The small RNA ErsA plays a role in the regulatory network of Pseudomonas aeruginosa pathogenicity in airways infection

Silvia Ferrara, Alice Rossi, Serena Ranucci, Ida De Fino, Alessandra Bragonzi, Cristina Cigana, Giovanni Bertoni

Preprint posted on 23 June 2020

Article now published in mSphere at

ErsA in aeruginosa: a small RNA modulates the pathogenicity of P. aeruginosa in airway infections

Selected by Zhang-He Goh

preLight Author’s note

This is the third preLight of a three-part series on airway inflammation, infection, autophagy and its mediators. Links to the first and second preLights.

Background of preprint

ErsA is a small RNA (sRNA) in Pseudomonas aeruginosa that plays a key role in its response to stressful conditions during host infection. By interacting with other transcriptional factors, ErsA has been reported to modulate virulence traits like biofilm formation and motility [1-3], stimulate exopolysaccharide production [2], regulate the P. aeruginosa transcriptome [2], mediate the interaction between P. aeruginosa and its host [2], and even contribute to antibiotic resistance [4]. Given the prevalent role of ErsA in P. aeruginosa’s pathogenicity, Ferrara et al. assessed its role in respiratory infections caused by P. aeruginosa (Fig. 1). They showed that in acute infection, ErsA mediates regulation and contributes to the host inflammatory response; while in chronic infection, ErsA aids in adaptation and promotes the development of antibiotic resistance in P. aeruginosa.

Figure 1. Role of ErsA in P. aeruginosa infections described by Ferrara et al..

Key findings of preprint

Ferrara et al. first evaluated ErsA’s role in regulating bacterial functions in cytotoxicity and stimulation of host inflammation in vitro. They infected pulmonary IB3-1 cells with two laboratory strains of P. aeruginosa, PA14 and PAO1, their knockout ErsA counterparts, and an ErsA-overexpressing PAO1 strain (pGM-ErsA). This experiment yielded two key observations. First, by comparing PA14 and PAO1 with their respective knockout ErsA counterparts, the authors showed that the loss of ErsA indeed attenuated the cytotoxic potential of P. aeruginosa. Second, IB3-1 cells infected with the PAO1 ErsA-knockout strain secreted less IL-8 than those infected with the PAO1 wild-type.

Having showed that ErsA enhances cytotoxicity and induces a pro-inflammatory response in host cells in vitro, the authors then infected immunocompetent C57BL/6NCrlBR mice with the PAO1 and PAO1 ErsA-knockout strains. Knocking out ErsA also decreased the mortality and attenuated the inflammatory response in mice acutely infected with the PAO1 strain. In contrast, neither the incidence of chronic colonisation in surviving mice nor the inflammatory response differed significantly between the PAO1 and PAO1 ErsA-knockout strains.

To determine whether the ErsA gene and its expression could be conserved independently of the origin of P. aeruginosa isolates, and whether patho-adaptive mutations are responsible for ErsA downregulation, the authors assessed the expression levels of ErsA in 31 clinical isolates of P. aeruginosa. They found that 13 of these clinical isolates exhibited a strong downregulation of ErsA compared to PAO1, a finding which suggests that ErsA is under selective pressure in patients with cystic fibrosis.

Finally, Ferrara et al. established a link between ErsA and the emergence of antibiotic resistance in the treatment cystic fibrosis patients. By knocking out ErsA from a P. aeruginosa isolate (RP73) that exhibited multidrug resistance, the authors were able to reverse the resistance to some cephalosporins.

Why I selected this preprint

I selected this preLight to conclude our three-part series on respiratory tract inflammation. In the earlier preLights, Josie Gibson and I discussed the roles of inflammation and autophagy in tuberculosis. In this preprint, we see how P. aeruginosa, too, modulates the host immune system in the respiratory tract.

P. aeruginosa belongs to a group of pathogens, known as the ESKAPE pathogens, which poses multiple challenges in the arena of antibiotic resistance today. Thus far, researchers have made inroads into large molecule antimicrobials, antivirulence compounds, bacteriophages, and even host-directed therapies. By shedding new light on the role of ErsA in the pathogenicity in P. aeruginosa infections, this work by Ferrara et al. opens new opportunities to target these pathways.

Another reason for my choice to highlight this preprint is its focus on cystic fibrosis patients. Because cystic fibrosis is a rare but chronic debilitating disease, the authors’ careful study of the role of ErsA in these patients has two main benefits. The first benefit is self-evident: it pertains to the benefits that cystic fibrosis patients accrues as a direct result of this research. Better understanding the mechanisms underlying the pathogenicity of P. aeruginosa, as well as the development of antibiotic resistance, will help clinicians and patients better manage these disease complications.

The second benefit from this work relates to the applicability of the authors’ findings to other vulnerable patient populations as well. With lengthening life expectancies, a greater number of patients with multiple comorbidities is expected in the coming decades. These patients will be more vulnerable to acute infections; more patients will also suffer from chronic infections. Coupled with the looming spectre of antimicrobial resistance, better antimicrobial stewardship and management of infections will be necessary. Understanding the mediators of infection will help.

Future work

The outstanding questions from this work can be classified into three main categories. First, from an epidemiological perspective, what is the prevalence of ErsA among P. aeruginosa infections? What are the regional and global infection patterns? Is there variability across different countries or regions?

Second, how targetable is the ErsA pathway? What are some targets related to this pathway that could be potentially inhibited in order to induce bacterial cell death? Specificity is important from a pharmacological perspective, so targets that are unique to the bacteria without equivalent isoforms in mammals will be more desirable.

Third, how might modulators of the ErsA pathway interact with currently known antibiotics? The reversal of antimicrobial resistance through the knockdown of ErsA suggests that such combinations may be synergistic, but this will need to be confirmed through further studies.

These questions will not be easy to answer—it will require the collaboration of experts from different fields, among them molecular biologists, epidemiologists, microbiologists, and pharmacologists. Throughout this three-part series, we have seen how the investigation of pathogenic mechanisms underlying infectious diseases is essential to the discovery of new targets for novel antibiotics. This preprint, along with previous work conducted by the preprint authors, is a step towards that goal. I will be holding my breath.


[1]        Miller CL, Van Laar TA, Chen T, Karna SLR, Chen P, You T, Leung KP, Global transcriptome responses including small RNAs during mixed-species interactions with methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, Microbiologyopen 6(3) (2017).

[2]        Falcone M, Ferrara S, Rossi E, Johansen HK, Molin S, Bertoni G, The Small RNA ErsA of Pseudomonas aeruginosa Contributes to Biofilm Development and Motility through Post-transcriptional Modulation of AmrZ, Frontiers in microbiology 9 (2018) 238-238.

[3]        Ferrara S, Carloni S, Fulco R, Falcone M, Macchi R, Bertoni G, Post-transcriptional regulation of the virulence-associated enzyme AlgC by the σ22-dependent small RNA ErsA of Pseudomonas aeruginosa, Environmental Microbiology 17(1) (2015) 199-214.

[4]        Zhang Y-F, Han K, Chandler CE, Tjaden B, Ernst RK, Lory S, Probing the sRNA regulatory landscape of P. aeruginosa: post-transcriptional control of determinants of pathogenicity and antibiotic susceptibility, Molecular Microbiology 106(6) (2017) 919-937.


Posted on: 25 July 2020


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