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Bacterial Adaptation Strategies to the Host: From Acute, Aggressive to Chronic, Dormant Infections

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Microbiology".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 25707

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Prof. Dr. Bettina Löffler

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Institute of Medical Microbiology, Jena University Hospital, Am Klinikum 1, D-07747 Jena, Germany
Interests: toxin-mediated effects in bacterial infections and viral-bacterial co-infections; persistence strategies of pathogens; infection models and testing of therapy strategies; diagnostic microbiology
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Dr. Lorena Tuchscherr

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Institute of Medical Microbiology, Jena University Hospital, 07747 Jena, Germany
Interests: host-pathogen interaction; bacterial interaction; chronic infections; dormant bacterial phenotype
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Dear colleagues,

Host-pathogen interaction is highly dynamic and can turn in aggressive, tissue destructive diseases or only harmless colonization. In this interaction, the microbes employ several strategies to attack the host and establish an infection and at the same time to survive within hosts and enable their long term survival. The microbial flexibility to be adapted to several environments is directly linked to bacterial fitness. To establish an infection microbes produce a lot of virulence factors to damage host cells, to enter deep tissue structures and get nutrients for their growth. However, this aggressive microbial behaviour awake the immune host response which try to eliminate the microbial population. During the infection process, the microbes can switch to a dormant or metabolically less-active phenotypes to enhance their survival. Thus, the chronic phase of infection is defined as an intrinsic relationship between microbes and host where the microbe have a niche to be hidden from antimicrobials and immune response.

Bacteria turn to dormant or sleeping bacterial phenotypes when the nutrients are limited and allow them to save energy in this hostile environment. Sleeping bacterial phenotypes represent a big challenge to physicians because they are tolerant to several antimicrobials that require actively dividing bacterial cells. Furthermore, dormant bacteria can turn to active and aggressive phenotype when new nutrient sources are available, representing a potential risk for developing a new infection.

This switch from aggressive to dormant bacterial phenotype depends on the expression of virulence factors driven by a fine regulatory network and plays an important role in the progress of infection from acute to chronic phase.

This special issue is dedicated to understand the mechanisms that enable bacteria to turn from aggressive to dormant phenotypes that influence the outcome of the infection. Reviews and research articles focusing on understanding the interchange between active/aggressive to chronic dormant bacterial phenotype by multiple approaches that include molecular and cell biology tools, advanced imaging tools and -omics techniques are welcome.

Prof. Dr. Bettina Löffler
Dr. Lorena Tuchscherr
Guest Editors

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Keywords

dormancy
phenotype switching
bacterial stress
survival strategies
persisters
resuscitation
starvation
cell cycle arrest
ATP homeostasis

Related Special Issue

Bacterial Adaptation Strategies to the Host: From Acute, Aggressive to Chronic, Dormant Infections 2.0 in International Journal of Molecular Sciences (2 articles)

Published Papers (8 papers)

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Research

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19 pages, 19940 KiB

Open AccessArticle

Insights into S. aureus-Induced Bone Deformation in a Mouse Model of Chronic Osteomyelitis Using Fluorescence and Raman Imaging

by Shibarjun Mandal, Astrid Tannert, Christina Ebert, Rustam R. Guliev, Yvonne Ozegowski, Lina Carvalho, Britt Wildemann, Simone Eiserloh, Sina M. Coldewey, Bettina Löffler, Luís Bastião Silva, Verena Hoerr, Lorena Tuchscherr and Ute Neugebauer

Int. J. Mol. Sci. 2023, 24(11), 9762; https://doi.org/10.3390/ijms24119762 - 5 Jun 2023

Cited by 1 | Viewed by 2099

Abstract

Osteomyelitis is an infection of the bone that is often difficult to treat and causes a significant healthcare burden. Staphylococcus aureus is the most common pathogen causing osteomyelitis. Osteomyelitis mouse models have been established to gain further insights into the pathogenesis and host response. Here, we use an established S. aureus hematogenous osteomyelitis mouse model to investigate morphological tissue changes and bacterial localization in chronic osteomyelitis with a focus on the pelvis. X-ray imaging was performed to follow the disease progression. Six weeks post infection, when osteomyelitis had manifested itself with a macroscopically visible bone deformation in the pelvis, we used two orthogonal methods, namely fluorescence imaging and label-free Raman spectroscopy, to characterise tissue changes on a microscopic scale and to localise bacteria in different tissue regions. Hematoxylin and eosin as well as Gram staining were performed as a reference method. We could detect all signs of a chronically florid tissue infection with osseous and soft tissue changes as well as with different inflammatory infiltrate patterns. Large lesions dominated in the investigated tissue samples. Bacteria were found to form abscesses and were distributed in high numbers in the lesion, where they could occasionally also be detected intracellularly. In addition, bacteria were found in lower numbers in surrounding muscle tissue and even in lower numbers in trabecular bone tissue. The Raman spectroscopic imaging revealed a metabolic state of the bacteria with reduced activity in agreement with small cell variants found in other studies. In conclusion, we present novel optical methods to characterise bone infections, including inflammatory host tissue reactions and bacterial adaptation. Full article

