The Role of Alveolar Macrophages in the Improved Protection against Respiratory Syncytial Virus and Pneumococcal Superinfection Induced by the Peptidoglycan of Lactobacillus rhamnosus CRL1505
Abstract
:1. Introduction
2. Materials and Methods
2.1. Microorganisms and Peptidoglycans
2.2. Animals and Treatments
2.3. Poly(I:C) Administration and Respiratory Infections
2.4. Lung Injury Parameters
2.5. In Vivo Depletion of Alveolar Macrophages
2.6. Alveolar Macrophages Primary Cultures
2.7. Cytokine Concentrations in BAL and Culture Supernatants
2.8. PCR Quantitative Expression Analysis by Real-Time PCR
2.9. Flow Cytometry Analysis
2.10. Statistical Analysis
3. Results
3.1. Effect of AM Depletions on the Ability of Nonviable L. rhamnosus CRL1505 and Its Peptidoglycan to Modulate the Respiratory Immune Response Triggered by Poly(I:C)
3.2. Effects of AM Depletions on the Ability of Nonviable L. rhamnosus CRL1505 and Its Peptidoglycan to Modulate the Resistance to Secondary Pneumococcal Pneumonia after Poly(I:C) Treatment
3.3. Effects of AM Depletions on the Ability of Nonviable L. rhamnosus CRL1505 and Its Peptidoglycan to Improve the Resistance to Secondary Pneumococcal Pneumonia after RSV Infection
3.4. Effects of Nonviable L. rhamnosus CRL1505 and Its Peptidoglycan on AMs Cytokine Profiles in Response to Different Challenges
3.5. Induction of Activated/Trained AMs by Nonviable L. rhamnosus CRL1505 and Its Peptidoglycan
4. Discussion
- (a)
- The role of AMs in the modulation of antiviral immunity by nasally administered NV1505 and PG1505. Research on the biology of RSV infection has established that AMs are required for an efficient viral clearance and control of immunopathology. The phagocytic activity of AMs is crucial for the elimination of infected cells during the course of the RSV infection. In addition, AMs play a prominent role in the defense against RSV by producing type I IFNs, which act on this same cell population or on other immune and nonimmune cells of the respiratory tract, modulating their expression of hundreds of IFN-stimulated genes (ISGs) that contribute to viral clearance [27,28]. IFN-α/β production by AMs also upregulate the expression of several chemokines in the respiratory tract that induce the recruitment of inflammatory monocytes/macrophages that further support the clearance of virus-infected cells [29]. On the other hand, it was reported that IFN-γ is of importance for the protection against the RSV [10,11]. The impairment in the production of IFN-γ by AMs was associated with an enhanced severe illness [13,14,15]. Then, the efficient and timely production of type I IFNs, ISGs, and IFN-γ by AMs is important to confer protection against the RSV. We previously reported enhanced levels of IFN-β and IFN-γ in BAL samples of infant mice treated with NV1505 or PG1505 after TLR3 activation or a RSV challenge [17,19]. In this work, we extended those previous findings by demonstrating the ability of NV1505 and PG1505 nasal treatments to enhance the production of type I IFNs and IFN-γ specifically by AMs in response to a RSV infection or poly(I:C) stimulation. Moreover, we reported here for the first time an improved expression of OAS1 and RNAseL in AMs after the nasal treatments with NV1505 or PG1505. OAS1 is capable of inhibiting protein synthesis and viral growth by degrading viral and cellular RNA, and it has been shown to interfere with RSV replication [27,30]. In addition, the members of the OAS family are able to activate RNAseL. The intracellular endoribonuclease RNaseL activated by OAS molecules cleaves viral and cellular RNA, resulting in apoptosis [31]. It was reported that IFN-γ is able to upregulate the activities of OAS/RNAseL, increasing the protection against the RSV infection [32]. Then, the enhancement of these antiviral factors is consistent with the improved clearance of the RSV observed previously [17,19] and in this work. Furthermore, the identification of the differential antiviral factors and cytokines profiles induced by the CRL1505 strain in AMs indicate that the immunobiotic treatment has the potential to protect against other respiratory viruses, as we have demonstrated for the influenza