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The programmed cell death protein 1 (PD-1) plays a critical role in cancer immune evasion. Blocking the PD-1-PD-L1 interaction by monoclonal antibodies has shown remarkable clinical efficacy in treating certain types of cancer. However, antibodies are costly to produce, and antibody-based therapies can cause immune-related adverse events. To address the limitations associated with current PD-1/PD-L1 blockade immunotherapy, we aimed to develop peptide-based inhibitors of the PD-1/PD-L1 interaction as an alternative means to PD-1/PD-L1 blockade antibodies for anti-cancer immunotherapy. Through the functional screening of peptide arrays encompassing the ectodomains of PD-1 and PD-L1, followed by the optimization of the hit peptides for solubility and stability, we have identified a 16-mer peptide, named mL7N, with a remarkable efficacy in blocking the PD-1/PD-L1 interaction both in vitro and in vivo. The mL7N peptide effectively rejuvenated PD-1-suppressed T cells in multiple cellular systems designed to recapitulate the PD-1/PD-L1 interaction in the context of T-cell receptor signaling. Furthermore, PA-mL7N, a chimera of the mL7N peptide coupled to albumin-binding palmitic acid (PA), significantly promoted breast cancer cell killing by peripheral blood mononuclear cells ex vivo and significantly curbed tumor growth in a syngeneic mouse model of breast cancer. Our work raises the prospect that mL7N may serve as a prototype for the development of a new line of peptide-based immunomodulators targeting the PD-1/PD-L1 immune checkpoint with potential applications in cancer treatment. [ABSTRACT FROM AUTHOR]

Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory syndrome associated with SARS-CoV-2 infection, shares clinical features with toxic shock syndrome, which is triggered by bacterial superantigens. Superantigen specificity for different V[beta] chains results in V[beta] skewing, whereby T cells with specific V[beta] chains and diverse antigen specificity are overrepresented in the T cell receptor (TCR) repertoire. Here, we characterized the TCR repertoire of MIS-C patients and found a profound expansion of TCR[beta] variable gene 11-2 (TRBV11-2), with up to 24% of clonal T cell space occupied by TRBV112 T cells, which correlated with MIS-C severity and serum cytokine levels. Analysis of TRBJ gene usage and complementarity-determining region 3 (CDR3) length distribution of MIS-C expanded TRBV11-2 clones revealed extensive junctional diversity. Patients with TRBV11-2 expansion shared HLA class I alleles A02, B35, and C04, indicating what we believe is a novel mechanism for CDR3-independent T cell expansion. In silico modeling indicated that polyacidic residues in the V[beta] chain encoded by TRBV11-2 (V[beta]21.3) strongly interact with the superantigen- like motif of SARS-CoV-2 spike glycoprotein, suggesting that unprocessed SARS-CoV-2 spike may directly mediate TRBV11-2 expansion. Overall, our data indicate that a CDR3-independent interaction between SARS-CoV-2 spike and TCR leads to T cell expansion and possibly activation, which may account for the clinical presentation of MIS-C., Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which started as an epidemic in China and culminated in a global pandemic. [...]

In Staphylococcus aureus, genes that should confer the capacity to metabolize fatty acids by β‐oxidation occur in the fadXDEBA locus, but their function has not been elucidated. Previously, incorporation into phospholipid through the fatty acid kinase FakA pathway was thought to be the only option available for S. aureus to metabolize exogenous saturated fatty acids. We now find that in S. aureus USA300, a fadX::lux reporter was repressed by glucose and induced by palmitic acid but not stearic acid, while in USA300ΔfakA basal expression was significantly elevated, and enhanced in response to both fatty acids. When cultures were supplemented with palmitic acid, palmitoyl‐CoA representing the first metabolite in the β‐oxidation pathway was detected in USA300, but not in a fadXDEBA deletion mutant USA300Δfad, which relative to USA300 exhibited increased incorporation of palmitic acid into phospholipid accompanied by a rapid loss of viability. USA300Δfad also exhibited significantly reduced viability in a murine tissue abscess infection model. Our data are consistent with FakA‐mediated incorporation of fatty acids into phospholipid as a preferred pathway for metabolism of exogenous fatty acids, while the fad locus is critical for metabolism of palmitic acid, which is the most abundant free fatty acid in human plasma. [ABSTRACT FROM AUTHOR]

