Human HLA prolongs the host inflammatory response in Streptococcus suis serotype 2 infection compared to mouse H2 molecules.

Streptococcus suis (S. suis) is widely acknowledged as a significant zoonotic pathogen in Southeast Asia and China, which has led to a substantial number of fatalities in both swine and humans. Despite the prevalent use of mice as the primary animal model to study S. suis pathogenesis, the substantial differences in the major histocompatibility complex (MHC) between humans and mice underscore the ongoing exploration for a more suitable and effective animal model. In this study, humanized transgenic HLA-A11/DR1 genotypes mice were used to evaluate the differences between humanized HLA and murine H2 in S. suis infection. Following intravenous administration of S. suis suspensions, we investigated bacterial load, cytokine profiles, pathological alterations, and immune cell recruitment in both Wild-type (WT) and humanized mice across different post-infection time points. Relative to WT mice, humanized mice exhibited heightened pro-inflammatory cytokines, exacerbated tissue damage, increased granulocyte recruitment with impaired resolution, notably more pronounced during the late infection stage. Additionally, our examination of bacterial clearance rates suggests that HLA-A11/DR1 primarily influences cell recruitment and mitochondrial reactive oxygen species (ROS) production, which affects the bacterial killing capacity of macrophages in the late stage of infection. The reduced IL-10 production and lower levels of regulatory T cells in humanized mice could underlie their compromised resolution ability. Intervention with IL-10 promotes bacterial clearance and inflammatory regression in the late stages of infection in transgenic mice. Our findings underscore the heightened sensitivity of HLA-A11/DR1 mice with impaired resolution to S. suis infection, effectively mirroring the immune response seen in humans during infection. The humanized HLA-A11/DR1 mice could serve as an optimal animal model for investigating the pathogenic and therapeutic mechanisms associated with sepsis and other infectious diseases.

Fpr2 exacerbates Streptococcus suis-induced streptococcal toxic shock-like syndrome via attenuation of neutrophil recruitment.

The life-threatening disease streptococcal toxic shock-like syndrome (STSLS), caused by the bacterial pathogen Streptococcus suis (S. suis). Proinflammatory markers, bacterial load, granulocyte recruitment, and neutrophil extracellular traps (NETs) levels were monitored in wild-type (WT) and Fpr2-/- mice suffering from STSLS. LXA4 and AnxA1, anti-inflammatory mediators related to Fpr2, were used to identity a potential role of the Fpr2 in STSLS development. We also elucidated the function of Fpr2 at different infection sites by comparing the STSLS model with the S. suis-meningitis model. Compared with the WT mice, Fpr2-/- mice exhibited a reduced inflammatory response and bacterial load, and increased neutrophil recruitment. Pretreatment with AnxA1 or LXA4 impaired leukocyte recruitment and increased both bacterial load and inflammatory reactions in WT but not Fpr2-/- mice experiencing STSLS. These results indicated that Fpr2 impairs neutrophil recruitment during STSLS, and this impairment is enhanced by AnxA1 or LXA4. By comparing the functions of Fpr2 in different S. suis infection models, inflammation and NETs was found to hinder bacterial clearance in S. suis meningitis, and conversely accelerate bacterial clearance in STSLS. Therefore, interference with neutrophil recruitment could potentially be harnessed to develop new treatments for this infectious disease.

Annexin A1 Attenuates Neutrophil Migration and IL-6 Expression through Fpr2 in a Mouse Model of Streptococcus suis-Induced Meningitis.