virus (IFV) [33]. The precise role of AMs in the protection against the RSV was demonstrated in animal models in which this immune cell population was specifically depleted. Experiments in CD169-diphtheria toxin receptor transgenic mice, which are depleted from CD169+ AMs after the administration of the diphtheria toxin, demonstrated that macrophage eliminations impaired the production of IFN-β, IL-6, and TNF-α in the respiratory tract in response to the RSV infection [34]. Similar results were obtained in New Zealand black mice, which lack normal macrophage functions and show an enhanced lung immunopathology upon an RSV exposure [28]. The depletion of murine AMs by the administration of clodronate liposomes before the challenge with the RSV significantly impaired lung IFN-α, TNF-α, and IL-6 productions and diminished the activation and recruitment of NK cells. Those changes were associated to an enhanced lung RSV load [35]. By using a similar approach, we demonstrated here that the depletion of AMs by clodronate liposomes at the time of NV1505 or PG1505 nasal priming significantly diminished, but not completely abolished, the ability of treated infant mice to produce improved levels of IFN-β or IFN-γ in response to TLR3 activation or a RSV infection. These results indicate that AMs have an important role in the production of IFN-β and IFN-γ, but other respiratory cell populations may also contribute to the improved levels of both antiviral factors, as discussed below. Of note, the depletion of AMs during the nasal priming with NV1505 or PG1505 completely abolished the ability of the treatments to improve IL-10 in the respiratory tract or to reduce the biochemical markers of a lung injury after TLR3 activation. Then, AMs had an essential role in the protection induced by NV1505 and PG1505 against the lung detrimental inflammation. The infection of human AMs by the RSV stimulates the secretion of several proinflammatory cytokines, including IL-6, TNF-α, IL-1β, and IL-8 [10]. Conversely, similar experiments have described the secretion of IL-10 by these respiratory innate immune cells [10]. This ability of AMs indicates that they not only have an important role in the generation of the inflammatory response but, also, in its regulation. It was widely shown that AMs are important in the control of detrimental inflammation in the context of respiratory virus infections. The alterations of AM functions by the infection with the RSV have been associated to an exacerbated viral-mediated bronchiolitis [15]. In fact, the depletion of AMs greatly increased the recruitment of inflammatory cells to the lungs during the early stage of the RSV infection, including CD11bhiGr1hi neutrophils and inflammatory CD11chiMHC-IIhiCD11b+ dendritic cells (DCs) that contribute to a hyperresponsiveness in infected mice [11]. Notably, this deregulated inflammatory response contributes poorly to the elimination of the virus while promoting local damage and affecting the lung functions. Then, the immunoregulatory functions of AMs seems crucial for avoiding the lung inflammatory-mediated damage during the course of the RSV infection. Several mechanisms have been proposed for the immunoregulatory functions of AMs in the context of viral infections, including the phagocytosis of virus-infected apoptotic cells, preventing the release of cellular contents and the triggering of further inflammatory factor productions [36], as well as the production of IL-10 [10,36]. Interestingly, another anti-inflammatory strategy of AMs is their ability to promote Treg cell responses by directly interacting with these cells or indirectly through the production of certain cytokines [37,38]. We previously reported increased levels of IL-10 in the respiratory tracts of NV1505- or PG1505-treated mice in response to the RSV infection, although the immune cell population producing this anti-inflammatory cytokine was not determined [17,19]. The data of this work indicate that Treg cells would be the cells responsible for the improved levels of IL-10 in the respiratory tract of RSV-infected infant mice and that AMs would indirectly contribute to this effect. We demonstrated here for