host depending on the site, stage and magnitude of infection.

Inducing host protection in pneumococcal sepsis by preactivation of the Ashwell-Morell receptor

“…For example, NanA remodels mucosal cell surface glycoproteins to promote bacterial colonization of the upper respiratory tract (11,12) and contributes to pulmonary inflammation along with the development of SPN pneumonia (13,14). However, the host has adapted to counteract the pathological effects of this SPN virulence factor by the clearance from blood circulation of host factors bearing AMR ligands that have been unmasked by NanA desialylation.…”

Experimental model to study co-infection of human immunodeficiency virus-type 1 (HIV-1IIIB) and influenza virus in cell culture

“…Our hypothesis and results could be extended over other exogenous co-infections in HIV-infected people with agents containing NA; for example, Streptococcus pneumoniae [19,20] or Trypanosoma cruzi. [21] Moreover, without any regard to HIV infection, it has been reported that a number of sialylated Gps and glycolipids can be desialylated in vivo by interaction with endogenous cellular NAs, thus changing their function.…”

Competence-induced protein Ccs4 facilitates pneumococcal invasion into brain tissue and virulence in meningitis

“…CbpA binds to the cerebral endothelial laminin receptor and platelet-activating factor receptor [5,6], and those interactions induce pneumococcal invasion into the host brain. NanA, which localizes on bacterial cell surfaces by its cell-wall anchoring motif, activates hBMECs via its lectin-like domain and increases pneumococcal invasion into hBMECs [7,8]. Therefore, it was considered important to assess pneumococcal cbpA and nanA expressions of the Δ ccs4 strain.…”