Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a serious global health problem that kills over 1 million people annually. Understanding the pathogenesis of TB and the emergence of drug-resistant strains of Mtb is a priority for the development of strategies against TB. Its DNA damage and repair systems are essential for maintaining genome stability in Mtb. Their aberrant work leads to hypermutability and is often associated with the emergence of resistant bacteria. On the other hand, Mtb infection also induces genome instability of host cells, which are involved in the pathogenesis of TB, including the formation of giant cells. Collectively, this review is an attempt to summarize our current understanding of the role of genome instability in the pathogenesis of TB and to shed light on the development of new strategies for TB treatment.

Introduction

Tuberculosis (TB) is a highly infectious disease caused by Mycobacterium tuberculosis (Mtb) and has led to great human suffering worldwide for centuries. According to the WHO report in 2019, approximately 10 million people (range: 8.9–11.0 million) were infected with TB, and 1 million deaths had occurred (Chakaya et al., 2021). While most drug-sensitive TB is curable in about 6 months of treatment, only 50% of multidrug-resistant TB (MDR-TB) cases can be cured using second-line drugs that are generally toxic over a longer usage period. To overcome these challenges, new drugs, including conventional antibiotics and host-directed therapy (HDT) drugs, are needed. One major challenge is the high frequency of spontaneous chromosomal mutations caused by the selective application of antibiotics, which has led to multiple drug resistance and drug efficacy reduction during TB treatment (Balganesh et al., 2012). However, HDT works via a different mechanism to conventional drugs, therefore, has been recognized as a promising strategy to overcome Mtb drug resistance.

Pathogenic bacteria have to cope with a variety of challenges, from host defense systems to antibiotics; they must develop the ability to survive and grow in various hostile environments. The inhalation of aerosol droplets containing intracellular pathogen Mtb into the alveoli of the lungs initiates the TB infection cycle (Smith, 2003). The biological niche of Mtb is the host macrophages. When Mtb enters the host cell, nucleotide damage occurs under various stress conditions, resulting in mutations in the genome and impairment of genomic integrity in the bacteria (Cadet & Wagner, 2014; Cadet et al., 2010). Genomic integrity is a prerequisite for the survival, development, and propagation of all organisms. The inability to rectify such damage is detrimental to the pathogen’s survival in the host. Therefore, Mtb’s ability to withstand various environments and cause disease suggests a strong DNA repair system is required to ensure efficient error-free transmission of genetic material. Years of studies have revealed that Mtb has a remarkably evolved and highly redundant DNA repair system, providing it with robust survivability in harsh environments, such as reactive oxygen species (ROS), reactive nitrogen species (Cole et al., 1998), and low pH generated by the host immune system (Ehrt & Schnappinger, 2009).

Genome instability is a major driver leading to the acquisition of drug resistance in bacteria (Booth et al., 2020). It describes a state of increased tendency to acquire distinct phenotypes based on genetic alterations and displays a process, such as DNA repair, as a consequence of deficient genome maintenance (Ben-David, 2015). Mtb has multiple DNA repair mechanisms, including base excision repair, nucleotide excision repair (NER), and other pathways to restore the damaged genome (Singh, 2017). Understanding these DNA systems is important to aid the development of therapeutic agents that can counteract Mtb evolutionary changes. Antibiotic tolerance is also involved in genome instability, including DNA damage repair and genetic mutations. However, at present, knowledge of genome instability in Mtb remains limited.

Here, we review the current knowledge of genomic instability, mainly targeting DNA damage and repair in mycobacteria in infection and pathogenicity, aiming to highlight their potential impact on the development of novel drugs against TB.

Mtb genomic instability and DNA repair systems

The DNA repair systems in Mtb play essential roles in the pathogenesis and maintenance of genome stability (Gorna et al., 2010). Recent studies have demonstrated that the DNA repair-related genes are expressed differentially at each stage of Mtb infection (Gorna et al., 2010). In the following sections, we briefly introduce some DNA repair systems in Mtb and aim to improve our understanding of how these systems impact the infection processes and pathogen evolution.

