Molecular Mechanisms of Host-Bacterial Pathogen Interactions: Novel Promising Drug Targets

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 26436

Special Issue Editor


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Guest Editor
IBB-Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Lisbon, Portugal
Interests: microbiology; antimicrobial agents; immunotherapy and vaccines against bacterial infections; nosocomial infections; Cystic Fibrosis
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Special Issue Information

Dear Colleagues,

Infectious diseases still constitute a threat to animal and human life. The increase in antibiotic resistance in a multitude of bacterial infectious diseases highlights the need for new targets for drug development. In particular, bacterial pathogens have evolved multiple mechanisms that interfere with or stimulate a variety of host-cell responses in order to invade, survive, and proliferate within their hosts. The knowledge of how pathogens interact with their hosts can be the basis for the development of novel therapeutic approaches for treatment and/or prevention of bacterial infections. Some promising bacterial targets have been already described, such as targets that regulate virulence factor expression and/or secretion and targets that modulate host-cells defense pathways. However, the identification of these drug targets is still complex, requiring an extensive knowledge about the complex interplay between the pathogen and the host. One of the current strategies that enable these studies is host-pathogen interactome analysis.

We cordially invite investigators within this field of study, to submit original research or review articles about the molecular mechanisms of specific host-bacteria interactions, and their potential as targets for drug discovery. 

Dr. Sílvia A. Sousa
Guest Editor

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Keywords

  • host-pathogen interactome
  • cell-to-cell communication during host–pathogen infection
  • bacteria-epithelium interaction
  • bacterial targets that regulate virulence factor expression and/or secretion
  • bacterial targets that modulate host-cells defense pathways

Published Papers (6 papers)