(This article belongs to the Special Issue Bacterial Adaptation Strategies to the Host: From Acute, Aggressive to Chronic, Dormant Infections)

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18 pages, 5216 KiB

Open AccessArticle

The Direct Anti-Virulence but Not Bactericidal Activity of Human Neutrophil Elastase against Moraxella catarrhalis

by Justyna Roszkowiak, Siobhán McClean, Aleksandra M. Mirończuk and Daria Augustyniak

Int. J. Mol. Sci. 2023, 24(7), 6607; https://doi.org/10.3390/ijms24076607 - 1 Apr 2023

Viewed by 1953

Abstract

Neutrophil elastase (NE) contributes to innate antibacterial defense at both the intracellular (phagocytosis) and extracellular (degranulation, NETosis) levels. Moraxella catarrhalis, a human respiratory pathogen, can exist in an inflammatory milieu which contains NE. No data are available on the action of NE against M. catarrhalis or on the counteraction of NE-dependent host defenses by this pathogen. Using time-kill assays we found that bacteria are able to survive and replicate in the presence of NE. Transmission electron microscopy and flow cytometry studies with NE-treated bacteria revealed that while NE admittedly destabilizes the outer membrane leaflet, it does not cause cytoplasmic membrane rupture, suggesting that the enzyme does not target components that are essential for cell integrity. Using LC-MS/MS spectroscopy we determined that NE cleaved at least three virulent surface proteins in outer membrane vesicles (OMVs) of M. catarrhalis, including OMP CD, McaP, and TbpA. The cleavage of OMP CD contributes to the significant decrease in resistance to serum complement in the complement-resistant strain Mc6. The cleavage of McaP did not cause any sensitization to erythromycin nor did NE disturb its drug action. Identifying NE as a novel but subtle anti-virulence agent together with its extracellularly not-efficient bactericidal activity against M. catarrhalis may facilitate the pathogen’s existence in the airways under inflammation. Full article

(This article belongs to the Special Issue Bacterial Adaptation Strategies to the Host: From Acute, Aggressive to Chronic, Dormant Infections)

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14 pages, 2227 KiB

Open AccessArticle

Liposomal Delivery of Saquinavir to Macrophages Overcomes Cathepsin Blockade by Mycobacterium tuberculosis and Helps Control the Phagosomal Replicative Niches

by David Pires, Manoj Mandal, Jacinta Pinho, Maria João Catalão, António José Almeida, José Miguel Azevedo-Pereira, Maria Manuela Gaspar and Elsa Anes

Int. J. Mol. Sci. 2023, 24(2), 1142; https://doi.org/10.3390/ijms24021142 - 6 Jan 2023

Cited by 8 | Viewed by 2076

Abstract

Mycobacterium tuberculosis is able to establish a chronic colonization of lung macrophages in a controlled replication manner, giving rise to a so-called latent infection. Conversely, when intracellular bacteria undergo actively uncontrolled replication rates, they provide the switch for the active infection called tuberculosis to occur. Our group found that the pathogen is able to manipulate the activity of endolysosomal enzymes, cathepsins, directly at the level of gene expression or indirectly by regulating their natural inhibitors, cystatins. To provide evidence for the crucial role of cathepsin manipulation for the success of tuberculosis bacilli in their intracellular survival, we used liposomal delivery of saquinavir. This protease inhibitor was previously found to be able to increase cathepsin proteolytic activity, overcoming the pathogen induced blockade. In this study, we demonstrate that incorporation in liposomes was able to increase the efficiency of saquinavir internalization in macrophages, reducing cytotoxicity at higher concentrations. Consequently, our results show a significant impact on the intracellular killing not only to reference and clinical strains susceptible to current antibiotic therapy but also to multidrug- and extensively drug-resistant (XDR) Mtb strains. Altogether, this indicates the manipulation of cathepsins as a fine-tuning strategy used by the pathogen to survive and replicate in host cells. Full article

(This article belongs to the Special Issue Bacterial Adaptation Strategies to the Host: From Acute, Aggressive to Chronic, Dormant Infections)

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Review

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15 pages, 684 KiB

Open AccessReview

Critical Assessment of the Prospects of Quorum-Quenching Therapy for Staphylococcus aureus Infection

by Michael Otto

Int. J. Mol. Sci. 2023, 24(4), 4025; https://doi.org/10.3390/ijms24044025 - 16 Feb 2023

