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Longitudinal changes in tear cytokines and antimicrobial proteins in trachomatous disease [1]

['Amber Barton', 'Clinical Research Department', 'Faculty Of Infectious', 'Tropical Diseases', 'London School Of Hygiene', 'Tropical Medicine', 'Keppel Street', 'London', 'United Kingdom', 'Nkoyo Faal']

Date: 2023-11

Kinetics of tear cytokine responses to C. trachomatis infection

These data represent the first report of cytokines and antimicrobial proteins longitudinally profiled in the tears of human participants over the course of ocular C. trachomatis infection and trachomatous disease. We found that CXC cytokines IL-8, IP-10 and CXCL1, and antimicrobial protein lactoferrin, were raised either during or following clinically inapparent infection. Consistently, following exposure to C. trachomatis the genes encoding IL-8 and IP-10 are upregulated by neutrophils [21], IL-8 and CXCL1 by macrophages [26], and CXCL1 by epithelial cells [19]. IL-8, IP-10 and CXCL1 are all transcriptionally regulated by NF-κB [27], suggesting that cytokine expression is likely induced by pattern recognition receptors: either directly by innate recognition of C. trachomatis [28,29], or indirectly in response to C. trachomatis-mediated cell damage [30].

Whereas lactoferrin is anti-inflammatory and prevents C. trachomatis invasion in vitro [31], CXC cytokines are a double edged-sword, recruiting neutrophils and T cells to sites of infection [32] (Fig 7A). While CD4+ T cell responses against C. trachomatis are necessary for resolution of infection, CD8+ T cells and neutrophils may mediate the tissue damage seen in trachomatous scarring (Fig 7B) [3,33]. Animal models suggest that while CD8+ T cells cause pathology through secretion of TNF-α [34,35], neutrophils may directly damage tissue through production of reactive oxygen species and matrix metalloproteinases [3,36]. In support of neutrophil recruitment playing a role in pathogenesis, a genetic variant resulting in lower levels of IL-8 increases resistance to trachomatous scarring [37].

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TIFF original image Download: Fig 7. A model for trachoma pathogenesis based on study findings. a. Infection results in activation of pattern recognition receptors and therefore an increase in CXC chemokines, resulting in recruitment of T cells, Neutrophils and Macrophages b. CD8+ T cells and neutrophils can mediate tissue damage, resulting in trachomatous scarring c. Inflammatory cytokines suppress lacrimal gland secretion, decreasing lysozyme tear concentration d. Immune cells recruited to the conjunctiva and/or immune memory result in enhanced inflammation in successive infection episodes e. At later stages of scarring lysozyme is raised, possibly due to secretion by recruited macrophages. https://doi.org/10.1371/journal.pntd.0011689.g007

Inflammatory cytokines can also inhibit lacrimal gland tear secretion [25,38]. This may explain why the antibacterial enzyme lysozyme, which is secreted by both the lacrimal gland and phagocytes in the conjunctiva, is suppressed two weeks after infection (p = 0.013) with a non-significant drop during active disease (p = 0.096) (Fig 7C). While lysozyme has not previously been measured in tears in relation to trachoma, a fall in levels has previously been observed in upper respiratory tract infections and dry eye disorders [25,39].

Interestingly, lactoferrin and CXCL1 were significantly higher than healthy controls two weeks prior to detectable infection (p = 0.045 and 0.021), suggesting an immune response is triggered well before C. trachomatis reaches a high enough bacterial load to be detected by 16s rRNA PCR. Furthermore, CXCL1, IP-10 and IL-8 peaked at around four weeks post-infection, even though by this time C. trachomatis was no longer detectable by PCR. One possibility is that after an infection has been resolved or suppressed, a positive feedback loop continues to propagate an inflammatory immune response [40]. Another possibility is that live C. trachomatis suppresses inflammatory responses during infection, and this suppression wanes once the bacteria are killed. For example, in vitro IP-10 levels inversely correlate with bacterial burden, suggesting active suppression by C. trachomatis [41]. It is also possible that while not detectable in the conjunctiva, C. trachomatis is present at a sub-detectable level, or persisting in other ocular tissues or the lacrimal gland. Finally, it may be that other bacteria contribute to inflammation following resolution of infection: for example, it has previously been found that Streptococcus pneumoniae and Haemophilus influenzae are more commonly cultured from those with active trachoma than healthy controls [42,43].

We also found that CXC chemokine responses were higher in the second infection episode relative to the first episode. This could explain why repeated infection episodes increase the likelihood of scarring and may be due to several mechanisms. Firstly, it may be that the immune cells recruited to the conjunctiva during the first episode are still present, and therefore mount a stronger inflammatory response in subsequent episodes (Fig 7D). Secondly, activation of memory T cells could result in an enhanced secondary immune response. Finally, epigenetic changes in immune cells could result in a “trained” innate immune response during subsequent infection episodes [44].

Our results contrasted to others in that unlike previous gene expression analyses, which found that infection induced IFN-γ in the conjunctiva [6,8,9,15], our assay was not sufficiently sensitive to consistently detect IFN-γ in the tears. Furthermore, we did not detect a significant change in IL-12 or IL-1β during infection [6,8,9].

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[1] Url: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0011689

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