# Host DNA damage and cellular fate in bacterial infections, with a focus on Staphylococcus aureus

Nadia Berkova, Eric Guedon, Yves Le Loir, Michael Otto

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Nadia Berkova, Eric Guedon, Yves Le Loir, Michael Otto. Host DNA damage and cellular fate in bacterial infections, with a focus on Staphylococcus aureus. FEMS Microbiology Reviews, 2025, 49, 10.1093/femsre/fuaf052. hal-05490880

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# Host DNA damage and cellular fate in bacterial infections, with a focus on *Staphylococcus aureus*

Nadia Berkova<sup>1,*,</sup> Eric Guedon<sup>1</sup>, Yves Le Loir<sup>1</sup>, Michael Otto<sup>1,2</sup>

## Abstract

*Staphylococcus aureus*, a leading human pathogen, is increasingly recognized as a genotoxic bacterium that reshapes host cell integrity beyond its classical virulence traits. By inducing DNA damage in host cells, *S. aureus* activates host DNA damage response (DDR) pathways that can determine the balance between bacterial clearance and persistence. By promoting chromatin remodeling and epigenetic reprogramming, through bacterial effectors such as phenol-soluble modulins and infection-induced metabolic changes, *S. aureus* modulates host immune responses and supports intracellular persistence. These interconnected mechanisms link DNA damage with immune evasion, chronic inflammation, and long-term tissue remodeling, which may contribute to carcinogenesis in chronically infected tissues. Recognizing *S. aureus* as both an infectious and genotoxic agent opens new therapeutic perspectives. Targeting DDR and epigenetic pathways, or modulating trained immunity to restore protective responses, offers promising strategies to counteract bacterial persistence and limit infection-associated pathologies. This integrative perspective redefines the pathogenesis of *S. aureus* by linking its genotoxic activity to host cellular reprogramming, and underscores the potential of host-directed therapeutic strategies as complementary approaches to conventional antibiotic treatment. It establishes a conceptual framework for understanding *S. aureus* persistence and pathogenicity in the context of rising antibiotic resistance.

**Keywords:** host-pathogen interaction; *Staphylococcus aureus*; host DNA damage; DNA damage response; DNA repair; epigenetic modifications

## Introduction

The development of disease results from a complex interplay between genetic susceptibility, host physiology, environmental factors, and random variation. In infectious diseases, pathogen activity adds a crucial dimension to this complexity, shaping disease outcome through multifactorial host-pathogen interactions (Baker et al. 2022, Bertagnolio et al. 2024). Understanding how these interactions disrupt host homeostasis is essential for improving disease prevention and therapy. Infectious diseases are highly prevalent on a global scale. According to the World Health Organization (WHO), of the estimated 13.7 million infection-related deaths that occurred in 2019, 7.7 million were linked to 33 bacterial pathogens across 11 infectious syndromes. Five key bacteria, *Staphylococcus aureus*, *Escherichia coli*, *Streptococcus pneumoniae*, *Klebsiella pneumoniae*, and *Pseudomonas aeruginosa*, were responsible for 54.9% of these deaths (Ikuta et al. 2022). Despite advancements in modern medical technologies, infection is becoming the second leading cause of death worldwide (Ikuta et al. 2022, Naghavi et al. 2024). The 21st century has seen an increase in infection outbreaks, posing ongoing challenges to human health due to rising drug resistance and emerging pathogens (Baker et al. 2022, Bertagnolio et al. 2024).

Pathogen-induced stress can compromise the stability of the host genome (Weitzman and Weitzman 2014), resulting in DNA lesions that activate the DNA damage response (DDR), a conserved signaling network that preserves genome integrity (Papamichos-Chronakis and Peterson 2013, Wu et al. 2024). DDR and checkpoint

pathways not only repair DNA and preserve genome stability but also promote cell survival or, when damage is irreparable, initiate senescence or cell death (Zhao et al. 2023, Jeon et al. 2024). Failure in the DDR mechanisms can lead to the accumulation of DNA damage and genomic instability (Chumduri et al. 2016, Xu et al. 2024), contributing to the disease development (Gao et al. 2023, Kwok et al. 2024, Siametis et al. 2024).

Increasing evidence suggests that bacterial infections can induce DNA damage in host cells (Hopfner and Hornung 2020, Imai et al. 2021). This damage can arise either directly through the production of toxins with genotoxic effects or indirectly due to the alteration of immune defense mechanisms (Chumduri et al. 2016, Bednarski and Sleckman 2019). Furthermore, DDR signaling pathways may be modified in response to an infection. Such alterations have the potential to generate mutations, promote chronic inflammation, impair immune function, and contribute to the development of cancer (Groelly et al. 2023).

Among the pathogens that compromise host genomic integrity, *S. aureus* requires particular attention due to its global prevalence, high clinical burden, and rising antibiotic resistance. It is a leading cause of both acute and chronic infections and exhibits a remarkable ability to evade immune responses, persist intracellularly, and adapt to diverse host environments. While DNA damage has been extensively characterized for other bacterial pathogens, its role in *S. aureus* pathogenesis is still insufficiently explored. Recent work has provided evidence that *S. aureus* induces host DNA damage and activates DDR pathways, identifying some of the underlying

<footnote n="1"><sup>1</sup>L'Institut national de recherche pour l'agriculture, l'alimentation et l'environnement (INRAE), Institut Agro, STLO, Rennes 35042, France</footnote>

<footnote n="2"><sup>2</sup>Pathogen Molecular Genetics Section, Laboratory of Bacteriology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health, Bethesda, MD 50 South Drive, Bethesda, MD 20814, United States</footnote>

<footnote>*Corresponding author. STLO, INRAE, 65, rue de Saint Brieuc, 35042 Rennes, France. E-mail: nadejda.berkova@inrae.fr</footnote>

<footnote>Editor: Fernando Maestre</footnote>
ing mechanisms and host responses (Deplanche et al. 2019). These findings suggest that DNA damage may contribute more substantially to *S. aureus* pathogenesis than previously recognized, with potential consequences including chronic inflammation, immune dysfunction, tissue degeneration, and even carcinogenesis in persistently infected tissues. Focusing on *S. aureus* in this context is therefore well-timed, as it not only highlights key knowledge gaps but also builds on new mechanistic insights to uncover novel host-directed therapeutic strategies. This review first outlines how diverse bacterial pathogens induce host DNA damage and activate DDR pathways, before discussing these processes in the specific context of *S. aureus* infection.

## Host DNA damage during bacterial infection
Endogenous and exogenous triggers of DNA damage

DNA damage can be triggered by exogenous or endogenous factors (Hoeijmakers 2009, Curtin 2012). Exogenous factors include physical elements like ionizing radiation, X-rays, UV light, and genotoxic agents such as various drugs, chemicals, or toxins (Blanpain et al. 2011). Endogenous DNA damage originates from chemical instability or reactions with intrinsic cellular metabolites, resulting in the production of reactive oxygen species (ROS), reactive nitrogen species (RNS), hydroxylation, deamination, S-adenosylmethionine alkylation, or the enzymatic activity of intracellular nucleases (Vitale et al. 2017, Srinivas et al. 2018) (Fig. 1).

DNA damage can be divided into several major categories, each defined by the specific type of lesion: base modifications, including alkylation damage and mispaired bases; intrastrand and inter-strand crosslinks; single-strand breaks (SSBs); and double-strand breaks (DSBs) (Tiwari and Wilson 2019). Additionally, bulky lesions occur when large molecules attach to or insert into the DNA strand, causing significant structural damage (Fig. 1). Pathogens can induce DNA damage in the infected host through various mechanisms.