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Research

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15 pages, 1801 KiB  
Article
Investigating the Antibacterial Properties of Prospective Scabicides
by Sara Taylor, Deonne Walther, Deepani D. Fernando, Pearl Swe-Kay and Katja Fischer
Biomedicines 2022, 10(12), 3287; https://doi.org/10.3390/biomedicines10123287 - 19 Dec 2022
Cited by 1 | Viewed by 2514
Abstract
Scabies is a dermatological disease found worldwide. Mainly in tropical regions, it is also the cause of significant morbidity and mortality due to its association with potentially severe secondary bacterial infections. Current treatment strategies for scabies do not consider the role of opportunistic [...] Read more.
Scabies is a dermatological disease found worldwide. Mainly in tropical regions, it is also the cause of significant morbidity and mortality due to its association with potentially severe secondary bacterial infections. Current treatment strategies for scabies do not consider the role of opportunistic bacteria, and here we investigate whether current and emerging scabicides can offer any anti-bacterial protection. Using the broth microdilution method, we examined antimicrobial potential of the current scabicide ivermectin and emerging scabies treatments: abametapir, mānuka oil, and its individual β-triketones. Our results demonstrate that the two novel scabicides abametapir and mānuka oil have antimicrobial properties against common scabies-associated bacteria, specifically Staphylococcus aureus, Streptococcus pyogenes, Streptococcus dysgalactiae subsp. equisimilis and Acinetobacter baumannii. The current scabicide ivermectin offers some antimicrobial activity and is capable of inhibiting the growth aforementioned bacteria. This research is important as it could help to inform future best treatment options of scabies, and scabies-related impetigo. Full article
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15 pages, 3943 KiB  
Article
VraSR Regulatory System Contributes to the Virulence of Community-Associated Methicillin-Resistant Staphylococcus aureus (CA-MRSA) in a 3D-Skin Model and Skin Infection of Humanized Mouse Model
by Nilakshi Barua, Ying Yang, Lin Huang and Margaret Ip
Biomedicines 2022, 10(1), 35; https://doi.org/10.3390/biomedicines10010035 - 24 Dec 2021
Cited by 4 | Viewed by 2848
Abstract
The vancomycin-resistance associated sensor/regulator, VraSR two-component regulatory-system (VraSR), regulates virulence and the response of Staphylococcus aureus (SA) to environmental stress. To investigate the role of VraSR in SA skin and soft tissue infections (SSTI), we inactivated the VraSR of a clinical [...] Read more.
The vancomycin-resistance associated sensor/regulator, VraSR two-component regulatory-system (VraSR), regulates virulence and the response of Staphylococcus aureus (SA) to environmental stress. To investigate the role of VraSR in SA skin and soft tissue infections (SSTI), we inactivated the VraSR of a clinical CA-MRSA ST30 strain by insertional mutation in vraR gene using the TargeTron-Gene Knockout System. We constructed an organotypic keratinocyte fibroblast co-culture (3D-skin model) and a humanized mouse as SSTI infection models. In the 3D-skin model, inactivation of VraSR in the strains ST30 and USA300 showed 1-log reduction in adhesion and internalization (p < 0.001) compared to the respective wildtype. The mutant strains of ST30 (p < 0.05) and USA300-LAC (p < 0.001) also exhibited reduced apoptosis. The wildtype ST30 infection in the humanized mouse model demonstrated increased skin lesion size and bacterial burden compared to BALB/c mice (p < 0.01). The response of the humanized mouse towards the MRSA infection exhibited human similarity indicating that the humanized mouse SSTI model is more suitable for evaluating the role of virulence determinants. Inactivation of VraSR in ST30 strain resulted in decreased skin lesion size in the humanized mouse SSTI model (p < 0.05) and reduction in apoptotic index (p < 0.01) when compared with the wildtype. Our results reveal that inactivating the VraSR system may be a potent anti-virulence approach to control MRSA infection. Full article
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18 pages, 1421 KiB  
Article
A Polyclonal Antibody Raised against the Burkholderia cenocepacia OmpA-like Protein BCAL2645 Impairs the Bacterium Adhesion and Invasion of Human Epithelial Cells In Vitro
by António M. M. Seixas, Sílvia A. Sousa, Joana R. Feliciano, Sara C. Gomes, Mirela R. Ferreira, Leonilde M. Moreira and Jorge H. Leitão
Biomedicines 2021, 9(12), 1788; https://doi.org/10.3390/biomedicines9121788 - 29 Nov 2021
Cited by 6 | Viewed by 2287
Abstract
Respiratory infections by bacteria of the Burkholderia cepacia complex (Bcc) remain a life threat to cystic fibrosis (CF) patients, due to the faster lung function decline and the absence of effective eradication strategies. Immunotherapies are regarded as an attractive alternative to control and [...] Read more.
Respiratory infections by bacteria of the Burkholderia cepacia complex (Bcc) remain a life threat to cystic fibrosis (CF) patients, due to the faster lung function decline and the absence of effective eradication strategies. Immunotherapies are regarded as an attractive alternative to control and reduce the damages caused by these infections. In this work, we report the cloning and functional characterization of the OmpA-like BCAL2645 protein, previously identified and found to be immunoreactive against sera from CF patients with a record of Bcc infections. The BCAL2645 protein is shown to play a role in biofilm formation, adherence to mucins and invasion of human lung epithelial cells. The expression of the BCAL2645 protein was found to be increased in culture medium, mimicking the lungs of CF patients and microaerophilic conditions characteristic of the CF lung. Moreover, a polyclonal antibody raised against BCAL2645 was found to inhibit, by about 75 and 85%, the ability of B. cenocepacia K56-2 to bind and invade in vitro CFBE41o- human bronchial epithelial cells. These results highlight the potential of anti-BCAL2645 antibodies for the development of passive immunization therapies to protect CF patients against Bcc infections. Full article
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Review