the first time that AMs from mice nasally primed with NV1505 or PG1505 had a significantly increased capacity to produce IL-27 in response to the RSV infection. The immunoregulatory cytokine IL-27 has been shown to protect against lung inflammatory damage during the course of viral infections. It was reported that the depletion of IL-27 enhanced the lung-damaging inflammation in RSV-infected mice [37]. In addition, it was shown that IL-27 helps in the control of the RSV infection severity by suppressing Th17- and Th2-mediated inflammations [39,40]. Interestingly, comparative studies of the IFV infections in IL-27RA-/- and IL-10-/- mice demonstrated that the former had a more severe disease course than the latter [41], demonstrating that not all the anti-inflammatory effects of IL-27 are mediated by the induction of IL-10 production, as it was suggested before [42,43]. Of note, it was reported that IL-27 is not sufficient for the optimal induction of Treg cell maturation in the respiratory tract and that IL-6 is required for the IL-27/Treg cell protections against inflammatory damage. The early production of IL-6 after the RSV infection induces the expression of IL-27 by myeloid cells, including AMs, which, in turn, stimulates Treg cell maturation. The depletion of IL-27 or IL-6 in the respiratory tract during the RSV have the same detrimental effect on the maturation of Treg cells and RSV-mediated immunopathology [37]. Then, our results show that the improved production of IL-27 and IL-6 by AMs of NV1505- and PG1505-treated mice may play an important role in limiting inflammation and protecting lung function during the RSV infection by increasing the maturation and activation of Treg cells. In this way, AMs indirectly increase IL-10 production in the respiratory tract of CRL1505-treated mice. It should be noted that similar results were observed when the TLR3 agonist poly(I:C) was used instead of the RSV challenge. Poly(I:C) significantly increased the production of IL-27 by AMs, which is consistent with previous findings, demonstrating that the stimulation of bone marrow-derived macrophages significantly increased the IL-27 expression in response to the TLR3 and TLR7 agonists [44]. Moreover, the ability of AMs to produce both IL-27 and IL-6 in response to TLR3 activation was enhanced in cells obtained from NV1505- and PG1505-treated mice. Then, it is tempting to speculate that NV1505 and PG1505 treatments would be capable of protecting against inflammatory-mediated lung injuries induced by other respiratory viruses with a dsRNA genome or that produce this molecule during their replication.
- (b)
- The role of AMs in the modulation of antipneumococcal immunity by nasally administered NV1505 and PG1505. Our results also demonstrated that AMs are necessary for the improved protection against primary and secondary pneumococcal pneumonia induced by the CRL1505 strain. The depletion of AMs by clodronate liposomes at the time of NV1505 or PG1505 nasal priming abolished the ability of the treatments to reduce lung and blood pneumococcal cell counts after the primary infection while significantly diminishing, but not completely abolishing, their capacity to reduce those parameters after the secondary infection. Similar to our findings in the RSV infection experiments, improved levels of IFN-β and IFN-γ were found in the respiratory tract of NV1505- and PG1505-treated mice after the primary or secondary pneumococcal challenges. Both cytokines have been associated with the protection against this respiratory pathogen. It was demonstrated in vitro that macrophages produce type I IFNs upon S. pneumoniae stimulation via a mechanism dependent on bacterial uptake, and in vivo studies confirmed that AMs are the main source of type I IFNs upon the pneumococcal challenge [45]. Type I IFNs produced by AMs act on alveolar type II pneumocytes, protecting them from cell death and increasing their resistance to the S. pneumoniae infection [45]. Moreover, it was reported that type I IFNs increase the pulmonary barrier function and protect against the pneumococcal invasive disease [46,47,48]. The treatment with recombinant IFN-β resulted in an increased