## TLR-mediated inflammatory signaling and oxidative stress triggers host DNA damage

Toll-like receptors (TLRs) are key innate immune sensors that detect conserved microbial motifs and activate pro-inflammatory signaling cascades, primarily via NF-κB. While essential for pathogen clearance, this signaling can also cause collateral tissue damage. NF-κB contributes to genomic instability by upregulating enzymes involved in the generation of reactive oxygen and nitrogen species (ROS/RNS), such as NADPH oxidases, uncoupled cytochrome P450s (which generate hydrogen peroxide and hydroxyl radicals), cyclooxygenase-2, and arachidonate 12-lipoxygenase (Martinon et al. 2009, Tschopp and Schroder 2010, Nathan and Cunningham-Bussel 2013, Morgan et al. 2022). For instance, during neutrophil phagocytosis, NADPH oxidase catalyzes the conversion of oxygen into ROS within the phagolysosome (Bardoel et al. 2014). These reactive species are not only antimicrobial but also act as signaling molecules. However, their accumulation leads to oxidative stress, which induces DNA lesions such as single-strand breaks (SSBs) and DSBs (Fang 2004, Trachootham et al. 2009). Among the oxidative DNA lesions, 8-oxo-7,8-dihydroguanine (8-oxoG) is one of the most prevalent and mutagenic. When unrepaired, it can cause DSBs during replication, contributing significantly to genomic instability (Jamsen et al. 2021). Different TLRs recognize distinct microbial compo-

nents: TLR2 detects bacterial lipoproteins and lipoteichoic acid, while TLR9 senses unmethylated CpG motifs in bacterial DNA (Hemmi et al. 2000, Krieg 2006). Persistent activation of TLR2 can induce replication stress and DNA damage in macrophages. This response activates the DNA damage pathway, leading to mitotic defects and the formation of polyploid cells within granulomas, which are hallmarks of chronic inflammation (Herrtwich et al. 2016).

## Epigenetic reprogramming associated with DNA damage

If DNA damage is extensive or persistent, it can overwhelm repair systems, leading to genomic instability (Wu et al. 2024). Bacteria-induced DNA damage may also drive epigenetic modifications, which are changes in gene expression that do not alter the underlying DNA sequence but arise from chemical modifications of DNA or histones, such as DNA methylation or histone post-translational modifications (Millán-Zambrano et al. 2022, Wu et al. 2023). These changes reshape chromatin structure and regulate gene expression (Strahl and Allis 2000, Morrison and Shen 2009, Zhao et al. 2021).

Bacteria can trigger epigenetic modifications either directly or indirectly through the host DDR. Bacterial infections may alter DNA methylation, silencing tumor suppressor genes or activating oncogenes, thereby contributing to cancer development (Padmanabhan et al. 2017, Sobhani et al. 2020). As shown for *H. pylori*, chronic bacterial infection can lead to oxidative DNA damage, particularly elevated levels of 8-oxo-2'-deoxyguanosine (8-OHdG) and DSBs, driven largely by ROS and NOS generated during inflammation (Ding et al. 2019). At the same time, *H. pylori* infection induces hypermethylation of CpG islands in promoters of tumor suppressor genes and dysregulates miRNAs involved in genomic stability (Ding et al. 2019). Oxidative DNA damage appears to drive these aberrant methylation patterns, linking DNA lesions to long-term epigenetic remodeling. Comparisons between germ-free and conventional mice further show reduced epithelial DNA methylation in germ-free models, underscoring the role of microbes in shaping epigenetic landscapes (Heppert et al. 2021). It is also worth mentioning that bacterial toxins and virulence factors can alter histone structures, affecting how tightly DNA is wrapped around histones and, in turn, regulating gene accessibility (Hamon et al. 2007, Lebreton et al. 2011).

## Bacterial genotoxins trigger host DNA damage.

Certain pathogens produce specific DNA-damaging agents. For example, some strains of *Escherichia coli* that contain the pathogenicity island *pks* encode enzymes that synthesize a genotoxic compound called colibactin, which may cause DNA damage in host cells (Cuevas-Ramos et al. 2010, Wilson et al. 2019, Mäklin et al. 2024). *Escherichia* and *Campylobacter* spp. produce the genotoxin cytotolethal distending toxin (CDT) that induces double-strand DNA breaks via its deoxyribonuclease activity (Wong and Yu 2019). Certain bacterial species, also including *E. coli*, produce reductase enzymes that facilitate the conversion of nitrates into nitrites, a process that promotes the formation of N-nitrosamines, which are potent mutagens that can cause damage to DNA (Kunisaki and Hayashi 1979, Poncin et al. 2019).

## Microbial metabolites induce genotoxic stress in host

Some intestinal bacteria can metabolize primary bile acids into secondary bile acids, primarily through deconjugation and 7α-
<figure><img src="image_2.png" /><figcaption>**Figure 1.** Overview of DNA damage and respective DDR. Schematic representation of DNA lesions caused by exogenous or endogenous factors: single-strand breaks (SSBs), double-strand breaks (DSBs), interstrand crosslinks, intrastrand crosslinks, base damage, bulky lesions, base mismatch, and respective DNA repair pathways (single-strand repair, non-homologous end joining (NHEJ), homologous recombination (HR), Fanconi anemia, base excision repair, nucleotide excision repair, mismatch repair).</figcaption></figure>

hydroxyl group removal, producing mutagenic deoxycholate and lithocholate. These secondary bile acids induce ROS release via host cell enzyme activation, prostaglandin synthesis, and mitochondrial damage. They also increase nitrosative stress by upregulating nitric oxide synthases, which further induces DNA damage (Chang and Parsonnet 2010).

## Bacterial extracellular vesicles and nucleases promote host DNA injury

Another way of bacteria-induced DNA damage was described by Okita et al. (2020), who observed that *Fusobacterium nucleatum* infection may trigger cellular DNA damage and contribute to genetic and epigenetic alterations, potentially initiating and promoting carcinogenesis.

*Fusobacterium* species, which produce extracellular deoxyribonucleases, are enriched in colorectal cancer (CRC) and associate with microsatellite instability-high and CpG (cytosine-phosphateguanine dinucleotide) island-hypermethylated CRC subtypes, inducing γH2AX (DNA DSBs marker) and promoting inflammation-driven microsatellite alterations.

Using a similar mechanism of DNA damage, *Actinomyces odontolyticus*, an anaerobic bacterium primarily found in the oral cavity, secretes lipoteichoic acid-rich membrane vesicles (MVs) that activate inflammatory signaling via TLR2. These MVs are simultaneously internalized by colonic epithelial cells, where they co-localize with mitochondria and cause mitochondrial dysfunction, resulting in excessive ROS production and DNA damage potentially contributing to CRC development (Miyakawa et al. 2024).

Thus, bacterial infections induce host DNA damage through genotoxins and inflammatory stress, creating lesions that can disrupt genomic integrity and contribute to chronic inflammation, cellular reprogramming, and long-term tissue pathology.

## Cellular DDR through sensing, signaling, and repair mechanisms

Following DNA damage, a complex and highly orchestrated cellular process known as DDR is triggered that comprises various mechanisms to ensure genomic integrity (Panier and Durocher 2013, Papamichos-Chronakis and Peterson 2013).

### Damage sensing

Upon DNA damage, initial damage sensing involves recognition by specialized sensor complexes. Following DNA damage, the Mre11/Rad50/Nbs1 (MRN) functions as a DNA damage sensor in the DSB module of DDR (Fig. 2) (Lee and Paull 2005). The interaction between the tumor suppressor P53-binding protein 1 (S3BP1) and the MRN complex amplifies the activation of key DDR transducers, particularly the ataxia-telangiectasia mutated (ATM) protein kinase. Additional kinases, such as ATR (ataxia telangiectasia and Rad3-related protein) and DNA-PK (DNA-dependent protein kinase), also play pivotal roles in DNA damage signaling (Shiloh and Ziv 2013, Gagnaire et al. 2017) (Table 1).

