Localization of the T‐cell response to RSV infection is altered in infant mice

Eichinger, Katherine M.; Kosanovich, Jessica L.; Empey, Kerry M.

doi:10.1002/ppul.23911

Cited by 13 publications

(16 citation statements)

References 39 publications

(77 reference statements)

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“…Taking into consideration the findings of this work demonstrating that orally administered L. rhamnosus CRL1505 influence the MHC-II expression of the alveolar macrophages during the course of RSV infection, it is tempting to speculate that the immunobiotic intervention would also beneficially modify the adaptive immune response against the viral pathogen in infant mice. In support of this hypothesis, it has been shown that IFN-γ is able to up-regulate MHC-II expression in alveolar macrophages improving their antigen presentation activities ( 55 ). The evaluation of the influence of L. rhamnosus CRL1505 in the adaptive immune response to RSV and the role of alveolar macrophages in this potential beneficial effect is an interesting topic for future research.…”

Section: Discussionmentioning

confidence: 89%

“…The inefficient production of IFN-γ in the respiratory tract during the course of RSV infection with the subsequent impaired activation of alveolar macrophages has been associated with an increase of severe bronchiolitis and pneumonia in neonates and infants ( 34 – 36 ). In addition, comparative studies of RSV challenge in infant and adult mice demonstrated that in IFN-γ production were associated to the distinct susceptibility of both groups to viral infection ( 36 , 55 ). Adult mice are able to induce the recruitment of CD8 + IFN-γ + and CD4 + IFN-γ + T cells in the lung, which activated alveolar macrophages and promoted an efficient viral clearance.…”

Section: Discussionmentioning

confidence: 99%

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Alveolar Macrophages Are Key Players in the Modulation of the Respiratory Antiviral Immunity Induced by Orally Administered Lacticaseibacillus rhamnosus CRL1505

et al. 2020

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The oral administration of Lacticaseibacillus rhamnosus CRL1505 differentially modulates the respiratory innate antiviral immune response triggered by Toll-like receptor 3 (TLR3) activation in infant mice, improving the resistance to Respiratory Syncytial Virus (RSV) infection. In this work, by using macrophages depletion experiments and a detailed study of their production of cytokines and antiviral factors we clearly demonstrated the key role of this immune cell population in the improvement of both viral elimination and the protection against lung tissue damage induced by the CRL1505 strain. Orally administered L. rhamnosus CRL1505 activated alveolar macrophages and enhanced their ability to produce type I interferons (IFNs) and IFN-γ in response to RSV infection. Moreover, an increased expression of IFNAR1, Mx2, OAS1, OAS2, RNAseL , and IFITM3 was observed in alveolar macrophages after the oral treatment with L. rhamnosus CRL1505, which was consistent with the enhanced RSV clearance. The depletion of alveolar macrophages by the time of L. rhamnosus CRL1505 administration abolished the ability of infant mice to produce increased levels of IL-10 in response to RSV infection. However, no improvement in IL-10 production was observed when primary cultures of alveolar macrophages obtained from CRL1505-treated mice were analyzed. Of note, alveolar macrophages from the CRL1505 group had an increased production of IL-6 and IL-27 suggesting that these cells may play an important role in limiting inflammation and protecting lung function during RSV infection, by increasing the maturation and activation of Treg cells and their subsequent production of IL-10. In addition, we provided evidence of the important role of CD4 + cells and IFN-γ in the activation of alveolar macrophages highlighting a putative pathway through which the intestinal and respiratory mucosa are communicated under the influence of L. rhamnosus CRL1505.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Alveolar Macrophages Are Key Players in the Modulation of the Respiratory Antiviral Immunity Induced by Orally Administered Lacticaseibacillus rhamnosus CRL1505

et al. 2020

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“…Cytokine concentrations were determined using the Bio-Plex Pro™ Mouse Cytokine 23-plex Assay (BioRad, CA), per manufacturer's protocol. The right lung was harvested and enzyme-digested into a single cell suspension for flow cytometry, as described previously ( 26 , 27 ). Where indicated, BAL cells and lung homogenate were stimulated ex-vivo for intracellular cytokine detection.…”

Section: Methodsmentioning

confidence: 99%

Prefusion RSV F Immunization Elicits Th2-Mediated Lung Pathology in Mice When Formulated With a Th2 (but Not a Th1/Th2-Balanced) Adjuvant Despite Complete Viral Protection

Eichinger

Kosanovich

Gidwani³

et al. 2020

Front. Immunol.

