As the global population ages, the impact of infectious diseases on the aging population becomes increasingly significant. Among the most relevant risk factors leading to higher susceptibility as well as severity in both community-acquired (CA) and healthcare-associated (HA) pneumonia is advanced age (≥60 years) (Torres et al., 2021). Particularly severe is pneumonia caused by Staphylococcus aureus (S. aureus) (Lee et al., 2022). S. aureus is a gram-positive bacterium that frequently colonizes humans but can manifest various pathologies, ranging from mild to more severe infections, including pneumonia (Howden et al., 2023; Jong et al., 2019). It accounts for a notable proportion of CA and HA cases (Lee et al., 2022; Torres et al., 2021). The bacterium exhibits a broad spectrum of virulence factors, including toxins, adhesins, and immune evasion strategies, contributing to its ability to establish infections in the lower respiratory tract (Howden et al., 2023). Aging is a central factor predisposing individuals to a higher risk for S. aureus pneumonia (Torres et al., 2021), as aging is impacting several important functions of the body such as the immune response and thus the capability to mount an effective defensive response (Montecino-Rodriguez et al., 2013). Aging-related dysregulation of the immune response is also characterized by inflammaging, defined as the presence of elevated levels of pro-inflammatory cytokines in the absence of an obvious inflammatory trigger (Franceschi et al., 2000; Mogilenko et al., 2022). Additionally, immune cells, such as macrophages, exhibit an activated state that alters their response to infection (Canan et al., 2014). In contrast, the immune response of macrophages to infectious challenges has been shown to be initially impaired in aged mice (Boe et al., 2017). Thus aging is a relevant factor impacting the pulmonary immune response. This highlights the vital connection between aging and S. aureus pneumonia, as well as the need for further research investigating this connection.

The process of aging is a multifaceted phenomenon that involves various underlying mechanisms, known as hallmarks (López-Otín et al., 2023). Among these hallmarks, telomere shortening is a significant factor in cellular aging. Telomeres serve as protective caps at the end of chromosomes, which shorten with every cell division until they reach a critical length where replication becomes impossible, eventually resulting in either apoptosis or senescence (López-Otín et al., 2023). However, this process can be counteracted by the telomerase, which can add new repeats to the ends of chromosomes and thus prevent the shortening of telomeres (Greider and Blackburn, 1985). The telomerase mainly consists of two parts: the telomerase reverse transcriptase (Tert), which harbors the enzymatic activity, and Terc, which serves as a template for the addition of new repeats (Sahin and Depinho, 2010; Shay and Wright, 2019). Telomerase activity is restricted to specific tissues and cell types, largely dependent on the expression of Tert. While Tert is highly expressed in stem cells, progenitor cells, and germline cells, its expression is minimal in most differentiated cells (Chakravarti et al., 2021). Consequently, the impact of telomerase dysfunction on tissues varies according to their self-renewal rate (Chakravarti et al., 2021).

One important aspect of telomere dysfunction is the impact of telomere shortening on the immune system as well as the hematopoietic system. Tissues or organ systems that are highly replicative, such as the skin or the hematopoietic system, are affected first by telomere shortening (Chakravarti et al., 2021). Due to the loss of the protective telomere caps, mutations can accumulate, and the cells ultimately become senescent (Chakravarti et al., 2021). Interestingly, while most differentiated cells do not exhibit telomerase activity, T cells display a high activity of this enzyme (Hodes et al., 2002). Aging T cells become senescent, which is characterized by short telomeres and the absence of CD28 expression (Hohensinner et al., 2011). Furthermore, telomere length and T cell functionality are closely connected. T cells with shorter telomeres are implicated in diseases related to aging like arthritis (Hohensinner et al., 2011). Additionally, CD4⁺ T cells from Terc knockout (Terc^ko/ko) mice displayed several characteristics of aged T cells such as a reduction in CD28 expression and changed secretion of cytokines. Furthermore the naïve T cell population was found to be reduced (Matthe et al., 2022). This highlights the importance of intact telomeres and telomerase on immune cell function.