### Signal transduction

Once DNA lesions are sensed, signal transduction pathways are activated to coordinate the cellular response. The kinases ATM, ATR, and DNA-PK activate critical downstream effectors, including checkpoint kinases 1 (CHK1) and 2 (CHK2), which regulate cell cycle progression, facilitate DNA repair, and promote apoptosis (Bauer et al. 2011). Another way of ATM activation is dependent on chromatin structure alteration (Arnould et al. 2023). DNA damage initiates the phosphorylation of histone H2AX, resulting in the formation of γH2Ax domains. This modification of histones extends beyond the site of DSBs into adjacent chromatin, establishing a DDR platform. This platform protects against end disassociation and degradation, thereby reducing the likelihood of chromosomal rearrangements (Collins et al. 2020). The phosphorylation of H2AX
<figure><img src="image_3.png" /><figcaption>**Figure 2.** Model of DNA damage and its consequences during *S. aureus* infection in non-immune cells. TLRs recognize components of *S. aureus*, initiating the production of inflammatory cytokines and activating NF-κB, which subsequently leads to DNA damage. This occurs through the generation of reactive oxygen species (ROS) produced by mitochondria, NADPH oxidase, peroxisomes, and the endoplasmic reticulum, along with the dysregulation of DNA repair mechanisms. The ROS induce 8-oxoG DNA lesions, resulting in DNA double-strand breaks (DSBs). These DNA damages activate the DDR marked by the phosphorylation of histone H2AX (γH2AX). The presence of γH2AX can also influence other histone modifications, such as methylation or acetylation, by altering the chromatin structure and facilitating or hindering the access of enzymes responsible for these modifications. This interplay between γH2AX and other histone modifications can impact gene expression and chromatin dynamics during the repair process.</figcaption></figure>

The phosphorylation of histone H2AX is linked to the recruitment of the apical kinases ataxia telangiectasia mutated (ATM) substrates, such as 53BP1 and BRCA1, leading to the accumulation of the MRN complex at DSBs and subsequent ATM activation. ATM then phosphorylates checkpoint kinase CHK2. Ultimately, these signaling cascades converge on the activation of p53, which governs critical cellular processes: DNA repair, senescence, cell cycle arrest, and apoptosis (represented by solid blue arrows). DNA damage may also predispose cells to *S. aureus*-induced inflammasome activation (illustrated by red dashed arrows). The hypothetical interplay between DNA damage and the Golgi apparatus, involving the GOLPH3 complex (comprising the peripheral membrane protein GOLPH3, myosin18A (MYO18A), and F-actin) is highlighted by blue dashed arrows. Upon DNA damage, GOLPH3 is phosphorylated at Thr143 by the DNA damage-activated protein kinase DNA-PK, leading to increased vesiculation and Golgi fragmentation.

triggers subsequent signaling events that recruit ATM substrates, such as 53BP1 and BRCA1. This leads to the accumulation of the MRN complex at DSBs and ATM activation. ATM then phosphorylates CHK1 and CHK2 checkpoint kinases, which interact with p53 and CDC25 (cell division cycle 25) phosphatases to coordinate various cellular responses. These responses, dependent on DNA damage severity and cell cycle stage, include apoptosis, temporary cell cycle arrest for DNA repair facilitation, and cellular senescence. For example, CHK2 activation leads to CDC25 and CDK1-mediated G2 to M phase cell cycle arrest (Gagnaire et al. 2017).

## Repair pathways

Subsequently, the type of DNA lesion determines which repair pathways are recruited to restore genome integrity. Base excision repair (BER) mechanisms excise and replace damaged bases and recognize SSBs. DNA lesions that distort the double helix are repaired by nucleotide excision repair (NER) mechanisms (Kumar et al. 2020). DSBs are repaired by non-homologous end joining (NHEJ) or homologous recombination (HR), whereas DNA replication mistakes are corrected by mismatch repair (MMR) (Scully et al. 2019) (Fig. 1). In addition, NF-κB modulates DNA repair mech-

anisms, including homologous recombination (HR), further influencing genome stability (Volcic et al. 2012, Morgan and Liu 2011).

## Cell fate and bacterial effectors

While the DDR aims to preserve genomic stability, its activation also influences cell fate decisions. Several bacterial pathogens have evolved strategies to exploit these pathways (Table 1). The DDR coordinates a multitude of molecular players comprising diverse protein kinases, leading to the activation of various checkpoints and repair mechanisms that include the involvement of cell cycle regulators, nucleases, helicases, polymerases, and ligases (Pilié et al. 2019). DNA-damaging agents may also activate cell cycle checkpoints, inducing a transient cell cycle arrest to facilitate the correction of potential defects (Branzei and Foiani 2008, Matthews et al. 2022). In cases where the DNA damage is irreversible, the DDR can initiate programmed cell death, or apoptosis, thus preventing the propagation of genetically compromised cells that ensure the integrity of the genetic material (Zhivotovsky and Kroemer 2004, Hafner et al. 2019).

Several proteins produced by bacterial pathogens can interfere with host defense mechanisms by targeting and interact-
<table><caption>**Table 1.** General bacterial mechanisms inducing host DNA damage and DDR activation, including *Helicobacter pylori*, *Escherichia coli*, *Campylobacter* spp., *Shigella dysenteriae*, *Yersinia pseudotuberculosis*, *Fusobacterium nucleatum*, and *Actinomyces odontolyticus*.</caption><thead><tr><th>Bacteria/toxin</th><th>DNA damage type</th><th>DDR pathway activated</th><th>Host cell type</th><th>Mechanism of induction</th><th>Reference</th></tr></thead><tbody><tr><td>Helicobacter pylori (inflammation-driven, no classical genotoxin)</td><td>Oxidative lesions (8-oxo-DG), SSBs, DSBs; aberrant CpG methylation</td><td>ATM and ATR signaling, CHK1 and CHK2 activation, γH2AX; Base Excision Repair (BER) for oxidized bases; Homologous Recombination (HR)/Non-Homologous End Joining (NHEJ) for DSBs</td><td>Gastric epithelial cells</td><td>Chronic inflammation leads to ROS/RNS production, causing oxidative DNA damage, epigenetic remodeling including CpG hypermethylation and mRNA dysregulation</td><td>Ding et al. (2019), Padmanabhan et al. (2017)</td></tr><tr><td>Escherichia coli (pks + strains, Colibactin)</td><td>Interstrand crosslinks, bulky adducts, DSBs</td><td>Fanconi anemia pathway for ICL repair; ATM and ATR signaling; HR and NHEJ</td><td>Intestinal epithelial cells, colonocytes</td><td>Colibactin alkylates DNA, causing replication fork collapse and resulting in DSBs</td><td>Cuevas-Ramos et al. (2010), Wilson et al. (2019)</td></tr><tr><td>Escherichia coli, Campylobacter spp., Shigella dysenteriae (Cytotoxic Distending Toxin, CDT)</td><td>DSBs, replication arrest</td><td>ATM-CHK2 activation; G2/M checkpoint; HR and NHEJ</td><td>Epithelial cells, lymphocytes</td><td>CDT has DNase-like activity, leading to direct DNA cleavage</td><td>Wong and Yu (2019), Nougayrède et al. (2005), Smith and Bayles (2006)</td></tr><tr><td>Escherichia coli (CNF), Yersinia pseudotuberculosis (CNF)</td><td>Replication stress; secondary DSBs</td><td>ATR-CHK1 activation due to replication stress; ATM signaling for DSBs</td><td>Epithelial cells, fibroblasts</td><td>CNF modifies Rho GTPases, causing cytoskeletal and mitotic defects that induce replication stress</td><td>Nougayrède et al. (2005), El-Aouar Filho et al. (2017)</td></tr><tr><td>Fusobacterium nucleatum (DNases, extracellular vesicles)</td><td>DSBs; microsatellite instability; CpG island hypermethylation</td><td>γH2AX; ATM and ATR signaling; HR and NHEJ</td><td>Colon epithelial cells</td><td>Secreted nucleases and vesicles induce DNA cleavage and promote inflammation-driven genomic and epigenetic instability</td><td>Okita et al. (2020)</td></tr><tr><td>Actinomyces odontolyticus (lipoteichoic acid-rich vesicles)</td><td>Oxidative lesions, SSBs, DSBs</td><td>ATM and ATR signaling; BER; HR</td><td>Colonic epithelial cells</td><td>Vesicles activate TLR2, leading to mitochondrial dysfunction, ROS overproduction, and DNA lesions</td><td>Miyakawa et al. (2024)</td></tr></tbody></table>

Abbreviations: SSBs (Single-Strand Breaks), DSBs (Double-Strand Breaks), ATM (Ataxia Telangiectasia Mutated), ATR (Ataxia Telangiectasia and Rad3 Related), CHK1 (Checkpoint Kinase 1), CHK2 (Checkpoint Kinase 2), γH2AX (Phosphorylated H2AX, Histone H2AX phosphorylated at Ser139), BER (Base Excision Repair), HR (Homologous Recombination), NHEJ (Non-Homologous End Joining), ROS (Reactive Oxygen Species), RMS (Reactive Nitrogen Species), ICL (Interstrand Crosslink), CNF (Cytotoxic Nectrotizing Factor), TLR2 (Toll-Like Receptor 2)
ing with the nuclei of eukaryotic cells. These nucleus-targeting
proteins fall into two categories: “nucleomodulins,” which ex-
ert epigenetic or nucleus-modulating activities, and “cyclomod-
ulins,” which specifically disrupt the host cell cycle (Nougayrède
et al. 2005, El-Aouar Filho et al. 2017, Radoshevich and Cossart
2018, Morgan et al. 2022). Chromatin, which consists of DNA
wrapped around histone proteins to form nucleosomes, is a key
bacterial target in the nucleus (Hamon and Cossart 2008). Its
structure dictates DNA accessibility for nuclear functions: un-
packed euchromatin promotes gene transcription, while com-
pacted heterochromatin inhibits it. Gene expression is regulated
through DNA-interacting transcription factors and chromatin’s
post-translational modifications, which affect nucleosome prop-
erties and recruit chromatin regulators (Carter and Zhao 2021).
Additionally, chromatin structure is closely linked to processes
like RNA splicing and DNA replication, recombination, and repair
(Hanford et al. 2021).