Staphylococcal superantigens are pyrogenic exotoxins that cause massive T cell activation leading to toxic shock syndrome and death. Despite the strong adaptive immune response induced by these toxins, infections by superantigen-producing staphylococci are very common clinical events. We hypothesized that this may be partly a result of staphylococcal strains having developed strategies that downregulate the T cell response to these toxins. Here we show that the human interleukin-2 response to staphylococcal superantigens is inhibited by the simultaneous presence of bacteria. Such a downregulatory effect is the result of peptidoglycan-embedded molecules binding to Toll-like receptor 2 and inducing interleukin-10 production and apoptosis of antigen-presenting cells. We corroborated these findings in vivo by showing substantial prevention of mortality after simultaneous administration of staphylococcal enterotoxin B with either heat-killed staphylococci or Staphylococcus aureus peptidoglycan in mouse models of superantigen-induced toxic shock syndrome., S. aureus is a common human commensal organism, present in the upper respiratory tract of 25-50% of the population (1). It is also one of the most frequent pathogens, being [...]

Lactobacillus reuteri RC-14 has previously been shown to inhibit Staphylococcus aureus infection in a rat surgical-implant model. To investigate the basis for this, communication events between the two bacterial species were examined. L. reuteri RC-14 and Staph. aureus Newman were grown in a co-culture apparatus that physically separates the two species, while allowing the passage of soluble compounds. Using two-dimensional gel electrophoresis (2D-E), protein expression changes in Staph. aureus were analysed in response to co-culture with medium alone, L. reuteri RC-14, and a Lactobacillus strain that did not inhibit Staph. aureus infection in the rat model. It was observed that one protein in particular, identified as staphylococcal superantigen-like protein 11 (SSL11), showed a dramatic decrease in expression in response to growth with L. reuteri RC-14. Genetic reporters that placed both gfp and lux under the transcriptional control of the SSL11 promoter confirmed the 2D-E results. Interestingly, using similar reporter gene experiments, it was observed that the Staph. aureus P3 promoter from the staphylococcal accessory gene regulator (agr) locus also showed a decrease in expression in response to growth in the presence of L. reuteri RC-14. It was further demonstrated that L. reuteri RC-14 supernatant contained small unidentified molecules that were able to repress the SSL11 and P3 promoters, but the repression of SSL11 occurred independently of the agr system. These results suggest that L. reuteri RC-14 has the potential to alter the virulence of Staph. aureus via secretion of cell-cell signalling molecules.

Results show that expression of the accessory gene regulator, agr locus, is repressed in serum and in vivo, in Staphylococcus aureus, even when virulence factors expression is high enough to cause toxic shock syndrome in the animals.

Research demonstrates that the environmental oxygen levels regulate the production of both exotoxin and virulence factors by the two-component system, staphylococcal respiratory response (Srr)A-SrrB. Results indicate that SrrA-SrrB may be involved in the anaerobic repression of the virulence factors.

Key Words Staphylococcus aureus, Streptococcus pyogenes, hypotension, T cell stimulation Abstract Toxic shock syndrome (TSS) is an acute onset illness characterized by fever, rash formation, and hypotension that can lead [...]

Strains of Carnobacterium divergens, LV13 and C. piscicola produce carnobacteriocin B2 through a general signal peptide-dependent secretory pathway. Carnobacteriocin B2 is a broad spectrum bacteriocin that is active against lactic acid bacteria. The export of this bacteriocin depends on specific ATP-binding cassette secretion proteins. C.divergens LV13, which produces divergicin A and carnobacteriocin B2, exhibits multiple bacteriocin expression through the general secretory pathway.