Base excision repair (BER)

BER is of interest due to its ability to repair uracil and 7, 8-dihydro-8-oxoguanine (8-oxoG) since mycobacteria possess a GC-rich genome (Mizrahi & Andersen, 1998; Naz et al., 2021). Uracil DNA glycosylase (MacMicking et al.) catalyzes the removal of uracil from DNA, which promotes the uracil excision repair pathway (Krokan et al., 2002; Kurthkoti & Varshney, 2011). Ung and UdgB, which belong to the UDG family and are involved in uracil excision repair of Mtb, were found not relevant to growth in vitro (Kurthkoti & Varshney, 2010). The simultaneous deletion of Ung and UdgB in Mycobacterium smegmatis (Msm) showed a synergistic effect on the accumulation of mutations (Malshetty et al., 2010). It would be of interest to generate similarly mutated strains in Mtb and look at the growth of pathogens in all conditions. In addition, two DNA glycosylases (Fpg/MutM and MutY) and a nucleotide hydrolase (MutT) involved in the GO repair pathway, minimized the chances of misincorporation into DNA (Jain et al., 2007; Kurthkoti et al., 2010). The GO system forms part of the BER pathway and specifically recognizes and repairs the oxidized form of 8-oxoG and associated mismatches (van der Veen & Tang, 2015). Mycobacterial DNA polymerases have different properties regarding the incorporation of 8-oxoG in DNA. Multiple homologs in Mtb mutated strains involved in the GO repair pathway are critical for the survival of Mtb in the host cell and require further exploration. Moreover, Khanam et al. found that Mtb class-II AP-endonuclease (XthA) engaged with NAD + -dependent DNA ligase (LigA) to counter futile cleavage and ligation cycles that might derail bacterial BER (Khanam et al., 2020).

Nucleotide excision repair (NER)

Nucleotide excision repair (NER) is an important DNA repair pathway that is used to remove many bulky DNA adducts, such as cisplatin interstrand cross-links, cyclobutene pyrimidine dimers, and alkylation adducts in bacteria (Grossman & Thiagalingam, 1993; Kisker et al., 2013). Similar to many other bacteria, NER plays a key role in the growth or virulence in Mtb, including Mtb uvrA, uvrB, or uvrC mutant strains induced by UV irradiation and mitomycin C (Darwin & Nathan, 2005). Mtb uvrA is implicated to be important for optimal growth in the presence of DNA damaging agents (Rossi et al., 2011; Springall et al., 2018). In uvrB-deficient Mtb infected mice, the virulence of Mtb is markedly reduced (Darwin & Nathan, 2005). Mtb UvrB possesses ATP-dependent DNA helicase activity and its formed dimers bound to UvrA in the absence of any ligands (Lahiri et al., 2018; Thakur et al., 2016). Mtb uvrC is essential for Mtb DNA repair system, particularly in response to DNA damage caused by UV irradiation (Prammananan et al., 2012). The pairwise relationships of the UvrABC incision complex has been reported to promote the development of new therapeutics (Mazloum et al., 2011; Thakur et al., 2020). Overall, the divergence of the bacterial NER machinery remains challenging.

Mismatch repair (MMR)

MMR recognizes mismatched bases and is widely conserved across prokaryotes, maintaining genetic stability and integrity (Li et al., 2016). The complete genome sequence of Mtb revealed that Mtb lacks the classical form of the MMR pathway, suggesting a high level of genetic variation occurred, and its loss has a pivotal role in the biological consequences (Cole et al., 1998; Mizrahi & Andersen, 1998). Recent reports discovered a non-canonical form of MMR in Msm and Mtb, NucS/EndoMS. This endonuclease reduces the hypermutator phenotype, avoids a transition-biased mutational spectrum, and decreases homologous recombination (Castaneda-Garcia et al., 2017; Cebrian-Sastreet al., 2021). MMR defects are often associated with the emergence of resistant bacteria; thus the NucS pathway seems to be a promising target on which to focus to prevent TB drug-resistant mutations in the future (McGrath et al., 2014).

