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. 2024 Aug 30;32(4):101330.
doi: 10.1016/j.omtm.2024.101330. eCollection 2024 Dec 12.

Synergy between Lactobacillus murinus and anti-PcrV antibody delivered in the airways to boost protection against Pseudomonas aeruginosa

Thomas Sécher  1   2 , Mélanie Cortes  1   2 , Chloé Boisseau  1   2 , Marie-Thérèse Barba Goudiaby  3   4 , Aubin Pitiot  1   2 , Christelle Parent  1   2 , Muriel Thomas  3   4 , Nathalie Heuzé-Vourc'h  1   2
Affiliations

Synergy between Lactobacillus murinus and anti-PcrV antibody delivered in the airways to boost protection against Pseudomonas aeruginosa

Thomas Sécher et al. Mol Ther Methods Clin Dev. .

Abstract

Therapeutic antibodies (Ab) have revolutionized the management of multiple illnesses including respiratory tract infections (RTIs). However, anti-infectious Ab displayed several limitations including antigen restrictiveness, narrowed therapeutic windows, and limited dose in the vicinity of the target when delivered by parenteral routes. Strategies enhancing further Ab-dependent containment of infection are currently needed. Here we showed that a combination of inhaled anti-infectious Ab and probiotics is an efficient formulation to protect against lung infection. Using a mouse model of Pseudomonas aeruginosa-induced pneumonia, we demonstrated a synergistic effect reducing both bacterial burden and pro-inflammatory response affording protection against primary and secondary infections. This is the first study showing that the local combination in the airways of anti-infective Ab and probiotics subverts suboptimal potency of Ab monotherapy and provides protection against respiratory pathogen.

Keywords: P. aeruginosa; airway delivery; pneumonia; probiotic; therapeutic antibody.

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Conflict of interest statement

N.H.-V. is co-founder and scientific expert for Cynbiose Respiratory. In the past 2 years, she received consultancy fees from Eli Lilly, Argenx, and Novartis and research support from Sanofi and Aerogen Ltd. M.T. is co-founder of the start-up Carembouche.