expression of tight junction proteins and the local containment of S. pneumoniae, while, in ifnar1−/− mice, which have an increased susceptibility to fatal pneumococcal disease, reduced expression levels of the tight-junction genes Tjp1, Cldn5, and Cldn18 were found [48]. On the other hand, the appropriate production of IFN-γ in the respiratory tract has been associated with the protection against S. pneumoniae. Improved levels of IFN-γ stimulates pulmonary macrophages that are critical for the host defenses against pneumococcal infections [49]. Genome-wide microarray-based transcriptional analysis of the whole lungs of mice infected with S. pneumoniae revealed that the upregulation of IFN-γ and IFN-γ-related genes was associated with the protection against this respiratory pathogen [50]. Our results show that the increase of both IFN-β and IFN-γ induced by NV1505 or PG1505 is necessary to protect against pneumococcal infections. Moreover, our data suggest that this effect may be dose-dependent. This fact would explain why AM depletions completely abolished the improved protection against the primary pneumococcal infection while only reduced the effect on the secondary infection. Other respiratory immune and nonimmune cell populations may be the sources of IFN-β and IFN-γ, which are triggered by the RSV infection and improved by NV1505 or PG1505. In addition, the depletion of AMs abolished the reduction of lung injuries and the enhancement of the respiratory IL-10 production induced by NV1505 or PG1505 in both the primary and secondary pneumococcal infections. These results are consistent with previous works reporting that the depletion of AMs before the infection with S. pneumoniae led to an increased local inflammatory response and enhanced mortality [51]. The improved production of IL-6 and IL-27 by AMs from NV1505- and PG1505-treated mice in response to the pneumococcal challenge suggest that these cells would also modulate the Treg cell activity and indirectly increase IL-10 production in the context of the S. pneumoniae infection, as it was described above for the RSV. The induction of a different cytokine profile in AMs by NV1505 or PG1505—in particular, the increases in type I IFNs, IFN-γ, IL-6, and IL-27—would be associated not only with an enhanced resistance to the primary RSV infection but, also, to the secondary pneumococcal challenge. An interesting question to answer in the future is to find out whether the immunomodulatory effects of NV1505 and PG1505 could also protect the host against the secondary bacterial pneumonia produced after the primary infection with other respiratory viruses. It should be noted that respiratory viruses are able to use different mechanisms to modulate the expressions of respiratory cytokines. In this regard, it has been shown that the increased susceptibility to the S. pneumoniae infection after the primary IFV challenge is associated to several changes in respiratory cytokines. The suppression of neutrophil activity and the impairment of AM functions by the excessive production of type I IFNs and IFN-γ, respectively, have been found to contribute to the enhanced susceptibility to secondary pneumococcal pneumonia [52,53,54]. In addition, it was reported that IL-27 production in an IFNAR-signaling-dependent manner induced by IFV impairs IL-17A-producing γδ T cells, leading to a reduced neutrophil response and resistance to a secondary pneumococcal infection [55]. Thus, experimental studies with other respiratory viruses are necessary to elucidate whether the immunomodulatory effects of NV1505 or PG1505 are beneficial only in post-RSV pneumococcal pneumonia or are more general. Moreover, considering that the correct regulation of both the induction and subsequent control of inflammation during respiratory infections is imperative in minimizing severe immunopathology, the detailed study of the influence of NV1505 and PG1505 on the kinetics of IFN-β, IFN-γ, IL-6, and IL-27 productions in the respiratory tract after primary viral infections and secondary pneumococcal pneumonia would be of great value to gain a better understanding of the mechanisms involved in their beneficial effects.
