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• W3136688574 abstract "I have read with interest the recent publication by Monin et al. “γ/δ T cells compose a developmentally regulated intrauterine population and protect against vaginal candidiasis” in a recent issue of Mucosal Immunology.1Monin L et al.γδ t cells compose a developmentally regulated intrauterine population and protect against vaginal candidiasis.Mucosal Immunol. 2020; 13 (1:CAS:528:DC%2BB3cXhtVCltrfL): 969-98110.1038/s41385-020-0305-7Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar While the majority of the results in the manuscript describe an elegant study characterizing developmentally regulated intrauterine γ/δ T cells, the final portion of the manuscript regarding the potential role of intrauterine γ/δ T cells in vulvovaginal candidiasis (VVC) is somewhat concerning. As a long-standing investigator who has studied the pathogenesis of vulvovaginal candidiasis (VVC) for over 30 years through clinical studies and animal models, I feel compelled to comment on the results and interpretations regarding the vaginal candidiasis experiments. Based on data using γ/δ T cell deficient mice (Tcrd−/−), the authors conclude that intrauterine γ/δ T cells provide some level of protection against experimental VVC via reduced infiltration of IL-17-dependent neutrophils (Fig. 7).1Monin L et al.γδ t cells compose a developmentally regulated intrauterine population and protect against vaginal candidiasis.Mucosal Immunol. 2020; 13 (1:CAS:528:DC%2BB3cXhtVCltrfL): 969-98110.1038/s41385-020-0305-7Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar While the presented results are supportive of the authors' conclusions, there are several technical concerns and conceptual inaccuracies/omissions that challenge the interpretations made by the authors. First, Candida vaginitis is strictly an infection of the lower genital tract in otherwise healthy immunocompetent women. This is true for humans and for the experimental mouse model. VVC is characterized as a superficial mycological infection with limited fungal invasion into the vaginal epithelium and no migration to the cervix or the uterus. Inflammatory cell infiltrates are subsequently recruited to the vaginal lumen in response to the fungus and are overwhelmingly composed of neutrophils.2Fidel Jr, PL Yano J Esher SK Noverr MC Applying the host-microbe damage response framework to Candida pathogenesis: current and prospective strategies to reduce damage.J. Fungi (Basel). 2020; 6 (1:CAS:528:DC%2BB3cXitVOjsbrE): 3510.3390/jof6010035Crossref PubMed Scopus (5) Google Scholar, 3Yano J Lilly E Barousse M Fidel Jr, PL Epithelial cell-derived S100 calcium-binding proteins as key mediators in the hallmark acute neutrophil response during Candida vaginitis.Infect. Immun. 2010; 78 (1:CAS:528:DC%2BC3MXhtlCgu7k%3D): 5126-513710.1128/IAI.00388-10Crossref PubMed Scopus (96) Google Scholar, 4Yano J Fidel Jr, PL Protocols for vaginal inoculation and sample collection in the experimental mouse model of Candida vaginitis.J. Vis. Exp. 2011; 58: 3382Google Scholar Hence, there is a lack of rationale to support the hypothesis that intrauterine T cells play a role in host defense against VVC unless they migrate to the vagina. Recognizing that Tcrd−/− mice will not only lack intrauterine γ/δ T cells but all γ/δ T cells, caution should be taken with the interpretation that intrauterine γ/δ T cells play a role in protection against VVC as inferred by the title of the publication. We would like to point out that similar studies were performed in our laboratory in 2001 with opposite results, which was neither discussed nor cited.5Wormley Jr, FL et al.Resistance of T-cell receptor delta-chain deficient mice to experimental Candida albicans vaginitis.Infect. Immun. 