Ribosomal Protein SA-Positive Neutrophil Elicits Stronger Phagocytosis and Neutrophil Extracellular Trap Formation and Subdues Pro-Inflammatory Cytokine Secretion Against Streptococcus suis Serotype 2 Infection

Abstract

Streptococcus suis serotype 2 (SS2), an important zoonotic pathogen that causes septicemia, arthritis, and irreversible meningitis in pigs and humans, can be transmitted to humans from pigs. S. suis causes huge economic losses to the swine industry and poses a serious threat to public health. Previously, we found that the brain tissues of mice with SS2-induced meningitis showed disrupted structural integrity and significantly enhanced polymorphonuclear neutrophil (PMN) infiltration. We showed that the brain tissues of SS2-infected mice had increased ribosomal protein SA (RPSA)-positive PMN counts. However, the inflammatory responses of RPSA+ PMNs to SS2 and their effects on the blood-brain barrier (BBB) remain unclear. Therefore, in studying the pathogenesis of SS2-induced meningitis, it is essential that we explore the functions of RPSA+ PMNs and their effects on the BBB. Herein, using flow cytometry and immunofluorescence microscopy analyses, we found that RPSA expression enhances PMN-induced phagocytosis and PMN-induced formation of neutrophil extracellular traps (NETs), which facilitate further elimination of bacteria. PMN surface expression of RPSA also alleviates local inflammation and tissue injuries by inhibiting secretion of the pro-inflammatory cytokines, TNF-α and IL-6. Moreover, the single-cell BBB model showed that RPSA disrupts BBB integrity by downregulating expression of tight junction-associated membrane proteins on PMNs. Taken together, our data suggest that PMN-surface expression of RPSA is a double-edged sword. RPSA+ PMN owns a stronger ability of bacterial cleaning and weakens inflammatory cytokines release which are useful to anti-infection, but does hurt BBB. Partly, RPSA+ PMN may be extremely useful to control the infection as a therapeutic cellular population, following novel insights into the special PMN population.

Neutrophils in Streptococcus suis Infection: From Host Defense to Pathology

“…In the CNS, neutrophil infiltration would then be a consequence of the inflammation, and not a cause, such as in the systemic infection. Some studies confirmed that neutrophils contribute to the clearance of S. suis in the CNS since a higher neutrophil mobilization in the brain is associated with a decrease of bacterial load [76,133].…”

“…Among the 46 articles studying in vitro activation of neutrophils by S. suis, only 13 studies (28%) measured neutrophil purity after isolation [44,45,54,62,[69][70][71][72][73][74][75][76][77] (Figure 3). A diversity of methods were used to assess cell purity: Giemsa/Wright's stain [44,73,74], Hoechst stain (microscopy) [71,72] or flow cytometry using different markers (for exam-ple, Ly6G+, CD11b+) [54,[75][76][77]. However, in these studies, the purity was comprised between 75% and 97% and the high risk of contaminating cells probably compromised the interpretation of the results when the purity was low.…”

“…Neutrophils seem to be involved not only in the systemic response to S. suis infection but also in CNS disease. Indeed, neutrophils infiltrate the brain in the course of the infection and studies recently quantified this infiltration, either after intraperitoneal or intracisternal infection in mouse models [76,77,133,145]. In pigs, only a study highlighted the presence of neutrophils in the brain of animals with meningitis by confocal microscopy [108].…”

Research Progress on the pathogenic mechanism of Streptococcus suis 2

“…Inflammation plays a crucial role in the pathogenesis of systemic and CNS infections caused by SS2 (Gottschalk et al, 2010). The pathogen induces excessive production of proinflammatory cytokines and recruitment and activation of different leukocyte populations, leading to inflammation in the central system (Sun et al, 2020). Central nervous system inflammation can lead to intracranial complications, including cerebral edema, increased intracranial pressure, and cerebrovascular damage (Fittipaldi et al, 2012).…”

Identification of RPSA as a Potential Biomarker in Bronchoalveolar Lavage Fluid for Acute Respiratory Distress Syndrome

“…Vania et al [17] showed that RPSA is involved in maintaining cell viability through apoptotic evasion, allowing tumor progression. RPSA is a complex protein with diverse functions and plays a major role in an in ammatory response, mediating cell adhesion, migration, proliferation, and survival [18][19][20].…”