Double-strand breaks (DSBs) repair

Cell death is inevitable when DSBs remain unrepaired. Common homologous recombination (HR), mycobacterial-specific non-homologous end-joining (NHEJ), and single-strand annealing (Gutierrez et al.) are considered to be the three main pathways for processing DSBs in Mtb (Dos Vultos et al., 2009). HR is an error-free mechanism of the DSB damage repair system when the chromosome is damaged, but the second copy is still available to use as a DNA template (Dos Vultos et al., 2009). RecA, a RecFOR pathway product, initiates the exchange between the damaged and homologous DNA strands with further help from the RuvABC (a helicase) and RecG (an endonuclease) complexes (Singh et al., 2016). A recent study established a link between DNA repair, drug efflux, and biofilm formation and validated RecA as an effective drug target in Mtb and Msm (Hans et al., 2020). Further studies are required to research the endonuclease involved in HR pathways. Repetitive DNA induces deletions and translocations and promotes speculation that NHEJ is the major pathway when there is no homologous DNA template (Kurahashi et al., 2006). The NHEJ apparatus is encoded by the evolutionarily conserved ku and ligD genes (Della et al., 2004; Kha et al., 2010; Pitcher et al., 2007). Ku is a DNA-end binding protein and stimulates LigD to seal the broken ends in NHEJ, but also activates the helicase activity of UvrD1 and UvrD2 (Brissett et al., 2007; Sinha et al., 2007; Williams et al., 2011). LigD acts as a multifunctional enzyme (Della et al., 2004). RecBCD, a helicase-nuclease complex, is associated with a SSA mechanism (Amundsen et al., 2012) and mediates non-recombination-based SSA in mycobacteria, and the recombination repair of DSBs in E. coli (Singh et al., 2016). Gupta et al. found that mycobacterial RecBCD is required for the RecA-independent SSA pathway. They further demonstrated that mycobacteria RecBCD and AdnAB helicase-nuclease machines dedicate to distinct repair pathway (Gupta et al., 2011). The RecA-dependent HR pathway is considered to be the major mechanism for repairing DSBs to date. Meanwhile, identification of orthologs of NHEJ and SSA in mycobacteria provide new insights (Heaton et al., 2014).

Antibiotic tolerance: Mtb genome instability in response to antibiotic stress

Tolerance is influenced by both environmental and genetic factors, and also refers to the bacterial host resisting deadly doses of antibiotics after a transient exposure (Balaban et al., 2019; Brauner et al., 2016). How does antibiotic tolerance occur in Mtb referring to the genetic aspects related to DNA repair?

The genetic basis of the balance of resistance development, including DNA damage, recombination, replication fidelity, mutation, and genome maintenance, help improve or extend the efficacy of anti-TB drugs. A novel notion of DNA damage repair interference might be an effective strategy to get rid of the persister cell population, as supported by the changes in post-antibiotic treatment (Mittal et al., 2020). For instance, inhibition of DNA gyrase by fluoroquinolone modulates Mtb growth and also contributes to the drug tolerance via RecA/LexA-mediated SOS response (Choudhary et al., 2019). Meanwhile, DNA gyrase knockdown Mtb decreased drug susceptibility to rifampin (RIF), isoniazid (INH), and ethambutol (EMB) post-treatment (Choudhary et al., 2019).

Many studies observed that bactericidal antibiotic-induced ROS could lead to cell death due to oxidative damages to DNA (Belenky et al., 2015; Kohanski et al., 2007; Nandakumar et al., 2014). In particular, lethal doses of bactericidal antibiotics inducing DSBs in a ROS-dependent manner were confirmed in Mtb and Msm (Belenky et al., 2015; Foti et al., 2012; Singh, 2017). Recent findings revealed the oxidized dGTP (8-oxo-dGTP) not only contributed to the generation of ROS but also incorporated DNA polymerase and generated DSBs through incomplete BER (Foti et al., 2012; Gutierrez et al., 2013). In an Mtb infected mice model, the deletion of mycobacterial mazG, which encodes 5-OH-dCTP (an oxidized form of dCTP), resulted in a high frequency of genomic mutation and caused attenuation of virulence (Lyu et al., 2013). A new model for 5-OH-dCTP was further provided to incorporate genomic DNA via DnaE2, and incomplete repair of 5-OH-dC lesions via Nth, resulting in the generation of lethal DSBs and provides a broad view of ROS-mediated antibiotic lethality in the stationary phase (Fan et al., 2018) (Fig. 1).

