Suppression of the Inflammatory Immune Response Prevents the Development of Chronic Biofilm Infection Due to Methicillin-Resistant Staphylococcus aureus

Abstract

Staphylococcus aureus is a common cause of prosthetic implant infections, which can become chronic due to the ability of S. aureus to grow as a biofilm. Little is known about adaptive immune responses to these infections in vivo. We hypothesized that S. aureus elicits inflammatory Th1/Th17 responses, associated with biofilm formation, instead of protective Th2/Treg responses. We used an adapted mouse model of biofilm-mediated prosthetic implant infection to determine chronic infection rates, Treg cell frequencies, and local cytokine levels in Th1-biased C57BL/6 and Th2-biased BALB/c mice. All C57BL/6 mice developed chronic S. aureus implant infection at all time points tested. However, over 75% of BALB/c mice spontaneously cleared the infection without adjunctive therapy and demonstrated higher levels of Th2 cytokines and anti-inflammatory Treg cells. When chronic infection rates in mice deficient in the Th2 cytokine interleukin-4 (IL-4) via STAT6 mutation in a BALB/c background were assessed, the mice were unable to clear the S. aureus implant infection. Additionally, BALB/c mice depleted of Treg cells via an anti-CD25 monoclonal antibody (MAb) were also unable to clear the infection. In contrast, the C57BL/6 mice that were susceptible to infection were able to eliminate S. aureus biofilm populations on infected intramedullary pins once the Th1 and Th17 responses were diminished by MAb treatment with anti-IL-12 p40. Together, these results indicate that Th2/Treg responses are mechanisms of protection against chronic S. aureus implant infection, as opposed to Th1/Th17 responses, which may play a role in the development of chronic infection.

Coxsackievirus A16 infection stimulates imbalances of T cells in children

“…At present, a significant amount of evidence indicates that inappropriate inflammation participates in the progression of HFMD (11,13). However, when more mild and benign symptoms are present following infection, little information has been unveiled concerning the adaptive immunity of the infected host.…”

“…This secretion specificity and the different kinds of T cell subsets are in balance under normal conditions; however, when organisms suffer from an infectious disease, the system becomes imbalanced. For example, following Staphylococcus aureus implant infection, the Th1/Th17 response increased while Th2/Treg also responded to chronic infection (13). In EV71-infected patients with HFMD, the percentages of Th1, Tc1 and Th17 cells were found to be increased, and the Th1/Th2 ratio and IL-17A and IFN-γ levels were upregulated (9).…”

Infectious Dose Dictates the Host Response during Staphylococcus aureus Orthopedic-Implant Biofilm Infection

“…Another important factor when translating mouse infection models to human disease is infectious dose. This is particularly relevant when considering the initial bacterial challenge to the immune system, especially since the number of organisms seeding a given site during human infection is usually lower than the high S. aureus inocula used in many mouse models (i.e., 10 5 to 10 7 CFU) (30,(44)(45)(46). For example, a high infectious dose is likely to elicit an immediate and robust proinflammatory response attributed to a greater bacterial biomass (mediated by lipoteichoic acids, peptidoglycan, etc.).…”

“…In terms of S. aureus biofilm infection, some models utilize a large infectious inoculum or introduce implants that are precoated with bacteria (30)(31)(32)(33)(34)(35)(36). A high-challenge dose, particularly in a confined space such as the joint/bone, would be predicted to elicit a vigorous proinflammatory cascade that could likely alter the course of the resultant immune response and bacterial survival.…”

Ephedrine hydrochloride inhibits PGN-induced inflammatory responses by promoting IL-10 production and decreasing proinflammatory cytokine secretion via the PI3K/Akt/GSK3β pathway

“…1 Gram-negative (G 2 ) bacteria were the predominant organisms causing sepsis from 1979 to 1987; however, Grampositive (G 1 ) bacteria are increasingly common causes of sepsis in these two decades. 1,2 In 2000, G 1 bacteria reportedly accounted for 52.1% of new incidences of sepsis, with G 2 bacteria accounting for 37.6%; polymicrobial infections, anaerobes and fungi accounted for the remaining cases. 1 Although the mortality rates of septic patients caused by G 2 bacteria have declined in recent years, they remain steady for cases caused by G 1 bacteria.…”