Streptococcus suis serotype 2 is a crucial pathogenic cause of bacterial meningitis, a life-threatening disease with neurological sequelae and high rates of mortality. Inflammation triggered by S. suis infection must be precisely regulated to prevent further tissue damage. As a glucocorticoid anti-inflammatory mediator, annexin A1 (AnxA1) mainly acts through formyl peptide receptor 2 (Fpr2) to alleviate inflammation in the peripheral system. In this study, we evaluated the roles of AnxA1 and Fpr2 in a mouse model of S. suis meningitis created via intracisternal infection in Fpr2-deficient (Fpr2-/-) and wild-type (WT) mice. We revealed that Fpr2-/- mice were highly susceptible to S. suis meningitis, displaying increased inflammatory cytokine levels, bacterial dissemination, and neutrophil migration compared with WT mice. Additionally, AnxA1 exerted anti-inflammatory effects through Fpr2, such as attenuation of leukocyte infiltration, inflammatory mediator production, and astrocyte or microglial activation in the brain. Importantly, we found that the antimigratory function of AnxA1 decreases neutrophil adherence to the endothelium through Fpr2. Finally, an in vitro study revealed that AnxA1 potentially suppresses interleukin-6 (IL-6) expression through the Fpr2/p38/COX-2 pathway. These data demonstrated that Fpr2 is an anti-inflammatory receptor that regulates neutrophil migration in mice with S. suis meningitis and identified AnxA1 as a potential therapeutic option.

The interaction between flagellin and the glycosphingolipid Gb3 on host cells contributes to Bacillus cereus acute infection.

BACILLUS CEREUS: is an opportunistic pathogen that can cause emetic or diarrheal foodborne illness. Previous studies have identified multiple pathogenic B. cereus strains and characterized a variety of virulence factors. Here, we demonstrate that the virulence and lethality of B. cereus for mammalian cells and host animals involve the interaction of B. cereus flagellin proteins and the host-cell-surface-localized glycosphingolipid Gb3 (CD77, Galα1-4Galß1-4Glcß1-Cer). We initially found that B. cereus infection was less lethal for Gb3-deficiencient A4galt-/- mice than for wild-type mice. Subsequent experiments established that some factor other than secreted toxins must account of the observed differential lethality: Gb3-deficiencient A4galt-/- mice were equally susceptible to secreted-virulence-factor-mediated death as WT mice, and we observed no differences in the bacterial loads of spleens or livers of mice treated with B. cereus strain vs. mice infected with a mutant variant of incapable of producing many secreted toxins. A screen for host-interacting B. cereus cell wall components identified the well-known flagellin protein, and both flagellin knockout strain assays and Gb3 inhibitor studies confirmed that flagellin does interact with Gb3 in a manner that affects B. cereus infection of host cells. Finally, we show that treatment with polyclonal antibody against flagellin can protect mice against B. cereus infection. Thus, beyond demonstrating a previously unappreciated interaction between a bacterial motor protein and a mammalian cell wall glycosphingolipid, our study will provide useful information for the development of therapies to treat infection of B. cereus.

Vitamin D induces autophagy of pancreatic ß-cells and enhances insulin secretion.

Epidemiological evidence indicates that vitamin D is involved in defense against diabetes; however, the precise underlying mechanism remains to be elucidated. In the present study, the effect of vitamin D on the pathogenesis of diabetes was investigated, with an emphasis on its direct effect on pancreatic ß­cells. A streptozotocin (STZ)­induced type 1 diabetes mellitus (T1DM) mouse model and MIN6 mouse insulinoma ß­cells were subjected to vitamin D treatment. Histopathological analysis of pancreatic islets was performed to investigate insulitis, and reverse transcription-quantitative polymerase chain reaction and western blotting were used to determine the mRNA and protein expression levels of markers of autophagy [microtubule-associated protein 1A/1B­light chain 3 (LC3) and Beclin 1] and regulation of apoptosis [B-cell lymphoma 2 (Bcl-2)]. Apoptosis of MIN6 cells was examined by flow cytometry following annexin V/propidium iodide labeling. The secretion of insulin was measured by ELISA. The results revealed that vitamin D reduced the incidence of T1DM, enhanced insulin secretion and relieved pancreatic inflammation in STZ­treated mice. Furthermore, vitamin D increased the mRNA expression levels of LC3 and Beclin 1, and increased Bcl­2 protein expression levels in STZ­treated MIN6 cells, while decreasing the apoptosis rate. The results of the present study demonstrated, for the first time to the best of our knowledge, that vitamin D induces autophagy and suppresses apoptosis of pancreatic ß­cells, as well as preventing insulitis. These findings regarding vitamin D provide insights into its involvement in diabetes, and suggest a potential novel strategy for the treatment of diabetes via agents enhancing autophagy in pancreatic ß-cells.