Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Jun 25;7(1):199.
doi: 10.1038/s41392-022-01056-1.

Pseudomonas aeruginosa: pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics

Shugang Qin #  1 , Wen Xiao #  1 , Chuanmin Zhou #  2   3 , Qinqin Pu  3 , Xin Deng  4 , Lefu Lan  5 , Haihua Liang  6 , Xiangrong Song  7 , Min Wu  8   9
Affiliations
Review

Pseudomonas aeruginosa: pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics

Shugang Qin et al. Signal Transduct Target Ther. .

Abstract

Pseudomonas aeruginosa (P. aeruginosa) is a Gram-negative opportunistic pathogen that infects patients with cystic fibrosis, burn wounds, immunodeficiency, chronic obstructive pulmonary disorder (COPD), cancer, and severe infection requiring ventilation, such as COVID-19. P. aeruginosa is also a widely-used model bacterium for all biological areas. In addition to continued, intense efforts in understanding bacterial pathogenesis of P. aeruginosa including virulence factors (LPS, quorum sensing, two-component systems, 6 type secretion systems, outer membrane vesicles (OMVs), CRISPR-Cas and their regulation), rapid progress has been made in further studying host-pathogen interaction, particularly host immune networks involving autophagy, inflammasome, non-coding RNAs, cGAS, etc. Furthermore, numerous technologic advances, such as bioinformatics, metabolomics, scRNA-seq, nanoparticles, drug screening, and phage therapy, have been used to improve our understanding of P. aeruginosa pathogenesis and host defense. Nevertheless, much remains to be uncovered about interactions between P. aeruginosa and host immune responses, including mechanisms of drug resistance by known or unannotated bacterial virulence factors as well as mammalian cell signaling pathways. The widespread use of antibiotics and the slow development of effective antimicrobials present daunting challenges and necessitate new theoretical and practical platforms to screen and develop mechanism-tested novel drugs to treat intractable infections, especially those caused by multi-drug resistance strains. Benefited from has advancing in research tools and technology, dissecting this pathogen's feature has entered into molecular and mechanistic details as well as dynamic and holistic views. Herein, we comprehensively review the progress and discuss the current status of P. aeruginosa biophysical traits, behaviors, virulence factors, invasive regulators, and host defense patterns against its infection, which point out new directions for future investigation and add to the design of novel and/or alternative therapeutics to combat this clinically significant pathogen.

PubMed Disclaimer

Conflict of interest statement

The authors have no financial conflict of interest. Xiangrong Song and Min Wu are editorial board members of Signal Transduction and Targeted Therapy, but they have not been involved in the process of the manuscript handling.