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Respiratory syncytial virus (RSV) remains the most common cause of lower respiratory tract infections in children worldwide. Development of a vaccine has been hindered by the risk of developing enhanced respiratory disease (ERD) upon natural exposure to the virus. Generation of higher quality neutralizing antibodies with stabilized pre-fusion F protein antigens has been proposed as a strategy to prevent ERD. We sought to test whether there was evidence of ERD in naïve BALB/c mice immunized with an unadjuvanted, stabilized pre-fusion F protein, and challenged with RSV line 19. We further sought to determine the extent to which formulation with a Th2-biased (alum) or a more Th1/Th2-balanced (Advax-SM) adjuvant influenced cellular responses and lung pathology. When exposed to RSV, mice immunized with pre-fusion F protein alone (PreF) exhibited increased airway eosinophilia and mucus accumulation. This was further exacerbated by formulation of PreF with Alum (aluminum hydroxide). Conversely, formulation of PreF with a Th1/Th2-balanced adjuvant, Advax-SM, not only suppressed RSV viral replication, but also inhibited airway eosinophilia and mucus accumulation. This was associated with lower numbers of lung innate lymphocyte cells (ILC2s) and CD4+ T cells producing IL-5+ or IL-13+ and increased IFNγ+ CD4+ and CD8+ T cells, in addition to RSV F-specific CD8+ T cells. These data suggest that in the absence of preimmunity, stabilized PreF antigens may still be associated with aberrant Th2 responses that induce lung Eichinger et al. Protection With Th1/Th2-Balanced Prefusion Adjuvant pathology in response to RSV infection, and can be prevented by formulation with more Th1/Th2-balanced adjuvants that enhance CD4+ and CD8+ IFNγ+ T cell responses. This may support the use of stabilized PreF antigens with Th1/Th2-balanced adjuvants like, Advax-SM, as safer alternatives to alum in RSV vaccine candidates.

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“…The IFN-γ-mediated activation of alveolar macrophages is essential for efficient viral clearance [41]. It was suggested that quantitative and qualitative differences in IFN-γ production could explain the different susceptibility of infant and adult mice to RSV infection [42]. While adult mice accumulate both CD8 + CD44 high IFN-γ + and CD4 + CD44 high IFN-γ + T in the alveolar space after the challenge with RSV, infant mice accumulate mainly CD8 + CD44 high IFN-γ + T cells in lung tissue and airway.…”

Section: Pigrum 040417 Similar To C Pseudodiphteriticum 090104 mentioning

confidence: 99%

The Ability of Respiratory Commensal Bacteria to Beneficially Modulate the Lung Innate Immune Response Is a Strain Dependent Characteristic

et al. 2020

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We investigated whether the ability of commensal respiratory bacteria to modulate the innate immune response against bacterial and viral pathogens was a shared or strain-specific characteristic. Bacterial strains belonging to the Corynebacterium pseudodiphtheriticum and Dolosigranulum pigrum species were compared by studying their influence in the Toll-like receptor (TLR)-2- and TLR3-triggered immune responses in the respiratory tract, as well as in the resistance to Respiratory Syncytial Virus (RSV) and Streptococcus pneumoniae infections. We demonstrated that nasally administered C. pseudodiphteriticum 090104 or D. pigrum 040417 were able to modulate respiratory immunity and increase the resistance against pathogens, while other strains of the same species did not influence the respiratory immune responses, demonstrating a clear strain-dependent immunomodulatory effect of respiratory commensal bacteria. We also reported here that bacterium-like particles (BLP) and cell walls derived from immunomodulatory respiratory commensal bacteria are an interesting alternative for the modulation of the respiratory immune system. Our study is a step forward in the positioning of certain strains of respiratory commensal bacteria as next-generation probiotics for the respiratory tract.

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Localization of the T‐cell response to RSV infection is altered in infant mice

Abstract: Together, these data suggest that quantitative and qualitative defects exist in the infant T-cell response to RSV but early, local IFN-γ exposure can increase the CD8 RSV-specific T-cell response.

Cited by 13 publications

References 39 publications

Alveolar Macrophages Are Key Players in the Modulation of the Respiratory Antiviral Immunity Induced by Orally Administered Lacticaseibacillus rhamnosus CRL1505

Alveolar Macrophages Are Key Players in the Modulation of the Respiratory Antiviral Immunity Induced by Orally Administered Lacticaseibacillus rhamnosus CRL1505

Prefusion RSV F Immunization Elicits Th2-Mediated Lung Pathology in Mice When Formulated With a Th2 (but Not a Th1/Th2-Balanced) Adjuvant Despite Complete Viral Protection

The Ability of Respiratory Commensal Bacteria to Beneficially Modulate the Lung Innate Immune Response Is a Strain Dependent Characteristic

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