Regulation of eukaryotic cell function by
bacterial nucleomodulins

Among the diverse bacterial effectors, nucleomodulins have emerged as key regulators of nuclear processes. Eukaryotic proteins that translocate to the nucleus contain a peptide motif called a nuclear localization signal (NLS) that facilitates transport through nuclear pore complexes. Some bacterial nucleomodulins also possess NLS sequences for transport into the host nucleus. However, not all nucleomodulins have the predicted NLS, but they still enter the nucleus, suggesting the involvement of additional mechanisms (Escoll et al. 2016, Hanford et al. 2021).

There are different strategies used by nucleomodulins to enter
the nucleus and modulate host cell response and gene expres-
sion. Nucleomodulins can enter the nucleus directly by diffusion
through nuclear pores, use an NLS to interact with the nuclear
pore complex for import, or depend on unknown mechanisms.
After their entry into the nucleus, nucleomodulins can modulate
the host cell epigenome by altering the nuclear ubiquitination and
signaling pathways, dysregulating protein localization and accu-
mulation in the nucleus or nucleolus, or directly targeting and
modifying host DNA and histones (Khan and Khan 2021).

Studies have shown that some bacteria, effector proteins tar-
get nuclear ubiquitination to disrupt cellular homeostasis, mod-
ulate nuclear protein balance via nuclear signaling pathways and
ribosomal biogenesis, and directly bind to host DNA or influence
the host epigenome by mimicking mammalian DNA methyltrans-
ferases (Escoll et al. 2016, Hanford et al. 2021). Additionally, some
bacterial nucleomodulins directly modify histones, altering im-
mune gene expression, enhancing intracellular replication, and
potentially reconfiguring the host genome during infection (Bierne
and Pourpre 2020).

Host cell cycle alteration by bacterial
cyclomodulins

Another class of bacterial effectors, known as cyclomodulins,
specifically target the host cell cycle machinery to modulate cel-
lular proliferation. Some bacterial pathogens produce cyclomod-
ulins that disrupt the eukaryotic cell cycle by altering cell division.
For example, inhibitory cyclomodulins such as cytolethal distend-
ing toxins (CDTs) from E. coli and Shigella dysenteriae block mitosis
(Nougayrède et al. 2005, Smith and Bayles 2006). This can help
pathogens evade the immune system by preventing lymphocyte
proliferation. Additionally, these inhibitors may compromise the

integrity of the epithelial barrier, facilitating bacterial invasion or
persistence at the infection site.

Conversely, cyclomodulins that promote cell proliferation, such as cytotoxic necrotizing factor (CNF) produced by E. coli and *Yersinia pseudotuberculosis*, interfere with normal cell differentiation and development. This disruption creates an environment favorable to bacterial survival and replication, further enhancing the pathogen's ability to colonize and persist within the host (Nougayrède et al. 2005, El-Aouar Filho et al. 2017).

Epigenetic reprogramming associated with DDR

Beyond immediate damage repair, DDR activation also reshapes the host's epigenetic landscape, with bacterial infections further influencing this regulation (Zhao et al. 2023). Bacteria can trigger epigenetic modifications indirectly by influencing the host's DDR and alter DNA methylation patterns, potentially silencing tumor suppressor genes or activating oncogenes, which may contribute to cancer development (Sobhani et al. 2020). For example, chronic *H. pylori* infection has been shown to cause abnormal DNA methylation in Mongolian gerbil models (Padmanabhan et al. 2017). The intestinal epithelium adapts to microbial stimuli. A comparison of DNA methylation in the epithelium of germ-free and conventionally raised mice shows reduced methylation at many genomic sites in germ-free mice. Additionally, histone modifications are essential for intestinal epithelial function in the presence of microorganisms (Heppert et al. 2021). It is also worth mentioning that bacterial toxins and virulence factors can alter histone structures, affecting how tightly DNA is wrapped around histones and, in turn, regulating gene accessibility (Hamon et al. 2007, Lebreton et al. 2011). Thus, the DDR not only manages immediate DNA repair but also plays a critical role in modifying the cell's epigenetic state, which can have lasting effects on cellular function and fate.

Genetic susceptibility

The critical connection between bacteria-induced DNA damage and genetic susceptibility to infectious disease has been examined intensely, e.g. during *H. pylori* infection. It was demonstrated that long-lasting *H. pylori*-induced inflammation is followed by DNA damage and the impairment of DDR (Gagnaire et al. 2017). Beyond inducing inflammation, *H. pylori* can directly cause genetic instability through DSBs (Toller et al. 2011, Imai et al. 2021). Furthermore, genetic variations in DNA repair genes can modulate DNA repair capacity and give rise to the accumulation of *H. pylori*-induced DNA damage, consequently leading to apoptosis and the unregulated proliferation of cells (Jia et al. 2016).

Thus, DDR activation represents a double-edged sword: pre-
serving host genome integrity but also creating niches favorable
for bacterial persistence.

Staphylococcus aureus: a versatile pathogen
with clinical significance

Commensal and opportunistic nature of S. aureus

Staphylococcus aureus, a Gram-positive bacterium, is commonly
found on the skin and mucosal surfaces of humans and animals
as part of their normal colonizing microbiota (Parlet et al. 2019,
Piewngam and Otto 2024). As a commensal bacterium, it resides
primarily in the nasal cavity, skin, and intestine (Krismer et al.
2017, Byrd et al. 2018, Raineri et al. 2022). However, under spe-
cific conditions, it can become a potentially hazardous pathogenic
agent, classifying it as an opportunistic pathogen (Masters et al.
2022). The transition from commensal to pathogenic state is facili-
tated by a weakened immune systems or breaches in the skin (Foster 2005, Uberoi et al. 2024). The remarkable adaptability and proficiency in toxin production of *S. aureus* considerably contribute to its pathogenic potential (Peschel and Otto 2013, Otto 2014, Holmes et al. 2024).

## Clinical manifestations and infection spectrum

Staphylococcus aureus infection can be acute, recurrent, or chronic and persistent (Howden et al. 2023). As a leading cause of both nosocomial and community-associated infections, *S. aureus* is responsible for a wide range of conditions, from mild skin issues to life-threatening diseases (Miller and Cho 2011, Tong et al. 2015, Holland et al. 2016). Beyond superficial infections like boils and impetigo, it causes deeper complications such as wound infections, abscesses, and surgical site infections (Uberoi et al. 2024). Chronic infections such as osteomyelitis, endocarditis, and pneumonia, particularly in immunocompromised hosts, are characterized by persistent inflammation, tissue destruction, and impaired resolution, leading to complications such as bone resorption and cardiac dysfunction, which pose significant challenges for clinical management. (Que and Moreillon 2011, De Benedictis et al. 2020, Masters et al. 2022, Miller and Arias 2024). While first-line immune cells like neutrophils are essential in defense, long-lived non-immune cells capable of internalizing *S. aureus* may also contribute to chronic infection persistence (Trouillet-Assant et al. 2016, Tuchscherr et al. 2016, Cheung et al. 2021).

