Abstract
Staphylococcus aureus is able to survive within host cells by switching its phenotype to the small-colony variant (SCV) phenotype. The emergence of SCVs is associated with the development of persistent infections, which may be both chronic and recurrent. This slow-growing subpopulation of S. aureus forms small colonies on solid-medium agar, is induced within host cells, presents a non-homogenous genetic background, has reduced expression of virulence factors and presents a variable phenotype (stable or unstable). While virtually all SCVs isolated from clinical specimens can revert to the parental state with rapid growth, the stable SCVs recovered in clinical specimens have been found to contain specific mutations in metabolic pathways. In contrast, other non-stable SCVs are originated from regulatory mechanisms involving global regulators (e.g., sigB, sarA, and agr) or other non-defined mutations. One major characteristic of SCVs was the observation that SCVs were recovered from five patients with infections that could persist for decades. In these five cases, the SCVs had defects in electron transport. This linked persistent infections with SCVs. The term “persistent infection” is a clinical term wherein bacteria remain in the host for prolonged periods of time, sometimes with recurrent infection, despite apparently active antibiotics. These terms were described in vitro where bacteria remain viable in liquid culture medium in the presence of antibiotics. These bacteria are called “persisters”. While SCVs can be persisters in liquid culture, not all persisters are SCVs. One mechanism associated with the metabolically variant SCVs is the reduced production of virulence factors. SCVs have consistently shown reduced levels of RNAIII, a product of the accessory gene regulatory (agrBDCA) locus that controls a quorum-sensing system and regulates the expression of a large number of virulence genes. Reduced Agr acitivity is associated with enhanced survival of SCVs within host cells. In this review, we examine the impact of the SCVs with altered metabolic pathways on agr, and we draw distinctions with other types of SCVs that emerge within mammalian cells with prolonged infection.
Highlights
The history of Staphylococcus aureus infections parallels the history of bacterial infections in general (Proctor, 2016)
Some of these phenomena were anticipated by the studies of Bigger in 1944 who showed that when staphylococci were exposed to penicillin, a small number of survivors remained viable despite exposure to bactericidal antibiotics (Bigger, 1944), and he designated this subpopulation as “persisters.” Since 1944, persisters have been a very reasonable postulate for antibiotic failures
Several pathways have been found to impact the growth rate of S. aureus and enhance the formation of small-colony variant (SCV), such as pathways related to energetic supplies (ATP), electron transport, cell wall biosynthesis, global regulatory genes, CO2 and fatty acids
Summary
The history of Staphylococcus aureus infections parallels the history of bacterial infections in general (Proctor, 2016). Data have accumulated over the past three decades, and SCVs are the best characterized subpopulation of bacteria recovered from chronic human infections. These SCVs are often extremely difficult to clear even when combined antimicrobial therapies are employed (Loffler et al, 2014; Tuchscherr et al, 2016; Bui et al, 2017). SCV phenotypes, associated with chronic infections, express fewer virulence factors than wild-type phenotypes and hide within human cells (Proctor et al, 2006; Tuchscherr et al, 2010b). These effects are dependent upon the reduced activity of the Agr system. An exploration of the pathways that contribute to altered agr regulation in stable and non-stable SCVs of S. aureus is presented
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