Short Term, Low Dose Simvastatin Pretreatment Alters Memory Immune Function Following Secondary Staphylococcus aureus Infection

Abstract

Statins are potent modulators of immune responses, resulting in their ability to enhance host survival from primary bacterial infections. Alterations in primary immune responses that may be beneficial for survival following infection may also result in alterations in the generation of the immunologic memory response and subsequently affect immune responses mounted during secondary bacterial infection. In this study, we report that levels of total serum IgG2c, following primary infection, were decreased in simvastatin pretreated mice, and investigate the effect of simvastatin treatment, prior to primary infection, on immune responses activated during secondary S. aureus infection. A secondary infection model was implemented whereby simvastatin pretreated and control mice were reinfected with S. aureus 14 days after primary infection, with no additional simvastatin treatment, and assessed for survival and alterations in immune function. While survivability to secondary S. aureus infection was not different between simvastatin pretreated and control mice, memory B and T lymphocyte functions were altered. Memory B cells, isolated 14 days after secondary infection, from simvastatin pretreated mice and stimulated ex vivo produced increased levels of IgG1 compared to memory B cells isolated from control mice, while levels of IgM and IgG2c remained similar. Furthermore, memory B and T lymphocytes from simvastatin pretreated mice exhibited a decreased proliferative response when stimulated ex vivo compared to memory cells isolated from control mice. These findings demonstrate the ability of a short term, low dose simvastatin treatment to modulate memory immune function.

Modulation of Staphylococcus aureus Biofilm Formation through Subinhibitory Concentrations of Biogenic Silver Nanoparticles and Simvastatin

“…Combining treatments enhances antimicrobial effects and provides a more comprehensive approach to biofilm inhibition [58,61], while concurrently reducing toxicity to host cells and minimizing the adverse effects on surrounding tissues [62]. Moreover, it helps to prevent recurrent infections, thereby improving long-term treatment effectiveness [63]. Notably, use of subinhibitory concentrations potentially leads to resource savings by reducing the total antimicrobial requirement, optimizing resource utilization and mitigating the risk of side effects associated with higher doses.…”

Differential effects of cotreatment of the antibiotic rifampin with host-directed therapeutics in reducing intracellular Staphylococcus aureus infection

“…For nearly two decades, researchers have examined statin drugs as potential host-directed therapeutics for infection, including invasive infection by S. aureus (Zumla et al, 2016;Hennessy et al, 2016;Caffrey et al, 2017;Parihar, Guler & Brombacher, 2019;Kaufmann et al, 2018). Our work had indicated therapeutic benefit may include limiting the spread of infection by reducing host cell invasion (Burns et al, 2013;Smelser et al, 2016;McDowell et al, 2011). We identified an underlying mechanism where simvastatin reduces invasion of S. aureus into host cells by sequestering small-GTPases CDC42, RAC, and RHO in the cytosol (Horn et al, 2008).…”

Peer Review #1 of "Differential effects of cotreatment of the antibiotic rifampin with host-directed therapeutics in reducing intracellular Staphylococcus aureus infection (v0.1)"

“…For nearly two decades, researchers have examined statin drugs as potential host-directed therapeutics for infection, including invasive infection by S. aureus [27,28,29,30,31]. Our work had indicated therapeutic benefit may include limiting the spread of infection by reducing host cell invasion [32,33,34]. We identified an underlying mechanism where simvastatin reduces invasion of S. aureus into host cells by sequestering small-GTPases CDC42, RAC, and RHO in the cytosol [13].…”