Schematics of genome instability in TB pathogenesis. Both of Mtb’s genome instability including DNA damage caused by antibiotics and host stress, and host cell’s genome instability induced by Mtb infection are involved in the pathogenesis of TB

Phenotypic diversity usually arises from transient changes in gene expression during clinical infections and is associated with drug tolerance and genetic resistance (Veening et al., 2008). Mtb is a very smart and successful pathogen. In terms of drug resistance, Mtb shows considerable heterogeneity and diversification (Dhar et al., 2016). The heterogeneity in these processes is always of importance to the clinical implication, and DNA repair systems in Mtb contribute to its long-term survival under mutagenic stress (Ackermann, 2015; Dhar et al., 2016; Flentie et al., 2016). RecA, a known cornerstone of the DNA damage-related SOS response, helps resolve DNA lesions when DNA repair has failed (Baharoglu & Mazel, 2014; Singh, 2017). RecA serine 207, a multifunctional signaling hub involved in DNA damage, controls mutagenesis and antibiotic resistance in mycobacteria through phosphorylation and cardiolipin-mediated inhibition of RecA coprotease function (Wipperman et al., 2018). Interestingly, Manina et al. reported that the preexisting phenotypic variation in the DNA damage response is associated with differential susceptibility to fluoroquinolones (Manina et al., 2019). Furthermore, a recent whole-genome sequencing-based study showed the detected drug-resistant mutations and their frequencies in TB patients were pncA G132S (0.5%), embB M306L (0.53%), and katG A65T (0.51%), suggesting that heteroresistance less than 1% is not associated with poor treatment outcomes (Chen et al., 2021). Therefore, further exploration of the interplay between genome instability and anti-TB drug tolerance will facilitate the development of new drugs with improved outcomes in TB patients.

DNA repair in bacterial survival and within host adaption

The interaction between the host and the pathogen is extremely complex and is affected by anatomical, physiological, and immunological diversity in the microenvironment. As one of the most successful human pathogens, Mtb can reside within host macrophages and evade macrophage defenses. Macrophages produce ROS and RNS, which are essential to control mycobacterial infection (Adams et al., 1997; Darwin et al., 2003; MacMicking et al., 1997) (Fig. 1). Progress in mycobacterial DNA repair has identified several processes that are important for survival within the host. The NER system is reported to counteract the oxidative and nitrosative stress within macrophages (Darwin & Nathan, 2005; Darwin et al., 2003). Transposon sequencing and genetic deletion experiments suggest that the Uvr system is required for optimal growth of Mtb in macrophages and the mouse model (Darwin & Nathan, 2005; Rengarajan et al., 2005). Other studies have also confirmed the role of the BER system in Mtb survival within the host. Nfo, a BER enzyme, is required 1 week after infection, while ung and xthA, members of the BER system, are required for in vivo growth at the 2-week time point (Sassetti & Rubin, 2003). nei2 (Rv3297), a BER glycosylase, is required for successful infection and growth of Mtb in primate hosts (Dutta et al., 2010). Targeting the BER and NER pathways would be a strategy to develop new anti-TB drugs.

Continuous exposure to a multitude of DNA-damaging stresses within the host also compromises bacterial fitness by increasing genomic instability. A recent study revealed that an enhanced mutation rate is associated with ROS and related to the host environment (Poetsch, 2020). High rates of mutations were observed from HIV-negative but not HIV-positive individuals, suggesting that the mutations could be driven by immune pressure (Liu et al., 2020). Single nucleotide polymorphism (SNP) analysis of DNA repair, recombination, and replication genes of Mtb strains revealed a high level of SNPs compared to house-keeping genes (Dos Vultos et al., 2008) (Fig. 1). A recent study provided evidence that DNA repair systems are involved in Mtb within host adaptation. Liu et al. (2021) showed specific positive selection for mutations in DNA repair-associated genes (dnaE2, recB, and mfd) from Tibetan strains, and those mutations in dnaE2 and recB tended to be loss-of-function mutations (Liu et al., 2021). Warner et al., (2010) found that the imuA’-imuB/dnaE2 might drive the evolution of Mtb within its host (Warner et al., 2010)This study provides evidence that local pressures (cold stress and hypoxia) on the Tibetan Plateau selected for Mtb strains that had adapted to this environment (Liu et al., 2021). Using the guinea pig model of infection, Naz et al. found that double deletion of ung and udgB resulted in significant accumulation of SNPs and higher survival levels, suggesting that absence of a BER pathway leads to higher mutations and provides a survival advantage under stress within the host (Naz et al., 2021). Developing “anti-evolution” drugs to prevent the DNA repair pathways in Mtb within host may also be an attractive strategy.