Cited by 15 | Viewed by 3106

Abstract

Staphylococcus aureus is an important pathogen that causes a high number of infections and is one of the leading causes of death in hospitalized patients. Widespread antibiotic resistance such as in methicillin-resistant S. aureus (MRSA) has prompted research into potential anti-virulence-targeted approaches. Targeting the S. aureus accessory gene regulator (Agr) quorum-sensing system, a master regulator of virulence, is the most frequently proposed anti-virulence strategy for S. aureus. While much effort has been put into the discovery and screening for Agr inhibitory compounds, in vivo analysis of their efficacy in animal infection models is still rare and reveals various shortcomings and problems. These include (i) an almost exclusive focus on topical skin infection models, (ii) technical problems that leave doubt as to whether observed in vivo effects are due to quorum-quenching, and (iii) the discovery of counterproductive biofilm-increasing effects. Furthermore, potentially because of the latter, invasive S. aureus infection is associated with Agr dysfunctionality. Altogether, the potential of Agr inhibitory drugs is nowadays seen with low enthusiasm given the failure to provide sufficient in vivo evidence for their potential after more than two decades since the initiation of such efforts. However, current Agr inhibition-based probiotic approaches may lead to a new application of Agr inhibition strategies in preventing S. aureus infections by targeting colonization or for otherwise difficult-to-treat skin infections such as atopic dermatitis. Full article

(This article belongs to the Special Issue Bacterial Adaptation Strategies to the Host: From Acute, Aggressive to Chronic, Dormant Infections)

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26 pages, 789 KiB

Open AccessReview

Staphylococcus aureus Genomic Analysis and Outcomes in Patients with Bone and Joint Infections: A Systematic Review

by Kevin Bouiller and Michael Z. David

Int. J. Mol. Sci. 2023, 24(4), 3234; https://doi.org/10.3390/ijms24043234 - 6 Feb 2023

Cited by 2 | Viewed by 2105

Abstract

Many studies have been published assessing the association between the presence of S. aureus genes and outcomes in patients with bone and joint infections (BJI), but it is not known if they have had similar findings. A systematic literature review was performed. All available data on studies in Pubmed between January 2000 to October 2022 reporting the genetic characteristics of S. aureus and the outcomes of BJIs were analyzed. BJI included prosthetic joint infection (PJI), osteomyelitis (OM), diabetic foot infection (DFI), and septic arthritis. Because of the heterogeneity of studies and outcomes, no meta-analysis was performed. With the search strategy, 34 articles were included: 15 articles on children and 19 articles on adults. In children, most BJI studied were OM (n = 13) and septic arthritis (n = 9). Panton Valentine leucocidin (PVL) genes were associated with higher biological inflammatory markers at presentation (n = 4 studies), more febrile days (n = 3), and more complicated/severe infection (n = 4). Other genes were reported anecdotally associated with poor outcomes. In adults, six studies reported outcomes in patients with PJI, 2 with DFI, 3 with OM, and 3 with various BJI. Several genes were associated with a variety of poor outcomes in adults, but studies found contradictory results. Whereas PVL genes were associated with poor outcomes in children, no specific genes were reported similarly in adults. Additional studies with homogenous BJI and larger sample sizes are needed. Full article

(This article belongs to the Special Issue Bacterial Adaptation Strategies to the Host: From Acute, Aggressive to Chronic, Dormant Infections)

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16 pages, 3308 KiB

Open AccessReview

Bacterial Infections and Cancer: Exploring This Association And Its Implications for Cancer Patients

by Kafayat Yusuf, Venkatesh Sampath and Shahid Umar

Int. J. Mol. Sci. 2023, 24(4), 3110; https://doi.org/10.3390/ijms24043110 - 4 Feb 2023

Cited by 23 | Viewed by 7175

Abstract

Bacterial infections are common in the etiology of human diseases owing to the ubiquity of bacteria. Such infections promote the development of periodontal disease, bacterial pneumonia, typhoid, acute gastroenteritis, and diarrhea in susceptible hosts. These diseases may be resolved using antibiotics/antimicrobial therapy in some hosts. However, other hosts may be unable to eliminate the bacteria, allowing them to persist for long durations and significantly increasing the carrier's risk of developing cancer over time. Indeed, infectious pathogens are modifiable cancer risk factors, and through this comprehensive review, we highlight the complex relationship between bacterial infections and the development of several cancer types. For this review, searches were performed on the PubMed, Embase, and Web of Science databases encompassing the entirety of 2022. Based on our investigation, we found several critical associations, of which some are causative: Porphyromonas gingivalis and Fusobacterium nucleatum are associated with periodontal disease, Salmonella spp., Clostridium perfringens, Escherichia coli, Campylobacter spp., and Shigella are associated with gastroenteritis. Helicobacter pylori infection is implicated in the etiology of gastric cancer, and persistent Chlamydia infections present a risk factor for the development of cervical carcinoma, especially in patients with the human papillomavirus (HPV) coinfection. Salmonella typhi infections are linked with gallbladder cancer, and Chlamydia pneumoniae infection is implicated in lung cancer, etc. This knowledge helps identify the adaptation strategies used by bacteria to evade antibiotic/antimicrobial therapy. The article also sheds light on the role of antibiotics in cancer treatment, the consequences of their use, and strategies for limiting antibiotic resistance. Finally, the dual role of bacteria in cancer development as well as in cancer therapy is briefly discussed, as this is an area that may help to facilitate the development of novel microbe-based therapeutics as a means of securing improved outcomes. Full article

