Targeting TREM-1 Signaling in the Presence of Antibiotics is Effective Against Streptococcal Toxic-Shock-Like Syndrome (STSLS) Caused by Streptococcus suis

Abstract

Streptococcus suis (S.suis), a major swine pathogen, is also a severe threat to human health. Infection with highly virulent strains of S. suis can cause human Streptococcal toxic-shock-like syndrome (STSLS), which is associated with high serum pro-inflammatory cytokine levels and a high mortality rate. Our previous study indicated that highly virulent S. suis infection could activate the TREM-1 signaling pathway, which promotes host clearance of S. suis during early infection. However, it remained to be elicited whether TREM-1 signaling could be a target against STSLS in the presence of antibiotic. In the present study, mice were infected with a highly virulent S. suis strain and then treated with rTREM-1 (the recombinant extracellular domain of TREM-1) to block TREM-1 signaling, antibiotics, both rTREM-1 and antibiotics, or PBS. The survival rates, clinical signs, serum IL-1β and TNF-α levels, and serum bacterial loads were evaluated. Treatment with rTREM-1 could aggravate the outcome of infection as described previously. Although the conventional treatment with antibiotics contributed to effective S. suis clearance, it did not improve survival significantly. In comparison, due to the reduction of the exaggerated pro-inflammatory response, treatment combined with rTREM-1 and antibiotics not only led to efficient bacterial clearance but also alleviated inflammation. In conclusion, TREM-1 signaling contributed to severe inflammatory response and benefited S. suis clearance. Therefore, blocking TREM-1 signaling could still be a target for the treatment of STSLS in the presence of antibiotics.

Triggering Receptor Expressed on Myeloid Cells-1 Signaling: Protective and Pathogenic Roles on Streptococcal Toxic-Shock-Like Syndrome Caused by Streptococcus suis

“…At present, the function of sTREM is not fully understood. It is possible that sTREM-1 may negatively regulate receptor signaling through neutralization of the ligands, which is supported by the findings that the TREM-1 signaling could be significantly inhibited by a fusion protein containing the TREM-1 extracellular domain and human IgG1 Fc fragment ( 23 ) or the recombinant TREM-1 extracellular domain ( 57 ).…”

“…To directly evaluate the role of TREM-1 on causing severe inflammation, an inhibitor of TREM-1 signaling was used in the presence of antibiotics, although the treatment effectiveness on S. suis infection remains controversial ( 18 ). Treatment with ampicillin alone could kill bacterial efficiently and also reduce the inflammatory cytokine response; however, it cannot significantly improve survival rates ( 57 ). These findings are similar to the outcomes of the clinical treatment of pigs and humans during S. suis infection.…”

“…These findings are similar to the outcomes of the clinical treatment of pigs and humans during S. suis infection. However, killing the bacteria and blocking the TREM-1-mediated inflammatory response at the same time could effectively alleviate the severe inflammation and protect the host against epidemic S. suis infection ( 57 ). Thus, these results indicate that TREM-1 signaling also contributes to the development of severe inflammation and STSLS.…”

The Impact of SsPI-1 Deletion on Streptococcus suis Virulence

“…A retrospective clinical study revealed that serum levels of proinflammatory cytokines were significantly more elevated in patients with STSLS than in those with meningitis only [22]. It later became established that the onset of a cytokine storm was essential for STSLS development and the associated high mortality [23][24][25]. Since the SsPI-1 PAI is specifically present in the genome of the epidemic S. suis strains but not in other clinical isolates [11], it is reasonable to propose that acquisition of SsPI-1 enables the strain to have the ability to cause a higher level of inflammatory cytokine production and subsequent STSLS development.…”

Identification of Extracellular Actin As a Ligand for Triggering Receptor Expressed on Myeloid Cells-1 Signaling

“…It can be induced at high levels on neutrophils and monocytes and further amplifies Toll-like receptor-initiated responses against microbial challenges, potentiating the secretion of pro-inflammatory cytokines with the help of the DAP12 adaptor protein in response to bacterial and fungal infections ( 6 – 8 ). Due to the key role of TREM-1 in amplifying the inflammatory response, TREM-1 was identified as an essential regulator of innate immunity in sepsis syndrome ( 9 , 10 ), and it was confirmed to be an attractive target for the treatment of sepsis ( 6 , 11 – 14 ). The natural ligand for TREM-1 is present on platelets ( 15 ), which is indispensable for regulating inflammatory processes such as sepsis ( 16 ).…”