Induction of host cell genome instability contributes to the pathogenesis of TB

It has been recognized that Mtb infection also induces host cell DNA damage. The level of DNA damage and chromosome damage was significantly higher in TB patients compared with healthy controls, suggesting that Mtb induces genome instability and leads to host DNA damage (Rao et al., 1990; Selek et al., 2012). da Silva et al. reported that TB patients presented with higher frequency of DNA damage and DNA repair dysfunction, but with a low frequency of permanent DNA damage (da Silva et al., 2015). Rv2346c, a member of ESAT-6 like family protein, and SecA2 secretome induce host DNA strand breaks (Lochab et al., 2020; Mohanty et al., 2016). DNA damage and genome instability induced by Mtb infection results in dysregulation of macrophage mitosis and consequently formation of polyploid cells, a hallmark of tuberculous granuloma. Mtb infection leads to activated TLR2-Myc signaling which resulted in inducing DNA damage response to promote the differentiation of polyploid macrophages in human granulomas (Herrtwich et al., 2016). The primary cellular component of granuloma is the macrophage, which can determine disease outcome for Mtb infections. Therefore targeting to host DNA damage-induced polyploid macrophage by Mtb could offer new opportunities for therapeutic strategy of TB. (Herrtwich et al., 2016). A recent study revealed that Mtb activates the host ATM-Chk2 pathway of DNA damage response (DDR) signaling instead of the classical ATM-Chk2 DDR to gain a survival advantage through the ATM-Akt signaling cascade. Combining ATM inhibitor, KU55933 with isoniazid promotes the clearance of Mtb in vivo and in vitro, suggesting the potential for targeting host ATM-Akt pathway for host-directed adjunct therapy (Lochab et al., 2020).

Conclusions

DNA repair pathways enable Mtb to survive DNA damage induced by antibiotic and host stress; therefore, targeting DNA repair pathways might prove efficacious when performed in combination with first and second-line TB drugs. As the DNA repair systems in Mtb are distinct from humans at the biochemical and structural level, drugs that inhibit Mtb DNA repair pathways have the potential advantage to be selective for Mtb with fewer side effects. For now, there is no approved TB drugs targeting DNA repair systems. Recently, several natural products were found to be effective in killing Mtb via targeting DNA repair-associated genes (Jadaun et al., 2015; Kling et al., 2015), which support the potential for new drug discovery in this area. However, it should be noted that antibiotic or host stress-induced mutations in DNA repair systems may also provide a mechanism for Mtb to develop resistance and evolve within the host. A detailed understanding of the different players, which are involved in mutagenesis can provide insights into the mechanism of drug resistance and allow better management of available therapeutics. Antibiotic tolerance in Mtb at the genetic level, such as DNA damage repair interference, has always been a research area worthy of further exploration and may shorten the duration of curative treatment. Besides, Mtb modulates the host genomic integrity for its survival and granuloma formation, targeting host cell DNA repair pathways might be a potential HDT strategy for TB treatment.

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Acknowledgements

This work was supported by the Natural Science Foundation of China (grant nos. 82072252 and 91942315) and Guangdong Provincial Key Laboratory of Regional Immunity and Diseases (grant no. 2019B030301009). We thank Dr. Jessica Tamanini at Shenzhen University Health Science Center for editing the manuscript prior to submission.

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Affiliations

1. Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, China

   Kehong Zhang, Yuping Ning, Xinchun Chen & Yi Cai

2. Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Philosophenweg 14, Jena, Germany

   Kehong Zhang & Yuping Ning

3. Harbin Thoracic Hospital, Harbin, China

   Fanhui Kong

Corresponding author

Correspondence to Yi Cai.

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Zhang, K., Ning, Y., Kong, F. et al. Genome instability in pathogenesis of tuberculosis. GENOME INSTAB. DIS. 2, 331–338 (2021). https://doi.org/10.1007/s42764-021-00057-8

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• Received08 October 2021

• Revised18 November 2021

• Accepted18 November 2021

• Published23 November 2021

• Issue DateDecember 2021

• DOIhttps://doi.org/10.1007/s42764-021-00057-8

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Keywords

• Genome instability

• Mycobacterium tuberculosis

• DNA damage and repair

• Drug-resistance

• Pathogenesis