(This article belongs to the Special Issue Bacterial Adaptation Strategies to the Host: From Acute, Aggressive to Chronic, Dormant Infections)

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13 pages, 951 KiB

Open AccessReview

The Lung Microbiome: A New Frontier for Lung and Brain Disease

by Jiawen Chen, Ting Li, Chun Ye, Jiasheng Zhong, Jian-Dong Huang, Yiquan Ke and Haitao Sun

Int. J. Mol. Sci. 2023, 24(3), 2170; https://doi.org/10.3390/ijms24032170 - 21 Jan 2023

Cited by 9 | Viewed by 4540

Abstract

Due to the limitations of culture techniques, the lung in a healthy state is traditionally considered to be a sterile organ. With the development of non-culture-dependent techniques, the presence of low-biomass microbiomes in the lungs has been identified. The species of the lung microbiome are similar to those of the oral microbiome, suggesting that the microbiome is derived passively within the lungs from the oral cavity via micro-aspiration. Elimination, immigration, and relative growth within its communities all contribute to the composition of the lung microbiome. The lung microbiome is reportedly altered in many lung diseases that have not traditionally been considered infectious or microbial, and potential pathways of microbe–host crosstalk are emerging. Recent studies have shown that the lung microbiome also plays an important role in brain autoimmunity. There is a close relationship between the lungs and the brain, which can be called the lung–brain axis. However, the problem now is that it is not well understood how the lung microbiota plays a role in the disease—specifically, whether there is a causal connection between disease and the lung microbiome. The lung microbiome includes bacteria, archaea, fungi, protozoa, and viruses. However, fungi and viruses have not been fully studied compared to bacteria in the lungs. In this review, we mainly discuss the role of the lung microbiome in chronic lung diseases and, in particular, we summarize the recent progress of the lung microbiome in multiple sclerosis, as well as the lung–brain axis. Full article

(This article belongs to the Special Issue Bacterial Adaptation Strategies to the Host: From Acute, Aggressive to Chronic, Dormant Infections)

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8 pages, 575 KiB

Open AccessReview

Innovations in Evaluating Statin Benefit and Efficacy in Staphylococcus aureus Intracellular Infection Management

by Erik T. Nesson and Susan A. McDowell

Int. J. Mol. Sci. 2022, 23(21), 13006; https://doi.org/10.3390/ijms232113006 - 27 Oct 2022

Cited by 1 | Viewed by 1373

Abstract

An emerging therapeutic approach in the treatment of infectious disease is to augment the host response through repurposing of well-tolerated, non-antibiotic, host-directed therapeutics. Earlier retrospective studies identify a positive association between statin use and a decreased risk of death due to sepsis or bacteremia. However, more recent randomized control trials fail to detect a therapeutic benefit in these complex infection settings. It is postulated that unrecognized biases in certain observational studies may have led to an overestimation of benefit and that statin use is instead a marker for health status, wealth, and demographic characteristics which may separately affect death due to infection. What remains unresolved is that in vitro and in vivo evidence reproducibly indicates that statin pharmacology limits infection and augments immunomodulatory responses, suggesting that therapeutic benefits may be attainable in certain infection settings, such as intracellular infection by S. aureus. Carefully considering the biological mechanisms capable of driving the relationship between statins and infections and constructing a methodology to avoid potential biases in observational studies would enable the examination of protective effects against infection and limit the risk of underestimating statin efficacy. Such an approach would rely on the examination of statin use in defined infection settings based on an underlying mode-of-action and pharmacology, where the inhibition of HMG-CoA-reductase at the rate-limiting step in cholesterol biosynthesis diminishes not only cholesterol levels but also isoprenoid intermediates central to host cell invasion by S. aureus. Therapeutic benefit in such settings, if existent, may be of clinical importance. Full article

(This article belongs to the Special Issue Bacterial Adaptation Strategies to the Host: From Acute, Aggressive to Chronic, Dormant Infections)

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