Figures

None
Graphical abstract
Figure 1
Figure 1
Dose-dependent protection conferred by locally administered anti-P. aeruginosa antibody (A) C57/BL6jRj mice were infected by the orotracheal instillation of 40 μL of P. aeruginosa PA103 containing 3 × 105 cfu. One hour later, mice were treated or not with 50 μg or 100 μg of mAb166 via the pulmonary route (airway). Body-weight loss (B) and survival (C) were monitored over 7 days. The results correspond to four pooled, independent experiments (n = 7–20 mice per group). Log rank test was used for survival analysis, ###p < 0.001 when compared with Vehicle group; ∗p < 0.05 when compared with mAb166-50-μg group. Two-way ANOVA followed by Tukey’s post-test was used for body-weight analysis, ##p < 0.01 when compared to Vehicle group; ∗p < 0.05 when compared with the mAb166-50 μg group.
Figure 2
Figure 2
Intranasal application of Lactobacillus murinus is tolerable in mice (A) C57/BL6jRj mice were daily treated or not by the intranasal administration of 40μL of L. murinus CNCM-I 4967 or CNCM-I 4968 containing 105, 106 or 107 cfu for 3 consecutive days. One day later, mice were sacrificed. Probiotic load in BAL (B) and lungs (C) were determined. (D and E) Body-weight loss was monitored over 3 days. (F and G) Neutrophils (CD45+ CD11c- CD11b+ SiglecF- Ly6G + Ly6C- cells) number in BAL were evaluated. The data are quoted as the mean values ±SEM. The results are representative of two independent experiments (n = 4–5 mice per group), ∗∗p < 0.01 with t test.
Figure 3
Figure 3
Synergistic effect of intranasal Lactobacillus murinus and therapeutic antibody in P. aeruginosa-induced pneumonia (A) C57/BL6jRj mice were daily treated or not by the intranasal administration of 40 μL of L. murinus CNCM-I 4967 or CNCM-I 4968 containing 105 cfu for 3 consecutive days. One day later, mice were infected and treated as in Figure 1A. Survival (B and C) and body-weight loss (D and E) were monitored over 7 days. The results correspond to four pooled, independent experiments (n = 10–20 mice per group). Log rank test was used for survival analysis, #p < 0.05, ###p < 0.001 when compared to Vehicle group; ∗∗∗p < 0.01 when compared to mAb166-50μg group. two-way ANOVA followed by Tukey’s post-test was used for body-weight analysis, ##p < 0.01 when compared with the Vehicle group; ∗p < 0.05, ∗∗p < 0.01, ∗∗∗: p < 0.01 when compared to mAb166-50μg group.
Figure 4
Figure 4
Improved host anti-bacterial response afforded by intranasal Lactobacillus murinus and therapeutic antibody C57/BL6jRj mice were treated and infected as described in Figure 3A. One day later, mice were sacrificed. P. aeruginosa PA103 burden in BAL (A and F) and in lungs (B and G) were quantified. Neutrophils (CD45+ CD11b+ SiglecF- Ly6G + cells) number in BAL (C and H) and in lungs (D and I) were determined. IL6 in BAL (E and J) was measured and standardized over total BAL protein. The data are quoted as the mean values ±SEM. The results correspond to two pooled, independent experiments (n = 10 mice per group), ∗: p < 0.05, ∗∗: p < 0.01, ∗∗∗: p < 0.001 with one-way ANOVA followed by Tukey’s post-test.
Figure 5
Figure 5
Combined intranasal Lactobacillus murinus and therapeutic antibody promotes long-term protection against P. aeruginosa (A) C57/BL6jRj mice were treated and infected as described in Figure 3A (primary infection). Surviving mice were challenged, 33 days later (secondary infection) by an orotracheal instillation of 40 μL of P. aeruginosa PA103 (3 × 105 cfu) without additional treatment. (B and C) Survival was monitored over a week after the challenge. The results correspond to four pooled, independent experiments (n = 10 for CNCM-I-4967 group and n = 5 for the others). Log rank test was used for survival analysis, #: p < 0.05, ###: p < 0.001 when compared to Vehicle group; ∗: p < 0.05 when compared to mAb166-50μg group. (D) The concentration of total anti- P. aeruginosa PA103 IgG in serum was determined by ELISA at days 1, 3, 7, 14, 21, and 28 after the primary infection. The data are quoted as individual values. The results correspond to two pooled experiments (n = 4–15 mice per group). (E) The concentration of total anti-P. aeruginosa PA103 IgG in serum was determined by ELISA at days −1, and +5 after the secondary infection. The data are quoted as individual values. The results correspond to two pooled experiments (n = 4 for mAb166-50 μg and CNCM-I 4968-mAb166-50μg group and n = 8 mice for CNCM-I 4967-mAb166-50μg group), ∗: p < 0.05; with a paired t test.
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References

    1. European Respiratory Society . European Respiratory Society; 2016. The burden of lung disease.
    1. World Health Organization . World Health Organization; 2017. WHO Publishes List of Bacteria for Which New Antibiotics Are Urgently Needed at.
    1. World Health Organization . World Health Organization; 2020. The top 10 causes of death.
    1. Mayor A., Chesnay A., Desoubeaux G., Ternant D., Heuzé-Vourc'h N., Sécher T. Therapeutic Antibodies for the Treatment of Respiratory Tract Infections-Current Overview and Perspectives. Vaccines. 2021;9 doi: 10.3390/vaccines9020151. - DOI - PMC - PubMed
    1. Nesbitt H., Burke C., Haghi M. Manipulation of the Upper Respiratory Microbiota to Reduce Incidence and Severity of Upper Respiratory Viral Infections: A Literature Review. Front. Microbiol. 2021;12 doi: 10.3389/fmicb.2021.713703. - DOI - PMC - PubMed

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