Murine Respiratory Tract Infection with Classical Klebsiella pneumoniae Induces Bronchus-Associated Lymphoid Tissue

Wasbotten, Rachel; Dahler, Aubree A; Mackel, Joseph J; Smith, Carter; Rosen, David A.

doi:10.1128/iai.00596-21

Cited by 10 publications

(5 citation statements)

References 37 publications

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“…To determine if the phenomenon of capsule shielding of O-antigen was specific to the more heavily encapsulated hv Kp strains, we investigated antisera binding to a c Kp isolate with the same capsule and O-antigen types (K2:O1). KR174 is a c Kp that was isolated from the lower respiratory tract of a patient with c Kp pneumonia and encodes an ESBL ( 29 ). It produces less capsule and displays decreased hypermucoviscosity relative to hv Kp 43816 ( SI Appendix , Fig.…”

Section: Resultsmentioning

confidence: 99%

Capsular polysaccharide inhibits vaccine-induced O-antigen antibody binding and function across both classical and hypervirulent K2:O1 strains ofKlebsiella pneumoniae

Wantuch¹,

Knoot²,

Robinson³

et al. 2022

Preprint

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Klebsiella pneumoniae presents as two circulating pathotypes: classical K. pneumoniae (cKp) and hypervirulent K. pneumoniae (hvKp). Classical isolates are considered urgent threats due to their antibiotic resistance profiles, while hvKp isolates have historically been antibiotic susceptible. Recently, however, increased rates of antibiotic resistance have been observed in both hvKp and cKp, further underscoring the need for preventive and effective immunotherapies. Two distinct surface polysaccharides have gained traction as vaccine candidates against K. pneumoniae: capsular polysaccharide and the O-antigen of lipopolysaccharide. While both targets have practical advantages and disadvantages, it remains unclear which of these antigens included in a vaccine would provide superior protection against matched K. pneumoniae strains. Here, we report the production of two bioconjugate vaccines, one targeting the K2 capsular serotype and the other targeting the O1 O-antigen. Using murine models, we investigated whether these vaccines induced specific antibody responses that recognize K2:O1 K. pneumoniae strains. While each vaccine was immunogenic in mice, both cKp and hvKp strains exhibited decreased O-antibody binding in the presence of capsule. Further, O1 antibodies demonstrated decreased killing in serum bactericidal assays with encapsulated strains, suggesting that the presence of K. pneumoniae capsule blocks O1-antibody binding and function. Finally, the K2 vaccine outperformed the O1 vaccine against both cKp and hvKp in two different murine infection models. These data suggest that capsule-based vaccines may be superior to O-antigen vaccines for targeting hvKp and some cKp strains, due to capsule blocking the O-antigen.

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Section: Resultsmentioning

confidence: 99%

Capsular polysaccharide inhibits vaccine-induced O-antigen antibody binding and function across both classical and hypervirulent K2:O1 strains ofKlebsiella pneumoniae

Wantuch¹,

Knoot²,

Robinson³

et al. 2022

Preprint

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“…iBALT is known to be formed in the lungs in response to a range of pathogens and inflammatory stimuli, including gram-negative bacteria such as Pseudomonas aeruginosa 34,35 and Klebsiella pneumonia 36 . A common feature of the iBALT during infection with these pathogens is that an initial lymphocyte accumulation can begin already on day 7 36 , leading us to the hypothesis that RB50Δ btrS could promote an early iBALT formation that leads to the robust protective immunity previously observed 17 .…”

Section: Resultsmentioning

confidence: 99%

Bordetella spp. block eosinophil recruitment to suppress lung iBALT formation

First¹,

Martínez²,

González‐Fernández³

et al. 2022

Preprint

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A characteristic that differentiates pathogenic and opportunistic bacteria is that pathogens have been selected by their ability to suppress host inflammatory responses allowing colonization and persistence. Bordetella spp. are respiratory pathogens characterized for the arsenal of mechanisms they use to manipulate host immune responses. We have previously characterized a B. bronchiseptica mutant, RB50DbtrS, that is not able to suppress host immune responses, resulting not only in rapid clearance of the infection but also long-term lung sterilizing immunity against reinfection with the three classical Bordetella spp. Interestingly, this strong immune response requires eosinophils. In this work our results indicate that wildtype B. bronchiseptica, RB50, blocks eosinophil pro-inflammatory functions to prevent the rapid recruitment of B and T cells to the lung that results in iBALT formation. Moreover, eosinophils promote a TH17 microenvironment within the iBALT that might be responsible for the long-term robust protective immunity generated by infection with this mutant. Overall, this work provides a novel role for eosinophils as promoters of adaptive immune responses and protective immunity, while also indicating that bacteria actively manipulate those cells to promote long-term persistence and reinfection.

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“…Furthermore, the increase in hypervirulent K. pneumoniae strains capable of causing community-acquired infections in otherwise healthy hosts [ 27 ] and the enhanced antibiotic resistance among clinical isolates [ 28 ] necessitate more in-depth studies of the pathogenesis and immune response, as well as preventive and therapeutic alternatives for these bacteria. Murine models of respiratory infections caused by classical and hypervirulent K. pneumoniae strains have been useful in gaining deeper knowledge of the immunobiology of these infections [ 29 , 30 ]. 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 ].…”

Section: Discussionmentioning

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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Murine Respiratory Tract Infection with Classical Klebsiella pneumoniae Induces Bronchus-Associated Lymphoid Tissue

Cited by 10 publications

References 37 publications

Capsular polysaccharide inhibits vaccine-induced O-antigen antibody binding and function across both classical and hypervirulent K2:O1 strains ofKlebsiella pneumoniae

Capsular polysaccharide inhibits vaccine-induced O-antigen antibody binding and function across both classical and hypervirulent K2:O1 strains ofKlebsiella pneumoniae

Bordetella spp. block eosinophil recruitment to suppress lung iBALT formation

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

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