While most differentiated cells lack the expression of Tert, almost all human cells and several murine tissues express Terc (Zhang et al., 2018). However, the function of ubiquitous Terc expression remains elusive (Chakravarti et al., 2021; Shay and Wright, 2019). Interestingly, recent studies identified a variety of functions of Terc, which are independent of its function as part of the telomerase. Notably, a study could show that Terc triggers inflammation via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway (Liu et al., 2019). Furthermore, Terc was identified to be involved in cell proliferation by enhancing the expression of several genes belonging to the phosphoinositide 3-kinase (Pi3K)-protein kinase B (AKT) pathway (Wu et al., 2022). The same study could show that this mechanism also contributed to CD4⁺ T cell expansion (Wu et al., 2022). Additionally, Terc deletion in mice induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in macrophages upon pulmonary infection with S. aureus, thereby revealing another connection between immune modulation and the presence of Terc (Kang et al., 2018). Thus, it appears that Terc could serve as a relevant immunomodulatory factor, potentially implicated in S. aureus - induced pathologies. Interestingly, downregulation of Terc and Tert expression in tissues of aged mice and rats has been found (Tarry-Adkins et al., 2021; Zhang et al., 2018). Therefore, as a potential immunomodulatory factor reduced Terc expression could be connected to aging-related pathologies.

Knockout of Terc in mice is a well-established model for premature aging, as telomeres of Terc^ko/ko mice shorten with every generation (Wong et al., 2009). Additionally, the telomeres shorten during each generation with increasing age of the mice (Wong et al., 2009). Furthermore, third-generation (G3) Terc^ko/ko mice with a C56Bl/6 background have a shorter lifespan, a smaller litter size, and a generally reduced body size and weight (Wong et al., 2009). Although G3 Terc^ko/ko mice with shortened telomeres were used in this study, they were infected at a young age (8 weeks). This approach allowed for the investigation of Terc deletion effects rather than telomere dysfunction. As control cohort age-matched young WT mice were utilized. To investigate whether Terc deletion, beyond critical telomere shortening, impacts the pulmonary immune response, we used young Terc^ko/ko mice. Additionally, naturally aged mice (2 years of age) were infected to explore the potential link to a fully developed aging phenotype.

In this study, we aimed to investigate the impact of Terc deletion, as an essential immunomodulatory factor, on the immune response to S. aureus - induced pneumonia in mice. For this purpose, G3 Terc^ko/ko mice were infected with S. aureus, and the progression of disease and immune response were evaluated. Strikingly, our data highlights that the deletion of Terc resulted in a more severe disease outcome and disrupted the innate and adaptive immune response. These findings suggest a possible connection between Terc and immune cell homeostasis.

Shortening of telomeres is a key factor in the aging process and has a significant impact on other hallmarks of aging, such as mitochondrial dysfunction and cellular senescence (Birch et al., 2018; López-Otín et al., 2023). In this context, the discussion surrounding the importance of Terc is primarily confined to its role within telomerase. Consequently, other potential functions of Terc in various cellular processes have been largely overlooked. Interestingly, various studies have linked Terc to inflammation, as it has been shown to activate the NF-κB and PI3K-AKT pathways (Liu et al., 2019; Wu et al., 2022). Another study could show that the deletion of Terc in mice resulted in NLRP3 inflammasome activation after infection with S. aureus, thus contributing to more severe pneumonia (Kang et al., 2018). These studies suggest a close association between Terc, inflammation, and the response to bacterial lung infections.

In our study, we utilized a Terc^ko/ko S. aureus pneumonia model to investigate this connection. In accordance with German animal welfare regulations and the 3R principle, we only had a reduced number of Terc^ko/ko mice available for the experiment, as some infections were fatal. This reduced number of mice is a limitation of our study. However, we could demonstrate that Terc^ko/ko mice presented with a more severe pneumonia, higher bacterial load, and increased mortality compared to old and young WT mice (Figure 1). Additionally, we could show that infected Terc^ko/ko mice are rather heterogeneous and display several degrees of severity, which we investigated separately. Of five infected mice, two died, two displayed signs of a systemic infection and only one had a mild infection. The mice with systemic infection were grouped based on the presence of bacteria in organs other than the lung, as well as the sequencing data, where they clustered separately. The detection of bacteria in extrapulmonary organs is of particular interest, as bacteremia is a symptom of severe pneumonia and is associated with high mortality (De la Calle et al., 2016). The grouping of Terc^koko mice, based on their disease severity, offers the possibility to investigate distinct features of bacterial infection. Terc^ko/ko mice were previously shown to have higher susceptibility to S. aureus pneumonia, although they exhibited a reduced bacterial load in their lungs (Kang et al., 2018). These differences may be attributed to the missing separation of infected Terc^ko/ko mice into different degrees of severity. Additionally, this heterogeneity in disease manifestation points toward the limitations of mouse models to study S. aureus pathologies. There are a variety of differences between S. aureus infections in humans and mice. For instance, several relevant virulence factors (e.g. Pantone-Valentine leukocidine) function less efficient in mice than in humans (Zheng et al., 2023). Therefore, higher infection doses are needed to successfully establish an infection that is comparable to humans (Zheng et al., 2023).