## Antimicrobial resistance and therapeutic challenges

The management of *S. aureus* infections is increasingly impeded by antimicrobial resistance (AMR), which compromises antibiotic efficacy and limits therapeutic options (Murray et al. 2022). Staphylococcus aureus, classified as an ESKAPE pathogen alongside Enterococcus faecium, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp., exhibits high virulence and multidrug resistance (Tommasi et al. 2015, Miller and Arias 2024). Resistance mechanisms include chromosomal mutations and horizontal gene transfer, enabling adaptation to diverse antibiotic classes (Grundmann et al. 2006). Methicillin-resistant *S. aureus* (MRSA) is particularly concerning, as a single genetic element confers broad β-lactam resistance and facilitates rapid dissemination in healthcare and community settings (Lee et al. 2018, Turner et al. 2019). MRSA infections exhibit diverse clinical manifestations and show growing resistance to established therapeutic strategies (Tong et al. 2015). The growing prevalence of multidrug-resistant *S. aureus* emphasizes the urgent need for rapid risk assessment and the development of novel therapeutics targeting resistance determinants and virulence factors (Foster 2005, Magalhães et al. 2021, Nigo et al. 2024).

## Host genetic factors influencing susceptibility to *S. aureus*

Beyond bacterial virulence and resistance, host genetic background also influences susceptibility to *S. aureus* infection. In mice, strain-dependent susceptibility indicates a role for host genetics, with neutrophils playing a central role (von Köckritz-Blickwede et al. 2008). In humans, IRAK4 (interleukin-1 receptor-associated kinase 4) deficiency, an inborn error of immunity, impairs TLR signaling and activation of NF-κB and MAPK pathways, reducing inflammatory cytokine production and increasing infection risk (Brodsky and Medzhitov 2009, Jia et al. 2020, Boisson 2020, Kawai et al. 2024). Mutations in TLR pathway components such

as MYD88, IRAK1, or TIRAP predispose to staphylococcal or pneumococcal infections (Boisson, 2020). A GLS2 variant, linked to glutamine metabolism and immune activation, has been associated with complicated *S. aureus* bacteremia (Scott et al. 2018). OTULIN haploinsufficiency disrupts ubiquitin signaling, causing caveolin-1 accumulation in dermal fibroblasts and enhancing susceptibility to *S. aureus* α-toxin-mediated cytotoxicity (Spaan et al. 2022).

## DNA damage induction during *S. aureus* infection

### Staphylococcus aureus triggers DNA damage in host cells and tissues

Staphylococcus aureus is increasingly recognized not only for its virulence but also for its ability to compromise host genomic integrity. Emerging evidence suggests that beyond inducing inflammation, *S. aureus* can directly cause DNA damage, although the underlying mechanisms are not yet fully elucidated. In a pioneer study, Deplanche et al. (2019) demonstrated that *S. aureus* induces DNA DSBs in non-immune cells, in vitro, as was shown by increased phosphorylation of H2AX (γH2AX), a well-established marker of DNA DSBs occurring independently of apoptosis (Rogakou et al. 1998). In line with these observations, in vivo investigations of DNA damage in the livers of mice exposed to various *S. aureus* isolates revealed significantly higher rates of DNA damage in infected animals compared to the control group (Elateek et al. 2021) (Table 2). Additionally, studies investigating the role of *S. aureus* in breast cancer tumorigenesis and progression have shown that the bacterium induces DNA DSBs in both normal human breast cells and breast cancer cells, resulting in activation of the ataxia-telangiectasia mutated (ATM)-p53 signaling pathway (Zhao et al. 2024). High-throughput mRNA sequencing, bioinformatics analysis, and pharmacological studies further revealed that *S. aureus* promotes metastasis through modulation of the innate immune pathway (Zhao et al. 2024). Furthermore, exposure of human primary keratinocytes to culture supernatants of *S. aureus* isolated from patients with premalignant lesions, such as actinic keratosis and cutaneous squamous cell carcinoma, resulted in increased oxidative stress and DNA damage (Krueger et al. 2022).

Together, these studies have established *S. aureus* as a potent inducer of host DNA damage, providing a foundation for understanding downstream consequences, including immune activation, inflammation, and altered host genomic stability.

## TLR signaling and ROS-mediated DNA damage

Host recognition of *S. aureus* relies largely on pattern-recognition receptors such as Toll-like receptors (TLRs). Among these, TLR2, in cooperation with TLR1 or TLR6, plays a central role in sensing staphylococcal lipoproteins and cell wall components, while TLR9 can detect unmethylated CpG motifs in bacterial DNA, and TLR4 has been implicated in responses to certain staphylococcal exotoxins (Takeuchi et al. 2000, Parker and Prince 2012). During *S. aureus* infection, various Toll-like receptors (TLRs) recognize distinct pathogenic components. TLR1, TLR4, TLR6, TLR9, and TLR10 contribute to recognizing specific *S. aureus* components (Shukla et al. 2015, Zahoor et al. 2020, Nicolas et al. 2022) (Fig. 2). Engagement of these receptors triggers canonical signaling pathways involving MyD88, NF-κB, and MAPKs, leading to the induction of pro-inflammatory cytokines and antimicrobial responses (Akira and Takeda 2004). Also, endosomal TLR7, 9, and 13 cooperate in sensing staphylococcal nucleic acids, and their combined absence
<table><caption>**Table 2.** Mechanisms of DNA damage induced by *Staphylococcus aureus* and associated DDR in host cells.</caption><thead><tr><th>Toxic substance/condition</th><th>DNA damage type</th><th>DDR pathway activated</th><th>Host cell type</th><th>Mechanism of induction</th><th>References</th></tr></thead><tbody><tr><td>PSMα peptides</td><td>Double-strand breaks (DSBs)</td><td>ATM activation with γH2AX and 53BP1 recruitment; CHK1/CHK2 activation; HR/NHEJ repair</td><td>Osteoblasts, epithelial cells</td><td>PSMα destabilizes host membranes, leading to intracellular stress and DSB formation; induction of H2AX phosphorylation</td><td>Deplanche et al. (2019), Kinner et al. (2008)</td></tr><tr><td>TLR-mediated ROS/RNS</td><td>Oxidative DNA lesions (8-oxoG, single-strand breaks, DSBs)</td><td>ATM/ATR signaling with CHK1/CHK2 activation; BER for SSBs; HR/NHEJ for DSBs</td><td>Macrophages, neutrophils, epithelial cells, hepatocytes</td><td>TLR1/2/4/6/7/9/10 sensing activates NF-κB and MAPK pathways, leading to NADPH oxidase activity, ROS/RNS accumulation, and oxidative DNA damage</td><td>Elastee et al. (2021), Nauseef (2019), Deplanche et al. (2019)</td></tr><tr><td>Enterotoxin B (SEB)</td><td>Epigenetic alterations affecting DNA accessibility</td><td>Altered chromatin regulation downstream of DDR; reduced accessibility of DNA repair genes</td><td>Nasal epithelial cells, immune cells</td><td>SEB exposure induces de novo DNA methylation and hypomethylation of immune-related genes, leading to altered DNA accessibility and indirect DNA damage</td><td>Pérez-Novo and Bachert (2015)</td></tr><tr><td>Lactate (from biofilms)</td><td>Chromatin remodeling and increased DNA accessibility</td><td>γH2AX formation; ATM activation; histone acetylation changes</td><td>Monocytes, macrophages</td><td>Lactate accumulation inhibits HDAC11, leading to hyperacetylation of histone H3K9/K14, chromatin decompaction, IL-10 upregulation, and increased susceptibility to DSBs</td><td>Heim et al. (2020), Modak et al. (2014)</td></tr><tr><td>α-hemolysin (Hla)</td><td>Epigenetic reprogramming and chromatin remodeling</td><td>ATM signaling and histone modification pathways</td><td>Epithelial cells, T cells</td><td>α-hemolysin alters immune cell programs, including modulation of Th17-related chromatin states, thereby reprogramming transcriptional responses</td><td>Howden et al. (2023)</td></tr><tr><td>Secreted factors (PSMα, others)</td><td>Replication stress and cell cycle arrest</td><td>ATR-CHK1 activation (replication stress); ATM-dependent G2/M checkpoint; HR/NHEJ repair</td><td>Osteoblasts, keratinocytes, epithelial cells</td><td>Secreted bacterial factors delay G2/M transition, inducing replication stress, persistent DDR activation, and DNA damage accumulation</td><td>Deplanche et al. (2015), Alekseeva et al. (2013), Nicolas et al. (2022)</td></tr><tr><td>ROS (chronic exposure)</td><td>Telomere damage and cellular senescence</td><td>ATM/ATR signaling leading to p53-dependent senescence-associated DDR; γH2AX formation</td><td>Osteoblasts, bone marrow cells</td><td>Chronic ROS exposure induces telomere shortening and damage, causing stable cell cycle arrest and senescence</td><td>Nicolas et al. (2022), Deng et al. (2023), Pezone et al. (2023)</td></tr></tbody></table>