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13 pages, 302 KiB  
Review
Recent Developments in Mycobacteria-Based Live Attenuated Vaccine Candidates for Tuberculosis
by Mario Alberto Flores-Valdez, Andreas Kupz and Selvakumar Subbian
Biomedicines 2022, 10(11), 2749; https://doi.org/10.3390/biomedicines10112749 - 29 Oct 2022
Cited by 9 | Viewed by 2245
Abstract
Vaccination is an excellent approach to stimulating the host immune response and reducing human morbidity and mortality against microbial infections, such as tuberculosis (TB). Bacillus Calmette–Guerin (BCG) is the most widely administered vaccine in the world and the only vaccine approved by the [...] Read more.
Vaccination is an excellent approach to stimulating the host immune response and reducing human morbidity and mortality against microbial infections, such as tuberculosis (TB). Bacillus Calmette–Guerin (BCG) is the most widely administered vaccine in the world and the only vaccine approved by the World Health Organization (WHO) to protect against TB. Although BCG confers “protective” immunity in children against the progression of Mycobacterium tuberculosis (Mtb) infection into active TB, this vaccine is ineffective in protecting adults with active TB manifestations, such as multiple-, extensive-, and total-drug-resistant (MDR/XDR/TDR) cases and the co-existence of TB with immune-compromising health conditions, such as HIV infection or diabetes. Moreover, BCG can cause disease in individuals with HIV infection or other immune compromises. Due to these limitations of BCG, novel strategies are urgently needed to improve global TB control measures. Since live vaccines elicit a broader immune response and do not require an adjuvant, developing recombinant BCG (rBCG) vaccine candidates have received significant attention as a potential replacement for the currently approved BCG vaccine for TB prevention. In this report, we aim to present the latest findings and outstanding questions that we consider worth investigating regarding novel mycobacteria-based live attenuated TB vaccine candidates. We also specifically discuss the important features of two key animal models, mice and rabbits, that are relevant to TB vaccine testing. Our review emphasizes that the development of vaccines that block the reactivation of latent Mtb infection (LTBI) into active TB would have a significant impact in reducing the spread and transmission of Mtb. The results and ideas discussed here are only based on reports from the last five years to keep the focus on recent developments. Full article
19 pages, 1538 KiB  
Review
Intracellular Habitation of Staphylococcus aureus: Molecular Mechanisms and Prospects for Antimicrobial Therapy
by Josefien W. Hommes and Bas G. J. Surewaard
Biomedicines 2022, 10(8), 1804; https://doi.org/10.3390/biomedicines10081804 - 27 Jul 2022
Cited by 20 | Viewed by 6174
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) infections pose a global health threat, especially with the continuous development of antibiotic resistance. As an opportunistic pathogen, MRSA infections have a high mortality rate worldwide. Although classically described as an extracellular pathogen, many studies have shown over the [...] Read more.
Methicillin-resistant Staphylococcus aureus (MRSA) infections pose a global health threat, especially with the continuous development of antibiotic resistance. As an opportunistic pathogen, MRSA infections have a high mortality rate worldwide. Although classically described as an extracellular pathogen, many studies have shown over the past decades that MRSA also has an intracellular aspect to its infectious cycle, which has been observed in vitro in both non-professional as well as professional phagocytes. In vivo, MRSA has been shown to establish an intracellular niche in liver Kupffer cells upon bloodstream infection. The staphylococci have evolved various evasion strategies to survive the antimicrobial environment of phagolysosomes and use these compartments to hide from immune cells and antibiotics. Ultimately, the host cells get overwhelmed by replicating bacteria, leading to cell lysis and bacterial dissemination. In this review, we describe the different intracellular aspects of MRSA infection and briefly mention S. aureus evasion strategies. We discuss how this intracellular niche of bacteria may assist in antibiotic tolerance development, and lastly, we describe various new antibacterial strategies that target the intracellular bacterial niche. Full article
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14 pages, 1850 KiB  
Review
Effect of Clostridium butyricum on Gastrointestinal Infections
by Tadashi Ariyoshi, Mao Hagihara, Motomichi Takahashi and Hiroshige Mikamo
Biomedicines 2022, 10(2), 483; https://doi.org/10.3390/biomedicines10020483 - 18 Feb 2022
Cited by 30 | Viewed by 8970
Abstract
Clostridium butyricum is a human commensal bacterium with beneficial effects including butyrate production, spore formation, increasing levels of beneficial bacteria, and inhibition of pathogenic bacteria. Owing to its preventive and ameliorative effects on gastrointestinal infections, C. butyricum MIYAIRI 588 (CBM 588) has been [...] Read more.
Clostridium butyricum is a human commensal bacterium with beneficial effects including butyrate production, spore formation, increasing levels of beneficial bacteria, and inhibition of pathogenic bacteria. Owing to its preventive and ameliorative effects on gastrointestinal infections, C. butyricum MIYAIRI 588 (CBM 588) has been used as a probiotic in clinical and veterinary medicine for decades. This review summarizes the effects of C. butyricum, including CBM 588, on bacterial gastrointestinal infections. Further, the characteristics of the causative bacteria, examples of clinical and veterinary use, and mechanisms exploited in basic research are presented. C. butyricum is widely effective against Clostoridioides difficile, the causative pathogen of nosocomial infections; Helicobacter pylori, the causative pathogen of gastric cancer; and antibiotic-resistant Escherichia coli. Accordingly, its mechanism is gradually being elucidated. As C. butyricum is effective against gastrointestinal infections caused by antibiotics-induced dysbiosis, it can inhibit the transmission of antibiotic-resistant genes and maintain homeostasis of the gut microbiome. Altogether, C. butyricum is expected to be one of the antimicrobial-resistance (AMR) countermeasures for the One-health approach. Full article
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