Inflammation and the activation of the NLRP3 inflammasome are necessary components to fight bacterial infections of the lung. However, excessive inflammation and over-activation of the NLRP3 inflammasome lead to lung injury and can impede pathogen clearance, thus contributing to S. aureus-induced pathologies (McVey et al., 2021; Wang et al., 2022). Upon examining the lungs of infected Terc^ko/ko mice with systemic infection, we identified a marked increase in inflammation parameters (Figure 2). Furthermore, we discovered that genes associated with the NLRP3 inflammasome pathway were elevated in the infected Terc^ko/ko mice but not in the corresponding non-infected control cohort. As published previously, this implies that Terc knockout on its own does not result in heightened inflammation and inflammasome activation but rather requires an external trigger (Kang et al., 2018). Inflammasome activation in Terc^ko/ko mice was connected to mitochondria dysfunction and an elevated reactive oxygen species production. Additionally, regulation of the inflammasome seems to be dysfunctional as TNAIFP3, an important negative regulator of the inflammasome was downregulated in the Terc^ko/ko mice in this study (Kang et al., 2018). However, we did not observe downregulation of TNFAIP3, but rather an upregulation in infected Terc^ko/ko mice (Figure 2C). These differences may however be attributed to the different study design. Kang et al. focused on telomere dysfunction studying macrophages of old Terc^ko/ko mice, while our study investigated the entire lung of young Terc^ko/ko mice. Of particular note were the heightened levels of IL-1β, a factor known for its ability to amplify the inflammatory response and facilitate the infiltration of pro-inflammatory immune cells, thereby fostering pulmonary injury (Chen et al., 2018; Hu et al., 2020). Additionally, pro-inflammatory macrophages infiltrating the lung are critical to inflammation-mediated lung injury (Chen et al., 2018; Guan et al., 2023). In our study, we could identify the upregulation of several pro-inflammatory macrophage markers in infected Terc^ko/ko mice, as well as several chemokine markers further exacerbating the inflammation in the lung via attraction of immune cells (Figure 3). Notably, we did not observe upregulation of inflammation parameters or activation of the inflammasome in the infected old WT mice. Although CD14 showed a slight increase in non-infected old WT mice compared to non-infected young WT mice, there was no upregulation of macrophage markers in the infected cohorts of these groups. Innate immune cells of aged individuals especially macrophages are associated with chronic low-grade inflammation contributing to injury during infection (Duong et al., 2021). However, studies could also show that macrophages of aged mice had a reduced response to stimulation of pathogen recognition receptors such as Toll-like receptor 2. This results in an initially diminished and delayed response of macrophages to infectious challenge, which could be a possible explanation for the lack of inflammation at 24 hpi (Boe et al., 2017; Hinojosa et al., 2009).

An overactive inflammatory response not only causes tissue damage but also leads to T cell dysfunction (Guan et al., 2023). A possible mechanism is the downregulation of CD247, which is the CD3ζ chain of the TCR. CD247/CD3ζ is necessary for the assembly of the receptor at the cell surface. Furthermore, due to its multiple immunoreceptor tyrosine-based activation motifs, it is a central factor in the signal transduction (Bronstein-Sitton et al., 2003; Jin et al., 2024). The downregulation or absence of CD247/CD3ζ is linked to reduced responsiveness in T cells and is commonly present in autoimmune diseases like rheumatoid arthritis and lupus (Dexiu et al., 2022). This mechanism also occurs in various chronic infectious diseases, including HIV and hepatitis C (Dexiu et al., 2022). However, it can also be a general regulatory process in T cells during infection, helping to maintain immune homeostasis and prevent excessive inflammation (Baniyash, 2004; van der Donk et al., 2021). Thus, the connection between CD247/CD3ζ downregulation during chronic inflammation and chronic infectious diseases has been well documented (Dexiu et al., 2022). Interestingly, we could show that expression of CD247 is entirely absent in infected Terc^ko/ko mice, while in the non-infected Terc^ko/ko mice expression of CD247 could be detected after 24 hr of infection. Hence, our data indicates that infection combined with deletion of Terc is associated with reduction of CD247 expression. Our study provides the first evidence of the total absence of CD247 expression during acute bacterial infection and inflammation (Figure 4).