Abbreviations: PSMα (Phenol-Soluble Modulin alpha), DSBs (Double-Strand Breaks), ATM (Ataxia Telangiectasia Mutated), γH2AX (Phosphorylated H2AX, Histone H2AX phosphorylated at Ser139), 53BP1 (Tumor Protein p53 Binding Protein 1), CHK1 (Checkpoint Kinase 1), CHK2 (Checkpoint Kinase 2), HR (Homologous Recombination), NHEJ (Non-Homologous End Joining), TLR ( Toll-Like Receptor), ROS (Reactive Oxygen Species), RNS (Reactive Nitrogen Species), BIER (Base Excision Repair), SEB (Staphylococcal Enterotoxin B), DDR (DNA Damage Response), HDAC11 (Histone Deacetylase 11), H3K9/K14 (Histone H3 lysine 9 and lysine 14), H1a (Alpha-Hemolysin), ATR (Ataxia Telangiectasia and Rad3 Related), IL-10 (Interleukin-10), NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells), MAPK (Mitogen-Activated Protein Kinase), G2/M (Gap 2/Mitosis phase of cell cycle), Th17 (T-helper 17 cells), p53 (Tumor Protein p53)
leads to markedly increased susceptibility to infection compared to TLR2 deficiency, due to impaired cytokine production, and neutrophil recruitment (Lentini et al. 2021).

The involvement of TLRs in S. aureus-induced host DNA damage has yet to be demonstrated, activation of TLRs is known to enhance ROS production and influence DNA-repair pathways (Haberts and Gaspari 2013), thereby providing a plausible indirect link to genomic stress. A major downstream outcome of TLR signaling is the induction of reactive oxygen and nitrogen species (ROS/RNS) by both immune and non-immune cells (West et al. 2011). These molecules are essential for bacterial clearance but, when produced in excess, contribute to oxidative stress and collateral host tissue injury (Bedard and Krause 2007). ROS and RNS generated upon TLR stimulation can cause oxidative DNA lesions, including SSBs and DSBs, 8-oxoguanine formation, and DNA-protein crosslinks. In human epithelial and osteoblast-like cells, S. aureus infection induces phosphorylation of histone H2AX, a hallmark of DNA DSB, in a process that depends on oxidative stress and ATM activation (Deplanche et al. 2019). Similarly, TLR-driven NADPH oxidase (NOX2) activity in macrophages promotes ROS production during S. aureus infection, linking innate immune recognition to genotoxic stress (Nauseef 2019). In addition, recent *in vivo* experiments using male mice injected with various S. aureus strains have demonstrated increased ROS generation, leading to the subsequent formation of 8-oxoG and resulting in DNA damage in liver cells, highlight the pivotal role of ROS in driving S. aureus-associated genomic instability (Elateek et al. 2021).

## Epigenetic reprogramming associated with DNA damage

Genomic instability is often accompanied by epigenetic alterations that reshape gene expression programs and contribute to disease progression. In the context of S. aureus infection, the interplay between DNA damage and epigenetic remodeling is increasingly recognized as a critical aspect of host-pathogen interactions, although the underlying mechanisms remain incompletely defined.

Staphylococcus aureus can reprogram the host epigenome through both direct and indirect mechanisms. Several S. aureus effectors can modulate host epigenetic pathways. For example, lactate produced by S. aureus biofilms inhibits histone deacetylase 11 (HDAC11), altering chromatin accessibility (Heim et al. 2020, Howden et al. 2023). α-Hemolysin modulates the expression of genes involved in the epigenetic regulation of Th17 cell function (Pastwińska et al. 2024). In airway epithelial cells, S. aureus has been implicated in changes to DNA methylation and histone post-translational modifications, contributing to chronic inflammatory diseases (Modak et al. 2014, Pérez-Novo and Bachert 2015). Furthermore, S. aureus enterotoxin B (SEB) induces intragenic DNA methylation in key immune genes. In nasal polyp tissues from chronic rhinosinusitis patients, SEB exposure led to *de novo* methylation of over 130 gene regions and hypomethylation of 70 others, affecting pathways involved in interleukin signaling, Toll-like receptor cascades, and glycosaminoglycan metabolism (Pérez-Novo and Bachert 2015). These epigenetic modifications are thought to contribute to immune evasion and bacterial persistence. However, there is currently no direct evidence that these bacterial effectors individually induce DNA damage.

Staphylococcus aureus also causes direct genotoxic stress in host cells. It induces DNA DSBs, as indicated by γH2AX accumulation. This damage is mediated in part by phenol-soluble modulins (PSMs), particularly PSMα peptides, and the production of

reactive oxygen species (ROS), which also generate oxidative lesions such as 8-oxo-7,8-dihydroguanine (8-oxoG) (Deplanche et al. 2019). While a direct causal relationship between individual bacterial effectors and DNA damage has not been completely established, ROS provide a plausible mechanistic link between bacterial activity and host genomic instability.

Importantly, ROS exerts a dual effect on the host. Beyond their direct genotoxic role, they act as potent regulators of the epigenetic landscape. ROS can disrupt DNA methylation patterns through altered activity of DNA methyltransferases (DNMTs), influence histone modifications by targeting redox-sensitive enzymes such as HDACs and histone demethylases, and modulate the expression of non-coding RNAs (García-Guede et al. 2020, Zheng and Sawalha 2022). This dual activity positions ROS as central mediators connecting DNA damage and epigenetic shifts.

Consistent with this mechanistic link, transcriptomic profiling of human osteoblasts persistently infected with S. aureus has revealed significant downregulation of genes encoding key epigenetic regulators, including DNMTs (DNA methyltransferases), HDACs (histone deacetylases), and components of repressive chromatin complexes such as NuRD (nucleosome remodeling and deacetylase complex) and PRC1 (Polycomb repressive complex 1) (Nicolas et al. 2022). Such deregulation is likely to drive long-lasting transcriptional changes, compromise genome stability, and favor cellular environments permissive to chronic infection.

Taken together, the interplay between S. aureus-induced DNA damage and oxidative stress reveals a mechanistic basis for host cell reprogramming. DNA DSBs arise partly through the action of PSMs, which destabilize host membranes and promote intracellular stress. In parallel, infection-driven ROS generation exacerbates DNA lesions, including 8-oxoG formation, providing a continuous source of genomic instability (Table 2). At the same time, S. aureus infection alters the expression and activity of major epigenetic regulators and repressive chromatin complexes. The combined action of genotoxic stress and disrupted epigenetic control imposes long-lasting transcriptional changes and genomic instability, creating a cellular environment favorable to S. aureus survival, facilitating chronic infection, and potentially driving long-term pathological outcomes.

## Chromatin remodeling facilitates DNA damage and immune evasion during S. aureus infection

Recent findings have extended the epigenetic perspective by demonstrating that chromatin itself is a direct bacterial target during S. aureus infection. Alterations in histone modifications and chromatin structure have been observed in multiple host cell types exposed to the pathogen, indicating that nuclear reprogramming is a conserved feature of infection.

In murine mammary and epithelial tissues, infection triggers hyperacetylation of histone H3 at lysines 9 and 14, which are associated with euchromatin and active transcription, suggesting chromatin decompaction at infection sites (Modak et al. 2014). Similarly, in human monocytes and macrophages, exposure to heat-killed S. aureus induces global H3 acetylation, a hallmark of trained immunity characterized by enhanced chromatin accessibility and increased inflammatory responsiveness (Carlile et al. 2024). These findings illustrate how S. aureus exploits both chromatin opening and transcriptional priming, depending on the cell context, to modulate host responses.