- (c)
- The generation of activated/trained AMs by NV1505 and PG1505 would be essential for enhanced protection against respiratory pathogens. Recent research has revealed that, after a primary immunologic challenge, innate immune cells such as macrophages can be trained to carry a nonspecific immune memory that improves their responses to subsequent related or unrelated immunologic exposures [56,57]. Such innate immune memory has been designated as “trained immunity”, and it has been recently evaluated in the context of respiratory infections [25,57]. The induction of innate immune training in the respiratory tract was demonstrated by studies of an adenoviral infection in mice. The work reported that the respiratory viral infection induced a trained immunity phenotype in AMs characterized by an increased expression of MHC-II and release of cytokines and chemokines upon restimulation [25]. Moreover, the induction of trained AMs resulted in a higher resistance against a heterologous bacterial infection. The study also demonstrated that IFN-γ production during the primary viral infection was associated to the generation of trained AMs [25]. The role of IFN-γ in the induction of trained macrophages was supported by several subsequent studies [56,57]. Interestingly, transcriptomic studies evaluating the expression of ISGs in macrophages prestimulated it with IFN-γ in response to a second stimulation with the same cytokine demonstrated the existence of an IFN memory. Some ISGs, including Mx1, Irf7, Ifi44, Nos2, Il12br, Ciita, and Tlr11, were expressed earlier and/or in higher levels in IFN-γ-prestimulated macrophages than in naïve cells [56]. In addition, in vivo studies in which IFN-γ primed AMs were subjected to a secondary challenge revealed a rapid upregulation of IFN-γ and STAT1 signaling pathways [57]. Moreover, primed AMs had improved proinflammatory cytokine responses upon a secondary exposure to Cryptococcus neoformans. The results of this work show some similarities with those mentioned reports. Steady-state mouse resident AMs do not express CX3CR1 or CD11b, while they have high levels of CD11c and Siglec-F expressions (reviewed in [26]). Our studies focused on this resident CD45+CD11c+SiglecF+ AMs, demonstrated that the nasal priming with NV1505 or PG1505 significantly increased their expression of MHC-II two days after the RSV and S. pneumoniae infections, which correspond to 7 and 12 days after the CRL1505 treatments, respectively. This is consistent with studies demonstrating that trained CD11c+CD64+SiglecF+ AMs began to develop between 5–7 days after the primary stimuli [25]. In addition, AMs from NV1505- and PG1505-treated infant mice had an improved in vitro production of IFN-γ, TNF-α, IL-6, CCL2, CXCL2, and CXCL10, which was correlated with a more intense and faster inflammatory response in vivo upon a secondary pneumococcal challenge. Then, it is tempting to speculate that the nasal priming of NV1505 or PG1505 would be capable of activating AMs and inducing trained cells that are involved in the protection of secondary infections produced after the primary RSV infection or the TLR3 activation. However, in order to define forcefully the generation of trained AMs by NV1505 or PG1505 treatments, several complementary studies are necessary that are related to the biology of the trained immunity. Specific histone modifications in methylation patterns, as well as transcription factors binding to the promoter regions of key immune genes, have been associated with the trained immunity in macrophages [56,57]. The epigenetic reprogramming of innate immune cells during the generation of trained immunity has been also strongly associated with changes in the cellular metabolism. In this sense, an increased glycolytic metabolism has been described in trained AMs after an adenovirus infection [25]. Furthermore, protection against secondary infectious challenges have been demonstrated to last for a long period: 10 to 16 weeks after the primary stimuli [25,57]. Then, future studies are needed to evaluate the specific histone modifications and/or transcription factor bindings, as well as the metabolic changes that occur after the NV1505 or PG1505 priming of AMs that likely aid in their improved response to the in vivo challenge with the RSV or S. pneumoniae. In addition, a more precise investigation of the duration of the immunomodulatory effects induced by NV1505 and PG1505 in AMs would help to better understand their mechanisms of action and foresee possible protections against other respiratory pathogens.