Figures

Fig. 1
Fig. 1
Schema of P. aeruginosa pathogenesis. P. aeruginosa can be traced everywhere including hospital environments and cause serious infection of almost any organ. LPS induces TLR-4-dependent and -independent inflammatory responses in the lung after bacterial infection, epithelial cells secrete cytokines and chemokines, thereby recruiting and activating innate immune cells and adaptive immune cells. The recruitment of neutrophils is a sign of inflammatory response activation. Although the activation of neutrophils is critical for host defense, excessively activated immune cell infiltration will cause severe tissue damage and aggravate bacterial infections. Therefore, studying the balance between the virulence factors secreted by bacteria and corresponding host immunity is important for the treatment of infections
Fig. 2
Fig. 2
Protein secretion systems in P. aeruginosa. The secretion systems are divided into two major classes, one-step secretion system (T1SS, T3SS, T6SS) and two-step secretion system (T2SS, T5SS). One-step secretion system exoproteins are directly absorbed into the cytoplasm through their cognate secretion mechanism. In contrast, the exoproteins of two-step secretion system are first exported to the periplasm through the Sec or Tat system, and then crossing outer membranes through specific secretion mechanisms
Fig. 3
Fig. 3
Mechanisms of T3SS and T6SS in regulating bacterial pathogenesis and host responses in P. aeruginosa. LPS is recognized by TLRs (TLR1/2 or TLR4/9) and then activates T3SS and T6SS. T3SS and and T6SS represent a critical network in regulating bacterial behaviors (growth, biofilm formation, and competition) and host defense (host cell apoptosis, inflammatory response, colonization, and motility). T6SS and T3SS interaction and inter-conversion are regulated by RtcB and YbeY. ExoS/ExoU induce P. aeruginosa-afflicted host cell apoptosis and colonization by targeting JNKS signal pathway. ExoY/ExoT reduces inflammasome activity through inhibition of bacterial motility to dampen NF-κB and caspase-1 activation. T6SS is a powerful antibacterial weapon that can be injected through multiple effectors to compete with other bacteria and allows P. aeruginosa colonization and biofilm formation,
Fig. 4
Fig. 4
Mechanisms of antimicrobial resistance in P. aeruginosa. Mechanisms of antimicrobial resistance in P. aeruginosa can be divided into intrinsic antibiotic resistance (① outer membrane permeability, ② efflux systems, and ④antibiotic-modifying enzymes or ⑤ antibiotic-inactivating enzymes), acquired antibiotic resistance (⑥ resistance by mutations and acquisition of resistance genes), and adaptive antibiotic resistance (③ biofilm-mediated resistance). Alteration of outer membrane protein porins decreases the penetration of drugs into cells by reducing membrane permeability. The efflux system directly pumps out drugs. Drug-hydrolyzing and modification enzymes render them inactive. Similarly, some enzymes cause target alterations so that the drug cannot bind its target, resulting in drug inactivity. Antibiotic resistance genes carried on plasmids can be acquired via horizontal gene transfer from the same or different bacterial species, quorum-sensing signaling molecules activate the formation of biofilms, which act as physical barriers and prevent antibiotics penetrating the cell
Fig. 5
Fig. 5
CRISPR-mediated adaptive immunity. Type I-C, type I-E, and type I-F CRISPR-Cas systems have been identified in P. aeruginosa. Type I CRISPR-Cas targeted endogenous LasR gene to decrease TLR4 expression and TLR4-mediated host inflammatory responses. Similarly, type I CRISPR-Cas systems elicited inflammasome activation by promoting mitochondrial-mediated autophagy. Ultimately, CRISPR-mediated adaptive immunity helps P. aeruginosa evade mammalian host immunity
Fig. 6
Fig. 6
Novel therapeutics for P. aeruginosa. Multidrug-resistant P. aeruginosa poses a major challenge to traditional antibiotics therapeutics, which have limited efficacy and cause serious side effects. Phage therapy, immunotherapy, gene editing therapy, antimicrobial peptides, and vaccine therapies have become the most promising strategy and garnered great expectations to overcome multidrug-resistant bacterial infections. A full-scale network of regulatory understanding of P. aeruginosa virulence is expected to be unveiled, thus, we will be in a much better position for rationale drug design to control Pseudomonas aeruginosa infections
Fig. 7
Fig. 7
Interlinked and mechanistic regulatory network in P. aeruginosa. Interactions between various regulatory systems of P. aeruginosa are linked to regulate adaptation, survival, and resistance to multiple antibiotics, enabling P. aeruginosa to survive environmental stresses. QS systems primarily comprise Las, Rhl, and Pqs and are driven by autoinducer signaling molecules N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C12-HSL) N-butanoyl-L-homoserine lactone (C4-HSL), and quinolone signal (PQS) activated through the interaction of transcription factors LasR/RhlR/Pqs and 3-oxo-C12-HSL/C4-HSL/PQS. When signaling molecules reach a putative threshold concentration in the cell environment, QS regulates toxicity expression by regulating two-component systems (TCSs). TCSs regulatory systems, consisting of sensor kinase and response regulator pairs, play roles in bacterial adaptation by regulating the expression of a variety of extracellular enzymes, virulence factors, and QS molecules. GacS/GacA TCS is regulated by sensor kinases RetS (positive regulation) and LadS (negative regulation). Transcription of non-coding regulatory RNAs of the RsmY/Z depends on the activation of GacS/GacA to activate RsmA and regulate the T3SS-mediated virulence secretion and biofilm formation. Biofilms are encapsulated in a self-generating extracellular polymer (EPS) matrix for species survival in surprising alterations of living conditions, like temperature fluctuations and nutrient availability, especially the antibiotic threat. Likewise, the secretory system activates the host immune response through virulence factors. TLRs play a key role in innate immunity. TLR1, 2, 4, 5, 6, and 9 are reported for recognizing P. aeruginosa infection and mediating inflammatory response signal pathways. T3SS and bacterial QS-dependent secretants have roles in modulating NLRP3 and NLRC4 inflammasome activation under P. aeruginosa challenge
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Rossi E, et al. Pseudomonas aeruginosa adaptation and evolution in patients with cystic fibrosis. Nat. Rev. Microbiol. 2021;19:331–342. doi: 10.1038/s41579-020-00477-5. - DOI - PubMed
    1. Jurado-Martin, I., Sainz-Mejias, M. & McClean, S. Pseudomonas aeruginosa: an audacious pathogen with an adaptable arsenal of virulence factors. Int. J. Mol. Sci. 22, 1–35 (2021). - PMC - PubMed
    1. Cendra MDM, Torrents E. Pseudomonas aeruginosa biofilms and their partners in crime. Biotechnol. Adv. 2021;49:107734. doi: 10.1016/j.biotechadv.2021.107734. - DOI - PubMed
    1. Sinha, M. et al. Pseudomonas aeruginosa theft biofilm require host lipids of cutaneous wound. Ann. Surg. 5252, 1–23 (2021). - PMC - PubMed
    1. Tang P, et al. BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the SARS-CoV-2 Delta variant in Qatar. Nat. Med. 2021;27:2136–2143. doi: 10.1038/s41591-021-01583-4. - DOI - PubMed

Publication types

Substances