Mechanistically, this remodeling is driven by both bacterial products and infection-induced gene repression. Lactate accumu-
lation during infection inhibits HDAC11, leading to excessive histone acetylation and increased IL-10 production, which promotes intracellular bacterial survival and immune evasion (Heim et al. 2020). Prolonged infection is also linked to transcriptional down-regulation of chromatin-modifying enzymes and repressive complexes such as NuRD, PRC1, and BAHD1 (Bromo Adjacent Homology Domain-containing 1), weakening chromatin condensation and destabilizing transcriptional homeostasis (Nicolas et al. 2022). Such repression of chromatin regulators may reinforce permissive transcriptional states, sustain inflammation, or favor pathogen persistence.

By increasing chromatin accessibility and disrupting the balance of histone modification enzymes, S. aureus creates a nuclear environment more vulnerable to genotoxic stress. These chromatin changes may not only facilitate the induction of DNA damage but also contribute to immune evasion and intracellular persistence. Thus, chromatin remodeling emerges as an early and critical component of S. aureus-associated genomic instability.

By increasing chromatin accessibility and disrupting the balance between histone acetylation and deacetylation, S. aureus creates a nuclear environment more vulnerable to genotoxic stress. Decompressed chromatin is more prone to DNA DSBs and oxidative lesions, thereby coupling epigenetic deregulation to genomic instability. At the same time, the suppression of repressive complexes compromises the host's ability to restore transcriptional control, promoting conditions that favor persistent infection.

Thus, chromatin remodeling emerges not only as an early marker of S. aureus infection but also as a central process integrating DNA damage with immune evasion strategies and driving long-term reprogramming of host cells. By altering histone modifications, weakening repressive complexes, and increasing chromatin accessibility, S. aureus establishes a nuclear environment prone to genomic instability while simultaneously reshaping immune responses. This coordinated remodeling provides the pathogen with both immediate advantages for intracellular survival and long-term conditions that sustain persistent infection.

Thus, S. aureus can act as a genotoxic pathogen, directly inducing DNA damage and epigenetic reprogramming that destabilize host genomic integrity, promote chronic inflammation, and establish cellular states favoring persistent infection and long-term tissue pathology.

## DDR in the context of S. aureus infection

During S. aureus infection, the DDR represents a key cellular mechanism engaged to counteract genotoxic stress. It operates with a dual effect: supporting the host by promoting repair and maintaining genomic stability, while at the same time creating conditions that the pathogen can exploit to dampen immune defenses and enhance persistence. This balance highlights the central role of DDR in the interplay between host protection and bacterial survival.

## Epigenetic reprogramming associated with the DDR

If the DNA damage is extensive or persistent, it can overwhelm the repair systems, leading to genomic instability (Wu et al. 2024). In such contexts, the DDR not only orchestrates immediate repair but also reshapes the cell's epigenetic landscape, with lasting consequences on cellular function and fate (Zhao et al. 2023).

Among the mechanisms of S. aureus-induced DNA damage, PSMα peptides have been shown to mediate double-strand breaks

linked to H2AX phosphorylation, a marker of DNA damage and repair. Other bacterial factors may also contribute, but their roles remain to be defined (Deplanche et al. 2019). The formation of γH2AX marks chromatin regions around DNA DSBs, promoting structural changes and serving as a platform for the recruitment of DNA repair proteins, thereby facilitating repair (Kinner et al. 2008). While γ-H2AX itself is not an epigenetic modification, γH2AX formation can influence nearby histone marks and re-shape the local epigenetic landscape, with consequences for gene expression (Carter and Zhao 2021). The recruitment of proteins involved in DNA repair may result in the addition or removal of epigenetic marks such as histone methylation or acetylation, thereby altering gene expression patterns (Fig. 2).

## Activation of DNA repair pathways

The early repair factor 53BP1 facilitates the end-joining of distal DNA ends at the infection site (Panier and Boulton 2014). It was shown that 53BP1 was recruited from the nucleoplasm to nuclear foci in human MG-63 osteoblast and lung epithelial A549 cells with S. aureus-induced DNA damage, implying that the formation of 53BP1 foci is a physiological response to DSBs, coordinated by the activation of the ATM kinase at damaged DNA sites (Deplanche et al. 2019). In addition, DNA repair pathways were identified by transcriptome analysis of human osteoblasts during S. aureus long-term infection (Nicolas et al. 2022). Involvement of the DNA repair in S. aureus infection was further demonstrated by downregulation of diverse repair mechanisms, including homologous recombination, mismatch, base excision, nucleotide excision, and DSB repair in human primary keratinocytes exposed to clinical isolates from patients with premalignant or cancerous skin lesions (Krueger et al. 2022).

## Staphylococcus aureus-induced alteration of host cell cycle progression

The cellular response to DNA damage involves cell cycle arrest, which represents a vital defense against genetic errors and genomic instability (Matthews et al. 2022). During infection, this interaction becomes more complex, as the temporary arrest of the host cell cycle provides time for repair processes, while pathogens manipulate DNA damage responses to enhance their replication and spread (Alekseeva et al. 2013, Naumann et al. 2017, van Elsland and Neefjes 2018). An analysis of the impact of S. aureus on host cell cycle progression showed that the bacteria induced a delay in the G2/M phase transition, which correlated with the accumulation of inactive Cdk1 and unphosphorylated histone H3 (Alekseeva et al. 2013), providing a window of opportunity for repair processes. Furthermore, in a long-term infection model of human osteoblast MG-63 cells with S. aureus with gene set enrichment analysis, altered expression of genes involved in cell cycle pathways, such as cell cycle checkpoints, mitosis, and chromosome maintenance, was detected in bacteria-bearing cells (Nicolas et al. 2022).

Additionally, the transcription of cell cycle pathways was downregulated in human primary keratinocytes exposed to culture filtrates prepared from S. aureus isolates obtained from intraepithelial carcinoma (Krueger et al. 2022). Transcriptomics and proteomics data further supported the notion that secreted S. aureus substances initiate a cell cycle arrest in primary keratinocytes, suggesting an S. aureus mechanism capable of modulating the eukaryotic cell cycle. Many cell cycle-associated genes are repressed in response to cellular stressors, such as oxidative stress and DNA damage. This allows cells to undergo temporary
cell cycle arrest and increase the expression of DNA repair mech-
anisms to facilitate the correction of oxidative lesions (Branzei
and Foiani 2008). The type of repair system that becomes acti-
vated depends on the type of lesion and cell-cycle phase (Branzei
and Foiani 2008). On the other hand, Alekseeva et al. demon-
strated that bacterial internalization and intracellular replication
occurs mostly in the G2 phase, which is associated with a de-
creased production of antimicrobial peptides (AMPs) (Alekseeva
et al. 2013). This suggests that delaying cell cycle transition may
be one of the mechanisms used by S. aureus to survive and propa-
gate inside the host, thereby contributing to the persistence of the
infection.

Putative S. aureus cyclomodulins and nucleomodulins

Knowledge of S. aureus cyclomodulins and nucleomodulins re-
mains limited, marking an emerging field in understanding host-
pathogen interactions. However, it has been demonstrated that
the S. aureus epidermal cell differentiation inhibitor (EDIN) affects
the growth and differentiation of cultured keratinocytes, suggest-
ing interference with host cell cycle control (Sugai et al. 1992).
Furthermore, recent research using human cervix cancer HeLa
cells showed that S. aureus-secreted virulence factors, PSMs, in-
duce a G2/M phase transition delay, which promotes intracellu-
lar bacterial proliferation. Specifically, PSMα1 prolonged this de-
lay, reducing the transcription of antimicrobial peptides hBD3
and hBD9, thereby further supporting S. aureus survival within
host cells (Alekseeva et al. 2013, Deplanche et al. 2015). These
findings suggest that S. aureus possesses effector molecules with
cyclomodulin- or nucleomodulin-like properties. Identifying addi-
tional factors and defining their nuclear targets will be crucial to
elucidate how S. aureus manipulates host genome integrity and to
establish this emerging area as a key aspect of S. aureus pathogen-
esis.

Cellular senescence in S. aureus-infected cells

This delay, reducing the transcription of antimicrobial peptides hBD3 and hBD9, thereby further supporting S. aureus survival within host cells. (Deplanche et al. 2015). Additionally, it was shown that staphylococcal enterotoxin-like toxin O (SEIO) inhibited the proliferation of a broad range of human tumor cell lines (Hodille et al. 2016). These findings may indicate a previously uncharacterized mechanism by which S. aureus promotes infection.

