Respiratory Commensal Bacteria Increase Protection against Hypermucoviscous Carbapenem-Resistant Klebsiella pneumoniae ST25 Infection

Maidana, Stefanía Dentice; Moyano, Ramiro Ortiz; Vargas, Juan M. Casa; Fukuyama, Kohtaro; Kurata, Shoichiro; Mel'nikov, V. G.; Jure, María Ángela; Kitazawa, Haruki; Villena, Julio

doi:10.3390/pathogens11091063

Cited by 7 publications

(9 citation statements)

References 38 publications

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“…Corynebacterium pseudodiphtheriticum is a commensal bacterium normally found in the human nasopharynx mucosa [ 3 , 4 ]. We demonstrated that the nasal administration of viable C. pseudodiphtheriticum 090104 to mice has a remarkable capacity to beneficially modulate the respiratory immune system, increasing the resistance to respiratory syncytial virus [ 5 ], Streptococcus pneumoniae [ 6 ], and hypermucoviscous carbapenemase-producing Klebsiella pneumoniae [ 7 ]. The protective effect of the 090104 strain against the different respiratory pathogens was related to its capacity to modulate the respiratory innate immune responses.…”

Section: Introductionmentioning

confidence: 99%

The Respiratory Commensal Bacterium Corynebacterium pseudodiphtheriticum as a Mucosal Adjuvant for Nasal Vaccines

et al. 2023

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Previously, we demonstrated that nasally administered Corynebacterium pseudodiphteriticum 090104 (Cp) or its bacterium-like particles (BLPs) increase the resistance of mice against bacterial and viral respiratory pathogens by modulating the innate immunity. In this work, we evaluated the ability of Cp and BLPs to stimulate alveolar macrophages, and to enhance the humoral immune response induced by a commercial vaccine against Streptococcus pneumoniae. In the first set of experiments, Cp or the BLPs were incubated with primary cultures of murine alveolar macrophages and the phagocytic activity, and the production of cytokines was evaluated. The results revealed that Cp and BLPs were efficiently phagocyted by respiratory macrophages and that both treatments triggered the production of TNF-α, IFN-γ, IL-6, and IL-1β. In the second set of experiments, 3-week-old Swiss mice were intranasally immunized at days 0, 14, and 28 with the pneumococcal vaccine Prevenar®13 (PCV), Cp + PCV, or BLPs + PCV. On day 33, samples of bronco-alveolar lavages (BAL) and serum were collected for the study of specific antibodies. In addition, immunized mice were challenged with S. pneumoniae serotypes 6B or 19F on day 33 and sacrificed on day 35 (day 2 post-infection) to evaluate the resistance to the infection. Both Cp + PCV and BLPs + PCV groups had higher specific serum IgG and BAL IgA antibodies than the PCV control mice. In addition, the mice that were immunized with Cp + PCV or BLPs + PCV had lower lung and blood pneumococcal cell counts as well as lower levels of BAL albumin and LDH, indicating a reduced lung damage compared to the control mice. Improved levels of anti-pneumococcal antibodies were also detected in the serum and BAL samples after the challenges with the pathogens. The results demonstrated that C. pseudodiphteriticum 090104 and its bacterium-like particles are capable of stimulating the respiratory innate immune system serving as adjuvants to potentiate the adaptive humoral immune response. Our study is a step forward in the positioning of this respiratory commensal bacterium as a promising mucosal adjuvant for vaccine formulations aimed at combating respiratory infectious diseases.

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Section: Introductionmentioning

confidence: 99%

The Respiratory Commensal Bacterium Corynebacterium pseudodiphtheriticum as a Mucosal Adjuvant for Nasal Vaccines

et al. 2023

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“…In our prior investigations, we demonstrated that nasal priming with Cp 090104 or CP-derived BLPs influences the respiratory innate immune response [10][11][12]. This prompted us to examine whether this respiratory commensal bacterium's innate immune modulation extends to adaptive immune responses.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, we demonstrated that C. pseudodiphtheriticum strain 090104 (Cp 090104) i.n. administered to mice enhanced the resistance to respiratory syncytial virus (RSV) [10], S. pneumoniae [11], and Klebsiella pneumoniae [12]. The protective ability of the Cp 090104 strain against the different pathogenic microorganisms was associated to its capacity to regulate the innate immune responses in the respiratory tract.…”

Section: Introductionmentioning

confidence: 99%

Bacterium-like Particles from Corynebacterium pseudodiphtheriticum as Mucosal Adjuvant for the Development of Pneumococcal Vaccines

