Intracellular Habitation of Staphylococcus aureus: Molecular Mechanisms and Prospects for Antimicrobial Therapy

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) infections pose a global health threat, especially with the continuous development of antibiotic resistance. As an opportunistic pathogen, MRSA infections have a high mortality rate worldwide. Although classically described as an extracellular pathogen, many studies have shown over the past decades that MRSA also has an intracellular aspect to its infectious cycle, which has been observed in vitro in both non-professional as well as professional phagocytes. In vivo, MRSA has been shown to establish an intracellular niche in liver Kupffer cells upon bloodstream infection. The staphylococci have evolved various evasion strategies to survive the antimicrobial environment of phagolysosomes and use these compartments to hide from immune cells and antibiotics. Ultimately, the host cells get overwhelmed by replicating bacteria, leading to cell lysis and bacterial dissemination. In this review, we describe the different intracellular aspects of MRSA infection and briefly mention S. aureus evasion strategies. We discuss how this intracellular niche of bacteria may assist in antibiotic tolerance development, and lastly, we describe various new antibacterial strategies that target the intracellular bacterial niche.

Differential survival of Staphylococcal species in macrophages

“…Macrophages are important professional phagocytes to combat infections. However, from in vitro and in vivo studies, it is evident that they fail to eradicate S. aureus (Hommes and Surewaard, 2022;Pidwillet al , 2021). S. aureus is provided with an impressive arsenal of virulence determinants that give pathogenic potential to this bacterium.…”

“…Staphylococcus aureus asymptomatically colonizes the nose of about 30% of the human population. Nasal carriage is a major risk factor for severe and invasive S. aureus infections (Howden et al, 2023;Turner et al, 2019;Wertheim et al, 2005), including bacteremia, which occurs when this opportunistic bacterial pathogen breaches through the epithelial barrier into the blood stream (Hommes and Surewaard, 2022;Thwaites et al, 2011). The organism is then rapidly phagocytosed by professional phagocytes.…”

Repurposing inhibitors of phosphoinositide 3-kinase as adjuvant therapeutics for bacterial infections

“…For example, keratinocyte invasion by S. aureus induces lysis continued invasion of the dermis layer. When engulfed by macrophages and neutrophils partial evasion of phagolysosome killing leads to escape and dissemination of infection (Oviedo-Boyso et al, 2011;Hommes and Surewaard, 2022) (Figure 4A). Interestingly, S. aureus internalization decreases in bovine epithelial cells when treated with PI3K inhibitors (Oviedo-Boyso et al, 2011).…”

Chitosan versus Carboxymethyl Chitosan Cryogels: Bacterial Colonization, Human Embryonic Kidney 293T Cell Culturing and Co-Culturing

“…One of the key issues in the engineering of biomaterials is the need for the development of dual- or multi-functional scaffolds which, aside from supporting cell proliferation and tissue regeneration, can prevent bacterial growth [ 1 , 2 , 3 , 4 ] or possess hemostatic properties [ 5 ]. This target in most cases is achieved by a combination of strategies, including the careful selection of the polymer or polymer blends, the incorporation of antimicrobial proteins [ 6 ] or silver nanoparticles [ 3 , 7 ], and surface patterning [ 8 ]. The high interest to the application of chitosan and its derivatives in cell culturing and biomedicine is determined by their structural similarity to glycosaminoglycans and, thus, to extracellular matrix [ 9 ], as well as hemostatic [ 5 ], pro-angiogenic [ 10 ], and antimicrobial properties [ 11 , 12 , 13 ].…”

“…A non-cancerous human embryonic kidney cell line (HEK-293T) was selected, since it is one of the most widely studied cellular model for different purposes, including manufacturing therapeutic proteins and viral vectors for research and pre-clinical studies [ 25 , 26 , 27 ], the evaluation of the selectivity [ 28 ] and nephrotoxicity [ 29 ] of anticancer drugs, and the efficiency of cell protective therapy [ 29 ]. The HEK-293T line was also used to study human cell–bacteria interactions [ 6 , 30 ] in order to examine the ability of Staphylococcus aureus to cross the epithelial barrier, transmigrate into deeper sections of host tissues, persist, and replicate intracellularly, causing cell death.…”