Previous work has already reported that constant stimulus with bacterial antigens reduces the expression of CD247/CD3ζ and impairs T cell function (Bronstein-Sitton et al., 2003). However, the complete absence of CD247/CD3ζ after a single antigenic stimulus, without chronic inflammation as well as the connection to knockout of Terc, are novel findings. These findings require further studies and investigations to gain a deeper understanding of the underlying mechanisms.

Downregulation of CD247/CD3ζ is facilitated by myeloid suppressor cells (MSCs), which accumulate at the site of inflammation (Baniyash, 2004; Dexiu et al., 2022; Ezernitchi et al., 2006). MSCs are cells which exert an immunosuppressive function on T cells in response to inflammation or infection (Medina and Hartl, 2018). Thus MSCs contribute toward the regulation of the immune response to pathogens to prevent an overshooting reaction of the immune system (Medina and Hartl, 2018). However, their immunosuppressive function can also exacerbate infections. For instance, elevated levels of MSC induced T cell dysfunctionality and caused an exacerbated and sustained chronic infection in an S. aureus mouse model (Tebartz et al., 2015). Immunosuppression of T cells is conveyed by multiple mechanisms, one of which is the downregulation of CD247/CD3ζ (Ezernitchi et al., 2006). This process is facilitated among others by the ability of MSCs to metabolize the amino acid arginine, as arginine seems to be essential for expression of CD247 in T cells (Ezernitchi et al., 2006; Rodriguez et al., 2004). Interestingly, we could identify several MSC markers, such as lymphocyte antigen 6 family member G (LY6G), to be upregulated in the infected Terc^ko/ko mice. This suggests a potential role of MSCs in the downregulation of CD247/CD3ζ (Figure 5—figure supplement 1D). Notably, we could identify reduced expression of CD247 in infected old WT mice compared to young WT mice. Moreover, our sequencing data did not show an increase in CD247 expression in infected old WT mice compared to the non-infected control group, which further suggests that the T cells of old WT mice may also exhibit some level of dysfunction (Figure 4). One potential underlying mechanism is the reduced ability of aged macrophages to activate T cells due to diminished expression of the receptor required for presentation of the antigen (Herrero et al., 2001). Furthermore, T cells of aged individuals become increasingly deficient due to immunosenescence and exhaustion (Mittelbrunn and Kroemer, 2021). Supporting this, we could observe downregulation of CD27 compared to infected young WT mice, while CTLA4 was upregulated in infected old WT compared to uninfected mice (Figure 2—figure supplement 1E and F). Downregulation of CD28 and CD27 is part of T cell aging and an essential marker of T cell senescence, while upregulation of CTLA4 is part of a signature pointing to T cell exhaustion (Zhao et al., 2020). Interestingly, senescent T cells have shorter telomeres and exhibit reduced telomerase activity, which indicates a possible connection between Terc and T cell function (Mittelbrunn and Kroemer, 2021). Interestingly, CD28 expression was downregulated in infected Terc^ko/ko mice compared to old WT infected mice (Figure 4A and C). However, we did not observe any other relevant changes of T cell senescence or exhaustion markers in infected Terc^ko/ko mice (Figure 4A and C). Thus, T cell senescence could be a contributing factor to the T cell dysfunctionality, but likely does not explain the complete phenotype. The differences in the expression of T cell senescence and exhaustion markers, in addition to the lack of increased inflammation in old WT mice, indicate that mechanisms causing downregulation of parts of the TCR and T helper cell markers in old WT and Terc^ko/ko mice differ from each other. As T cell senescence is however a known consequence of Terc deletion, the lack of in depth investigation of this process in the present study is a limitation (Matthe et al., 2022). It is important to note that telomere shortening has a significant impact on the immune system (Chakravarti et al., 2021). Although young Terc^ko/ko mice were used in this study, telomere shortening is still likely to be a contributing factor. Therefore, further experiments investigating the role of T cell senescence in this model should be conducted.

Nevertheless, old WT mice exhibit certain immune cell dysfunction similarities. However, given the intricate nature of aging, other mechanisms contribute to the distinct response observed in Terc^ko/ko and old WT mice following infection. This highlights the necessity of employing a knockout model to specifically examine the influence of Terc on infection, isolating it from the multifaceted processes involved in aging.

