RESUMO
The peroxide response transcriptional regulator, PerR, is thought to contribute to virulence of group A Streptococcus (GAS); however, the specific mechanism through which it enhances adaptation for survival in the human host remains unknown. Here, we identify a critical role of PerR-regulated gene expression in GAS phagocytosis resistance and in virulence during pharyngeal infection. Deletion of perR in M-type 3 strain 003Sm was associated with reduced resistance to phagocytic killing in human blood and by murine macrophages in vitro. The increased phagocytic killing of the perR mutant was abrogated in the presence of the general oxidative burst inhibitor diphenyleneiodonium chloride (DPI), a result that suggests PerR-dependent gene expression counteracts the phagocyte oxidative burst. Moreover, an isogenic perR mutant was severely attenuated in a baboon model of GAS pharyngitis. In competitive infection experiments, the perR mutant was cleared from two animals at 24 h and from four of five animals by day 14, in sharp contrast to wild-type bacteria that persisted in the same five animals for 28 to 42 d. GAS genomic microarrays were used to compare wild-type and perR mutant transcriptomes in order to characterize the PerR regulon of GAS. These studies identified 42 PerR-dependent loci, the majority of which had not been previously recognized. Surprisingly, a large proportion of these loci are involved in sugar utilization and transport, in addition to oxidative stress adaptive responses and virulence. This finding suggests a novel role for PerR in mediating sugar uptake and utilization that, together with phagocytic killing resistance, may contribute to GAS fitness in the infected host. We conclude that PerR controls expression of a diverse regulon that enhances GAS resistance to phagocytic killing and allows adaptation for survival in the pharynx.
Assuntos
Proteínas de Bactérias/fisiologia , Viabilidade Microbiana , Proteínas Repressoras/fisiologia , Streptococcus pyogenes/patogenicidade , Fatores de Transcrição/fisiologia , Metabolismo dos Carboidratos/genética , Perfilação da Expressão Gênica , Humanos , Viabilidade Microbiana/genética , Estresse Oxidativo/genética , Faringe , Streptococcus pyogenes/genética , Virulência/genéticaRESUMO
A 4.3-y-old, colony-bred female baboon (Papio hamadryas anubis) of low social rank and exhibiting no clinically significant signs of illness or distress was found dead at the Oklahoma University Health Sciences Center baboon breeding facility at El Reno, OK. Prior to death she exhibited excessive grooming behavior both toward herself and other baboons. In addition, she was consistently shy, timid, reclusive, and prone to minimal sustained movement (that is, generally lethargic behavior). Animals of low social rank typically exhibit some degree of these behaviors in order to avoid surplus interactions with other animals within their groups, which can lead to conflict and injury. Accordingly, her death was surprising in view of the apparent lack of clinical signs. Necropsy established the cause for death as systemic shock with resultant cardiovascular collapse resulting from a massive jejunal intussusception. This intussusception and resulting entrapment of the jejunal mesenteric vasculature caused total occlusion of the small bowel blood supply, with resulting hemorrhage and ischemic necrosis (small bowel infarction). Jejunal intussusceptions generally are considered to be uncommon and therefore are rarely reported in either the veterinary or human literature. Of special interest was the cause for this intussusception, determined to have been a large hairball located at the most proximal portion of the jejunum. Extending from this hairball and traversing essentially the entire length of the jejunum was a braided strand of hair acting as a string foreign body about which the intussusception formed. In light of our findings we suggest that animals of low social rank exhibiting excessive grooming behavior and lethargy might merit clinical evaluation to rule out possible abdominal disorders.