Transcriptome Profiling Reveals CD73 and Age-Driven Changes in Neutrophil Responses against Streptococcus pneumoniae.

Neutrophils are required for host resistance against Streptococcus pneumoniae, but their function declines with age. We previously found that CD73, an enzyme required for antimicrobial activity, is downregulated in neutrophils (also known as polymorphonuclear leukocytes [PMNs]) from aged mice. This study explored transcriptional changes in neutrophils induced by S. pneumoniae to identify pathways controlled by CD73 and dysregulated with age. Pure bone marrow-derived neutrophils isolated from wild-type (WT) young and old and CD73 knockout (CD73KO) young mice were mock challenged or infected with S. pneumoniae ex vivo. RNA sequencing (RNA-Seq) was performed to identify differentially expressed genes (DEGs). We found that infection triggered distinct global transcriptional changes across hosts that were strongest in CD73KO neutrophils. Surprisingly, there were more downregulated than upregulated genes in all groups upon infection. Downregulated DEGs indicated a dampening of immune responses in old and CD73KO hosts. Further analysis revealed that CD73KO neutrophils expressed higher numbers of long noncoding RNAs (lncRNAs) than those in WT controls. Predicted network analysis indicated that CD73KO-specific lncRNAs control several signaling pathways. We found that genes in the c-Jun N-terminal kinase (JNK)-mitogen-activated protein kinase (MAPK) pathway were upregulated upon infection in CD73KO mice and in WT old mice, but not in WT young mice. This corresponded to functional differences, as phosphorylation of the downstream AP-1 transcription factor component c-Jun was significantly higher in neutrophils from infected CD73KO mice and old mice. Importantly, inhibition of JNK/AP-1 rescued the ability of these neutrophils to kill S. pneumoniae. Together, our findings revealed that the ability of neutrophils to modify their gene expression to better adapt to bacterial infection is in part regulated by CD73 and declines with age.

A1 adenosine receptor signaling reduces Streptococcus pneumoniae adherence to pulmonary epithelial cells by targeting expression of platelet-activating factor receptor.

Extracellular adenosine production is crucial for host resistance against Streptococcus pneumoniae (pneumococcus) and is thought to affect antibacterial immune responses by neutrophils. However, whether extracellular adenosine alters direct host-pathogen interaction remains unexplored. An important determinant for lung infection by S. pneumoniae is its ability to adhere to the pulmonary epithelium. Here we explored whether extracellular adenosine can directly impact bacterial adherence to lung epithelial cells. We found that signaling via A1 adenosine receptor significantly reduced the ability of pneumococci to bind human pulmonary epithelial cells. A1 receptor signaling blocked bacterial binding by reducing the expression of platelet-activating factor receptor, a host protein used by S. pneumoniae to adhere to host cells. In vivo, A1 was required for control of pneumococcal pneumonia as inhibiting it resulted in increased host susceptibility. As S. pneumoniae remain a leading cause of community-acquired pneumonia in the elderly, we explored the role of A1 in the age-driven susceptibility to infection. We found no difference in A1 pulmonary expression in young versus old mice. Strikingly, triggering A1 signaling boosted host resistance of old mice to S. pneumoniae pulmonary infection. This study demonstrates a novel mechanism by which extracellular adenosine modulates resistance to lung infection by targeting bacterial-host interactions.

Evaluating the Translational Potential of Bacteriocins as an Alternative Treatment for Staphylococcus aureus Infections in Animals and Humans.

Antibiotic resistance remains a global threat to human and animal health. Staphylococcus aureus is an opportunistic pathogen that causes minor to life-threatening infections. The widespread use of antibiotics in the clinical, veterinary, and agricultural setting combined with the increasing prevalence of antibiotic-resistant S. aureus strains makes it abundantly clear that alternatives to antibiotics are urgently needed. Bacteriocins represent one potential alternative therapeutic. They are antimicrobial peptides that are produced by bacteria that are generally nontoxic and have a relatively narrow target spectrum, and they leave many commensals and most mammalian cells unperturbed. Multiple studies involving bacteriocins (e.g., nisin, epidermicin, mersacidin, and lysostaphin) have demonstrated their efficacy at eliminating or treating a wide variety of S. aureus infections in animal models. This review provides a comprehensive and updated evaluation of animal studies involving bacteriocins and highlights their translational potential. The strengths and limitations associated with bacteriocin treatments compared with traditional antibiotic therapies are evaluated, and the challenges that are involved with implementing novel therapeutics are discussed.

Investigational agents for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia: progress in clinical trials.

INTRODUCTION: Bacteremia caused by Staphylococcus aureus is common. Cases caused by methicillin-resistant S. aureus (MRSA) are particularly formidable and often lethal. The mortality associated with MRSA bacteremia has not significantly decreased over the past couple of decades and concerns regarding efficacy and toxicity of standard therapy highlight the need for novel agents and new therapeutic approaches. AREAS COVERED: This paper explores clinical trials investigating novel therapeutic approaches to S. aureus bacteremia. There is a special focus on MRSA bacteremia. Monotherapy and combination therapies and novel antimicrobials and adjunctive therapies that are only recently being established for therapeutic use are discussed. EXPERT OPINION: The unfavorable safety profile of combination antimicrobial therapy in clinical trials has outweighed its benefits. Therefore, future investigation should focus on optimizing duration and de-escalation protocols. Antibody and bacteriophage lysin-based candidates have mostly been limited to safety trials, but progress with these agents is demonstrated through a lysin-based agent receiving a phase III trial. Antibiotics indicated for use in treating MRSA skin infections see continued investigation as treatments for MRSA bacteremia despite the difficulty of completing trials in this patient population. Promising agents include dalbavancin, ceftobiprole, ceftaroline, and exebacase.

Oxygen and Metabolism: Digesting Determinants of Antibiotic Susceptibility in the Gut.

Microbial metabolism is a major determinant of antibiotic susceptibility. Environmental conditions that modify metabolism, notably oxygen availability and redox potential, can directly fine-tune susceptibility to antibiotics. Despite this, relatively few studies have discussed these modifications within the gastrointestinal tract and their implication on in vivo drug activity and the off-target effects of antibiotics in the gut. In this review, we discuss the environmental and biogeographical complexity of the gastrointestinal tract in regard to oxygen availability and redox potential, addressing how the heterogeneity of gut microhabitats may modify antibiotic activity in vivo. We contextualize the current literature surrounding oxygen availability and antibiotic efficacy and discuss empirical treatments. We end by discussing predicted patterns of antibiotic activity in prominent microbiome taxa, given gut heterogeneity, oxygen availability, and polymicrobial interactions. We also propose additional work required to fully elucidate the role of oxygen metabolism on antibiotic susceptibility in the context of the gut.