- (d)
- Other immune and nonimmune cell populations in the respiratory tract may contribute to the improved protections against bacterial and viral infections induced by NV1505 and PG1505. As mentioned before, the depletion of AMs did not completely abolish the ability of NV1505 or PG1505 to increase the respiratory levels of IFN-β and IFN-γ, indicating that other respiratory cell populations would contribute to this effect. Another source of improved IFN-β production could be airway and lung epithelial cells. For instance, our studies in intestinal epithelial cells demonstrated that L. rhamnosus CRL1505 is able to increase the expression of type I IFNs and ISGs, enhancing the protections against viral infections [58,59]. The nasal priming with NV1505 or PG1505 could have a similar effect on respiratory epithelial cells that would contribute to the protection against the RSV. In addition, the production of IFN-β by epithelial cells would be involved in the protection against pneumococcal infection through the improved production of antimicrobial factors [60] and pulmonary barrier functions [45,48]. On the other hand, an earlier production of IFN-γ in response to a respiratory viral infection has been attributed to NK cells, and several studies have demonstrated the ability of nasally administered lactobacilli to improve the activity of this immune cell population (reviewed in [61]). We have not previously evaluated the effect of nasally administered L. rhamnosus CRL1505 or its peptidoglycan on respiratory NK cell numbers and activities, which is an interesting topic for future near research. Another potential source of the improved levels of IFN-γ in the respiratory tract of NV1505- or PG1505-treated mice is CD4+ T cells. In this sense, we demonstrated previously that NV1505 is capable of increasing the number of lung CD11c+CD11blowCD103+ DCs [19], which have been reported to be a potent inducer of Th1 responses in the respiratory tract [62]. Consistently, the number of CD4+IFN-γ+ T cells were increased as earlier as three days after the challenge with the RSV in NV1505-treated infant mice [19].
- (e)
- The immunomodulatory properties of NV1505 and PG1505 are strain-specific. The comparative analysis performed in this work with nonviable L. rhamnosus CRL1505 and CRL489 and their peptidoglycans revealed that the protection against the primary RSV infection and secondary pneumococcal pneumonia induced by CRL1505 in infant mice are strain-dependent characteristics. This is consistent with our previous reports demonstrating a strain-dependent effect of lactobacilli peptidoglycan in the context of a primary pneumococcal infection in immunocompromised malnourished mice [63]. The studies with PG1505 and the peptidoglycans from the nonimmunomodulatory strain L. rhamnosus CRL534 or with the immunobiotic L. plantarum CRL1506 showed that PG1505 has unique functional properties that cannot be extended to peptidoglycans, even from other immunomodulatory lactobacilli strains. Supporting our findings, it was shown that the nasal priming with heat-inactivated L. reuteri F275 significantly increased the protection of mice against the pneumonia virus of mice (PVM) infection, while its purified peptidoglycan did not confer protection [64,65]. Further comparative studies with L. rhamnosus CRL1505 peptidoglycan and a higher number of peptidoglycans isolated from the same species in terms of their structure, as well as their interactions with the receptors and cells of the respiratory immune system, could contribute significantly to the understanding of the molecular basis of the interaction between beneficial microorganisms and the host and its impact on respiratory infections.
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Clua, P.; Tomokiyo, M.; Raya Tonetti, F.; Islam, M.A.; García Castillo, V.; Marcial, G.; Salva, S.; Alvarez, S.; Takahashi, H.; Kurata, S.; et al. The Role of Alveolar Macrophages in the Improved Protection against Respiratory Syncytial Virus and Pneumococcal Superinfection Induced by the Peptidoglycan of Lactobacillus rhamnosus CRL1505. Cells 2020, 9, 1653. https://doi.org/10.3390/cells9071653
Clua P, Tomokiyo M, Raya Tonetti F, Islam MA, García Castillo V, Marcial G, Salva S, Alvarez S, Takahashi H, Kurata S, et al. The Role of Alveolar Macrophages in the Improved Protection against Respiratory Syncytial Virus and Pneumococcal Superinfection Induced by the Peptidoglycan of Lactobacillus rhamnosus CRL1505. Cells. 2020; 9(7):1653. https://doi.org/10.3390/cells9071653
Chicago/Turabian StyleClua, Patricia, Mikado Tomokiyo, Fernanda Raya Tonetti, Md. Aminul Islam, Valeria García Castillo, Guillermo Marcial, Susana Salva, Susana Alvarez, Hideki Takahashi, Shoichiro Kurata, and et al. 2020. "The Role of Alveolar Macrophages in the Improved Protection against Respiratory Syncytial Virus and Pneumococcal Superinfection Induced by the Peptidoglycan of Lactobacillus rhamnosus CRL1505" Cells 9, no. 7: 1653. https://doi.org/10.3390/cells9071653