Ortiz Moyano,

Raya Tonetti,

Elean

et al. 2024

Vaccines

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Previously, it was shown that intranasally (i.n.) administered Corynebacterium pseudodiphtheriticum 090104 (Cp) or CP-derived bacterium-like particles (BLPs) improve the immunogenicity of the pneumococcal conjugate vaccine (PCV). This work aimed to deepen the characterization of the adjuvant properties of Cp and CP-derived BLPs for their use in the development of pneumococcal vaccines. The ability of Cp and CP-derived BLPs to improve both the humoral and cellular specific immune responses induced by i.n. administered polysaccharide-based commercial pneumococcal vaccine (Pneumovax 23®) and the chimeric recombinant PSPF (PsaA-Spr1875-PspA-FliC) protein was evaluated, as well as the protection against Streptococcus pneumoniae infection in infant mice. Additionally, whether the immunization protocols, including Cp and CP-derived BLPs, together with the pneumococcal vaccines can enhance the resistance to secondary pneumococcal pneumonia induced after inflammatory lung damage mediated by the activation of Toll-like receptor 3 (TLR3) was assessed. The results showed that both Cp and CP-derived BLPs increased the immunogenicity and protection induced by two pneumococcal vaccines administered through the nasal route. Of note, the nasal priming with the PSPF T-dependent antigen co-administered with Cp or CP-derived BLPs efficiently stimulated humoral and cellular immunity and increased the resistance to primary and secondary pneumococcal infections. The CP-derived BLPs presented a stronger effect than live bacteria. Given safety concerns associated with live bacterium administration, especially in high-risk populations, such as infants, the elderly, and immunocompromised patients, BLPs emerge as an attractive mucosal adjuvant to improve the host response to pneumococcal infections and to enhance the vaccines already in the market or in development.

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“…In this regard, we have used mice as a model to characterize respiratory infections caused by multiresistant K. pneumoniae isolates from the ST25 considering that among the KPC-2-producing strains, this sequence type has emerged as a persistent and overrepresented cause of hospital-associated infections in the Northwest of Argentina [ 5 , 6 , 7 ]. We demonstrated that K. pneumoniae ST25 strains were able to infect the respiratory tract of adult immunocompetent mice after the nasal challenge, inducing a potent innate immune response characterized by the increase in inflammatory cytokines and chemokines and the recruitment of inflammatory cells into the lung [ 23 , 24 ]. In fact, our previous and present results demonstrated that the nasal challenge of mice with the ST25 K. pneumoniae strains LABACER 01 and LABACER 27 increased the levels of TNF-α, IL-1β, IL-6, IFN-γ, IL-17, KC and MPC-1 in the respiratory tract and blood, as well as the numbers of BAL neutrophils and macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…Mice in the control group were administered only 100 µL from PBS. The infective dose selected for this work was determined previously [ 23 , 24 ].…”

Section: Methodsmentioning

confidence: 99%

Oral Administration of Lacticaseibacillus rhamnosus CRL1505 Modulates Lung Innate Immune Response against Klebsiella pneumoniae ST25

et al. 2023

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Orally administered Lacticaseibacillus rhamnosus CRL1505 enhances respiratory immunity, providing protection against respiratory viruses and Streptococcus pneumoniae. However, the capacity of the CRL1505 strain to improve respiratory immunity against Gram-negative bacterial infections has not been evaluated before. The aim of this work was to evaluate whether the Lcb. rhamnosus CRL1505 was able to beneficially regulate the respiratory innate immune response and enhance the resistance to hypermucoviscous KPC-2-producing Klebsiella pneumoniae of the sequence type 25 (ST25). BALB/c mice were treated with the CRL1505 strain via the oral route and then nasally challenged with K. pneumoniae ST25 strains LABACER 01 or LABACER 27. Bacterial cell counts, lung injuries and the respiratory and systemic innate immune responses were evaluated after the bacterial infection. The results showed that K. pneumoniae ST25 strains increased the levels of TNF-α, IL-1β, IL-6, IFN-γ, IL-17, KC and MPC-1 in the respiratory tract and blood, as well as the numbers of BAL neutrophils and macrophages. Mice treated with Lcb. rhamnosus CRL1505 had significantly lower K. pneumoniae counts in their lungs, as well as reduced levels of inflammatory cells, cytokines and chemokines in the respiratory tract and blood when compared to infected controls. Furthermore, higher levels of the regulatory cytokines IL-10 and IL-27 were found in the respiratory tract and blood of CRL1505-treated mice than controls. These results suggest that the ability of Lcb. rhamnosus CRL1505 to help with the control of detrimental inflammation in lungs during K. pneumoniae infection would be a key feature to improve the resistance to this pathogen. Although further mechanistic studies are necessary, Lcb. rhamnosus CRL1505 can be proposed as a candidate to improve patients’ protection against hypermucoviscous KPC-2-producing strains belonging to the ST25, which is endemic in the hospitals of our region.

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Respiratory Commensal Bacteria Increase Protection against Hypermucoviscous Carbapenem-Resistant Klebsiella pneumoniae ST25 Infection

Cited by 7 publications

References 38 publications

The Respiratory Commensal Bacterium Corynebacterium pseudodiphtheriticum as a Mucosal Adjuvant for Nasal Vaccines

The Respiratory Commensal Bacterium Corynebacterium pseudodiphtheriticum as a Mucosal Adjuvant for Nasal Vaccines

Bacterium-like Particles from Corynebacterium pseudodiphtheriticum as Mucosal Adjuvant for the Development of Pneumococcal Vaccines

Oral Administration of Lacticaseibacillus rhamnosus CRL1505 Modulates Lung Innate Immune Response against Klebsiella pneumoniae ST25

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