We observed an increase in pro-inflammatory macrophages in the lungs of Terc^ko/ko mice during infection. To explore the role of macrophages in regulating T cell function during infection, we investigated whether AMs were sufficient to induce CD247/CD3ζ downregulation in T cells. While CD247/CD3ζ expression increased with bacterial stimulation in T cells from young WT mice, we failed to induce such an increase in CD247/CD3ζ expression in T cells from Terc^ko/ko mice (Figure 5). The expression pattern of CD247/CD3ζ was similar to that observed in the sequencing data, as initial levels of CD247/CD3ζ expression in non-infected Terc^ko/ko mice were higher than those of young WT mice. However, there was no significant reduction of CD247/CD3ζ after stimulation with bacteria in the T cells of Terc^ko/ko mice. One potential explanation for this finding is the absence of MSCs and other infiltrating cells, which can contribute to the inflammatory environment and lead to T cell dysfunction. Furthermore, after 24 but not 2 hr of infection, we observed a reduced release of the pro-inflammatory cytokine IL-1α from Terc^ko/ko T cells, suggesting a time-dependent reduction of T cell function. The results of the experiment conducted on T cells of Terc^ko/ko mice revealed an insufficient response to the bacterial stimulation, as there was no significant increase in CD247/CD3ζ expression or IL-1α release after 24 hpi. As total CD4⁺ T cells were analyzed in this study, it would be useful to investigate specific T cell populations such as memory and effector T cells to elucidate the potential mechanism leading to T cell dysfunctionality in further detail. Additionally, analysis of differences in immune cell recruitment to the lungs between young WT and Terc^ko/ko mice would be relevant. Thus, additional experiments are needed to validate and further investigate the underlying mechanisms leading to T cell dysfunctionality in Terc^ko/ko mice.

Our data points toward the pivotal role of Terc in the regulation of inflammation as well as maintaining immune homeostasis during infection. We could demonstrate that S. aureus pneumonia in Terc^ko/ko mice resulted in an overshooting inflammation and activation of the NLRP3 inflammasome. The elevated inflammation eventually leads to T cell dysfunction, which impairs the host’s ability to mount an effective immune response against the pathogen, resulting in increased bacterial load and mortality. As T cell dysfunctionality is caused by the excessive inflammation, other pathogens inducing high inflammatory responses in the host could also lead to a similar phenotype in Terc^ko/ko mice (Figure 6).

Figure 6 with 1 supplement see all

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This study linked T cell dysfunction to Terc deletion, which is supported by previous studies reporting a connection between reduced expression of Terc and apoptosis in human CD4⁺ T cells (Gazzaniga and Blackburn, 2014). These findings provide insights into possible mechanisms contributing to a more severe S. aureus pneumonia in the aging population.

The data supporting this study's findings were made available as supplementary and source data files. The DEG lists generated via RNA sequencing were made available at Mendeley Data.

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Author details

1. Yasmina Reisser

   Institute of Medical Microbiology, Jena University Hospital, Jena, Germany

   Contribution

   Visualization, Methodology, Writing – original draft, Writing – review and editing

   For correspondence

   yasmina.reisser@med.uni-jena.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0009-0007-9757-5036

2. Franziska Hornung

   Institute of Medical Microbiology, Jena University Hospital, Jena, Germany

   Contribution

   Visualization, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

3. Antje Häder

   Institute of Medical Microbiology, Jena University Hospital, Jena, Germany

   Contribution

   Visualization, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

4. Thurid Lauf

   1. Institute of Medical Microbiology, Jena University Hospital, Jena, Germany
   2. Else Kröner Graduate School for Medical Students 'JSAM', Jena University Hospital, Jena, Germany

   Contribution

   Visualization, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

5. Sandor Nietzsche

   Center for Electron Microscopy, Jena University Hospital, Jena, Germany

   Contribution

   Visualization, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

6. Bettina Löffler

   Institute of Medical Microbiology, Jena University Hospital, Jena, Germany

   Contribution

   Resources, Supervision, Funding acquisition, Visualization, Writing – review and editing

   Competing interests

   No competing interests declared

7. Stefanie Deinhardt-Emmer

   Institute of Medical Microbiology, Jena University Hospital, Jena, Germany

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Visualization, Writing – original draft, Writing – review and editing

   For correspondence

   stefanie.deinhardt-emmer@med.uni-jena.de

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4495-4052

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