Currently, no nucleomodulins have been conclusively identified
in S. aureus. Nevertheless, there are indirect clues indicating the
existence of staphylococcal nucleomodulins. For example, Ahn et
al. predicted several nuclear targeting proteins with nuclear lo-
calization signals (NLSs) in S. aureus using bioinformatic analysis
(Ahn et al. 2015). These authors identified a total of 51 S. aureus
proteins, 24 of which have known or presumed functions and are
predicted to carry putative NLSs. Among those, β-lactamase and
MsrR were selected to determine nuclear targeting in host cells.
Such screening for nuclear targeting proteins with NLSs and de-
termination of their impact on host cells may lead to important
novel insight into S. aureus pathogenesis.

Cellular senescence in S. aureus-infected cells

Cellular senescence involves stable cell cycle arrest and phe-
notypic alterations, including chromatin modifications and pro-
duction of a pro-inflammatory secretome, preventing the uncon-
trolled growth of damaged cells. Bacteria can trigger senescence
through the induction of chronic DNA damage. This damage oc-

curs either indirectly, via chronic inflammation and subsequent
oxidative stress, or directly through the production of genotox-
ins (Pezone et al. 2023). *Staphylococcus aureus* infection of human
osteoblast MG-63 cells revealed a significant enrichment of the
senescence pathway in infected cells (Nicolas et al. 2022). More-
over, intraperitoneal injections of heat-killed S. aureus induced cel-
lular senescence in mouse limb bones, as was shown by increased
levels of β-galactosidase, an enzyme that is present exclusively in
senescent cells (Deng et al. 2023). It is possible that telomere stress
contributes to this senescence, aligning with its established in-
volvement in infections (Pezone et al. 2023). Systemic S. aureus ex-
posure may also drive telomere shortening in bone marrow cells,
either by triggering immune cell replication and expansion, lead-
ing to telomere shortening through terminal replication effects
(Shay and Wright 2019), or as an inducer of oxidative stress that
causes telomere damage (Fouquerel et al. 2016).

Staphylococcus aureus-induced DNA damage
promotes a host cells apoptosis

If genome integrity is irreparably compromised, e.g. due to DNA
damage, cells can undergo cell death, which can occur via apopto-
sis (Roos et al. 2016, Carneiro and El-Deiry 2020). During infection,
S. aureus induces apoptosis among a wide range of target cells (Du
Toit 2014, Missiakas and Winstel 2021). Using a model of a long-
term S. aureus infection in human osteoblasts, followed by gene
set enrichment analysis, an enhancement of the apoptosis cell
cycle, senescence, and DDR pathways was detected (Nicolas et al.
2022). Furthermore, mice infected with methicillin-resistant S. au-
reus demonstrated higher rates of ROS generation, DNA damage,
apoptosis, up-regulation of pro-apoptotic, and down-regulation
of anti-apoptotic genes in liver tissues compared to the control
group (Elateek et al. 2021). All these findings highlight the con-
nection between DNA damage and apoptosis during S. aureus
infection.

Potential interplay between S. aureus-induced DNA damage, inflammasome activation, and Golgi apparatus dynamics

Bacteria-induced DNA damage can trigger inflammasome ac-
tivation; e.g. type I interferon-dependent DDR signaling in
macrophages promotes inflammasome activity and cytokine pro-
duction (Morales et al. 2017). *Staphylococcus aureus* induces type
I interferon via TLR9, suggesting its DNA damage may similarly
stimulates inflammasome activity.

The Golgi apparatus also responds to DNA damage: the
GOLPH3-MYO18A complex controls vesicle trafficking, and phos-
phorylation of GOLPH3 enhances vesiculation and Golgi frag-
mentation, promoting cell survival following genotoxic stress
(Buschman et al. 2015). *Staphylococcus aureus*-induced host DNA
damage could plausibly induce comparable Golgi dynamics, af-
fecting host-pathogen interactions.

Thus, during S. aureus infection, the DDR both protects the host
by promoting repair and genomic stability, and is subverted by the
bacterium to remodel host epigenetics, enabling persistence and
immune evasion.

Staphylococcus aureus and host DDR: friend or foe?

Staphylococcus aureus induces ROS-mediated DNA damage, triggering subsequent DNA repair mechanisms (Deplanche et al. 2019). It also delays the G2/M phase transition (Alekseeva et al. 2013), a process that likely facilitates the repair of damaged DNA
(Matthews et al. 2022). The DDR mechanisms depend on both the type of damage and the cell-cycle stage. In the G2 phase, DSBs are efficiently repaired through homologous recombination (HR) using the sister chromatid as a template. However, as cells progress into G2-M, chromatin condensation complicates the homology search, hindering efficient repair (Branzei and Foiani 2008).

The consequences of *S. aureus*-induced G2/M delay have been shown to promote bacterial intracellular replication during the G2 phase, which is associated with reduced production of AMPs. This reduction may contribute to the persistence of the infection. DDR activation may therefore create a more favorable environment for bacterial replication by suppressing immune responses or maintaining host cell viability.

This duality raises a critical question: Is DDR activation a genuine host cellular response aimed at repairing damage caused by *S. aureus* infection, or is it subverted by *S. aureus* to enhance its intracellular survival? Elucidating this interplay could uncover novel targets for host-directed therapies against persistent staphylococcal infections.

## Conclusion and outlook: from DNA damage to disease progression

Persistent *S. aureus* infections demonstrate how bacterial genotoxic stress not only damages host DNA but also reshapes cellular programs through immune suppression, epigenetic remodeling, and chronic inflammation. These interconnected processes create a cellular environment that supports bacterial persistence while predisposing infected tissues to long-term pathologies, including cancer.

A key emerging concept is the link between DNA damage and epigenetic regulation. By altering chromatin organization and transcriptional control, *S. aureus* can evade host immunity and drive durable cellular reprogramming. Recognizing *S. aureus* as both a toxin-producing and a genotoxic pathogen emphasizes its long-term impact on host health. Importantly, these insights reveal new therapeutic strategies, including interventions targeting DNA damage-induced epigenetic changes or stimulating trained immunity (a form of innate immune memory driven by metabolic and epigenetic reprogramming). Such approaches may complement conventional antibiotic therapy to limit bacterial persistence and chronic pathology. Ongoing research will further clarify the temporal and mechanistic links between DNA damage and epigenetic remodeling, guiding the development of host-directed therapies.

Looking forward, broader questions remain:

How do DDRs integrate with host stress responses, such as inflammasome activation, Golgi sensing, or autophagy? At what stage of infection (acute vs. chronic) does DNA damage play the most decisive role in persistence or disease progression? Addressing these gaps will require advanced multi-omics and spatial biology approaches, such as single-cell and spatial transcriptomics to integrate molecular, cellular, and tissue-level responses. Such approaches timing and context of DDR activation, and identify actionable therapeutically relevant host pathways.

Overall, this integrated perspective redefines *S. aureus* pathogenesis, highlighting its genotoxic activity as a driver of persistent infection and long-term host remodeling, and emphasizes the potential of host-directed and epigenetic-targeting strategies as innovative therapeutic options in the era of antibiotic resistance.

## Acknowledgments

We are grateful to Dr. Aurélie Nicolas for assistance with figure preparation and formatting for publication

## Author contribution

Nadia Berkova (Conceptualization, Writing – original draft, Visualization, Funding acquisition, Supervision, Writing – review & editing), Eric Guédon (Funding acquisition, Review & Editing), Yves Le Loir (Visualization, Funding acquisition, Review & Editing), Michael Otto (Conceptualization, Funding acquisition, Supervision, Writing – review & editing)

*Conflict of interest:* The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Funding

This work has received financial support from INRAE (Rennes, France) and Institut Agro (Rennes, France) (NB, EG, YLL). YLL and NB were supported by a Metaprogram INRAE, GISA, LONGhealth- MPP10573. MO was supported by Intramural Research Program of the National Institute of Allergy and Infectious Diseases (project number AI000904, M.O.). The contributions of the NIH authors were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services.

## Data Availability

Data sharing is not applicable to this article as no new data were created or analyzed in this study. All data and information are cited within the manuscript's reference list.

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