Genetic requirements forStaphylococcus aureusabscess formation and persistence in host tissues

Abstract

Staphylococcus aureus infections are associated with abscess formation and bacterial persistence; however, the genes that enable this lifestyle are not known. We show here that following intravenous infection of mice, S. aureus disseminates rapidly into organ tissues and elicits abscess lesions that develop over weeks but cannot be cleared by the host. Staphylococci grow as communities at the center of abscess lesions and are enclosed by pseudocapsules, separating the pathogen from immune cells. By testing insertional variants in genes for cell wall-anchored surface proteins, we are able to infer the stage at which these molecules function. Fibrinogen-binding proteins ClfA and ClfB are required during the early phase of staphylococcal dissemination. The heme scavenging factors IsdA and IsdB, as well as SdrD and protein A, are necessary for abscess formation. Envelope-associated proteins, Emp and Eap, are either required for abscess formation or contribute to persistence. Fluorescence microscopy revealed Eap deposition within the pseudocapsule, whereas Emp was localized within staphylococcal abscess communities. Antibodies directed against envelope-associated proteins generated vaccine protection against staphylococcal abscess formation. Thus, staphylococci employ envelope proteins at discrete stages of a developmental program that enables abscess formation and bacterial persistence in host tissues.

Naturally occurring IgG antibody levels to theStaphylococcus aureusprotein IsdB in humans

“…Importantly, enhanced protection from lethal sepsis in rodent models was mediated by both IsdB-specific CD4+ T cells, 16 and IsdB-specific mAb. 10,13,[17][18][19] The protection afforded by vaccination with IsdB in rodents was lost if the animals were challenged with an IsdB fluid (9), surgical tissue (22), synovial fluid (17), sputum (9), or other sites (5) during routine clinical care. Of the 52 S. aureus isolates, 51 were spa typed; a single isolate failed to grow sufficiently in culture for spa determination.…”

Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase

“…Genome sequencing revealed that all S. aureus isolates encode 17-21 surface proteins with LPXTG sorting signals, which fulfill diverse functions during the infectious process (11). SrtA mutants cannot assemble surface proteins into their envelope and are unable to form abscess lesions in organ tissues or cause lethal bacteremia when inoculated into the bloodstream of mice (12,13). In contrast, mutations that abrogate the expression of secreted virulence factors may cause attenuation but do not abrogate the ability of S. aureus to cause infectious diseases (12).…”

Propofol Sedation Exacerbates Kidney Pathology and Dissemination of Bacteria during Staphylococcus aureus Bloodstream Infections

“…Monocytes and macrophages are important for the efficient formation of abscesses in response to tissue injury or infection, and studies have shown that monocytes direct interstitial migration of neutrophils through tissues to effectively form abscesses (59). Additional studies have suggested that macrophage recruitment occurs after inflammatory neutrophilic infiltrate has formed focal abscesses surrounding sites of infection, and these macrophages serve to limit the size of the abscess (39) and the associated tissue damage through phagocytosis of necrotic neutrophil cell debris (36). At early time points following acute MRSA infection in the presence of propofol, monocyte/macrophage populations did not appear significantly different in absolute numbers between drug-treated and non-drug-treated control animals; however, by 14 days postinfection anesthetized animals exhibited distinct phenotypic differences in immune effector cell populations (Fig.…”

“…Host immunity to both local and systemic MRSA infections depends on neutrophil chemotaxis to sites of infection (45,65); in the kidney, abscess formation results in the "walling off" of discrete foci of pathogenic infiltrate by initially surrounding bacteria with an eosinophilic pseudocapsule (66) with subsequent neutrophil recruitment to surround the pseudocapsule (36). The overall size of the abscess can be limited by fibrin deposits that serve to partition areas of inflammation from healthy tissue (67).…”

“…Interestingly, inflammation in kidneys isolated from control animals was limited to the kidney cortex at 14 days postinfection (Fig. 3A, left), with bacteria efficiently walled off within eosinophilic pseudocapsules (36) (Fig. 2B, second row).…”