2001; 69 (1:CAS:528:DC%2BD3MXnvFWjtrk%3D): 7162-716410.1128/IAI.69.11.7162-7164.2001Crossref PubMed Scopus (48) Google Scholar In our studies using Tcrd−/− mice, we observed reduced vaginal fungal burden thereby concluding that γ/δ T cells exert an immunoregulatory role that limits vaginal host responses to C. albicans. A technical distinction with our study is the fact that CFU assays were restricted to vaginal lumen lavage samples, where the organism resides in the experimental mouse model as in women as well. In addition, CFU levels were normalized to a specific volume of vaginal lavage fluid. In the current manuscript the CFUs were assessed using combined uterine and vaginal tissue homogenates that may have diluted or misrepresented the vaginal burden, and were additionally not normalized to any weight or volume of material. Second, decades of experimental evidence from the mouse model and clinical studies supports the current paradigm that vaginal Candida infection results in a pathological inflammatory response mediated by neutrophil recruitment into the vaginal lumen, which is responsible for the characteristic signs and symptoms of VVC. More recent studies demonstrated that the recruited neutrophils are dysfunctional in their ability to kill C. albicans due primarily to the presence of a competitive inhibitor of the interaction between the neutrophil and Candida, heparin sulfate,6Yano J Noverr MC Fidel Jr, PL Vaginal heparan sulfate linked to neutrophil dysfunction in the acute inflammatory response associated with experimental vulvovaginal candidiasis.MBio. 2017; 8 (1:CAS:528:DC%2BC1cXhsVGgurnE, 5350465, 28292981): e00211-e00217Crossref PubMed Scopus (43) Google Scholar a phenomenon termed neutrophil anergy.7Yano J Peters BM Noverr MC Fidel Jr, PL Novel mechanism behind the immunopathogenesis of vulvovaginal candidiasis: “Neutrophil anergy”.Infect. Immun. 2018; 86: e00617-e0068410.1128/IAI.00684-17Crossref Scopus (53) Google Scholar The immunopathogenesis of VVC was not discussed in the current manuscript but is critically important to the interpretations. The increased CFUs shown in the Tcrd−/− mice were concomitant with evidence of reduced neutrophil levels in cell suspensions from tissue digests compared to WT infected mice. While the neutrophils indeed migrate through the tissue, their endpoint is the vaginal lumen, where the vast majority of the organism resides. Hence, a more relevant readout to correlate with vaginal fungal burden would be the neutrophils in the lumen from vaginal lavage samples. Even if vaginal lumen neutrophils were shown to be reduced in Tcrd−/− mice, this result would not be expected to have any influence on fungal burden due to impaired antifungal activity of the neutrophils in the vaginal lumen. Instead, reduced neutrophils would be expected to correlate with reductions in other established hallmarks of VVC immunopathogenesis and inflammation (LDH, S100A8, IL-1β). However, these types of conclusions cannot be drawn because the vaginal inflammatory response was not monitored in these studies. This is compounded further by the choice of C. albicans isolate used in the experiments, 529 L. This particular Candida isolate has been shown to be relatively inert in the VVC mouse model, and avirulent in general,8Rahman D Mistry M Thavaraj S Challacombe SJ Naglik JR Murine model of concurrent oral and vaginal Candida albicans colonization to study epithelial host-pathogen interactions.Microbes Infect. 2007; 9 (1:CAS:528:DC%2BD2sXksVyit7k%3D): 615-62210.1016/j.micinf.2007.01.012Crossref PubMed Scopus (61) Google Scholar, 9Schonherr FA et al.The intraspecies diversity of C. albicans triggers qualitatively and temporally distinct host responses that determine the balance between commensalism and pathogenicity.Mucosal Immunol. 2017; 10 (1:CAS:528:DC%2BC2sXisVGnsr0%3D): 1335-135010.1038/mi.2017.2Crossref PubMed Scopus (68) Google Scholar with little to no triggering of the vaginal neutrophil response and associated inflammatory mediators. Hence, the neutrophils present may have been triggered to migrate in the WT mice independent of C. albicans with some other reason for the reduced levels in Tcrd−/− mice. In reality, data presented in Fig. 7 may reflect this because the neutrophil levels were similar in uninfected vs infected WT mice and likely similar as well for uninfected vs infected Tcrd−/− mice, neither of which was analyzed statistically. Third, the authors suggest that reduced responses by IL-17-dependent neutrophils in the Tcrd−/− mice are responsible for observed increased fungal burden, inferring a protective role for neutrophils. Irrespective of the point noted above regarding functionally anergic neutrophils against C. albicans during VVC, the issue of a dependence on IL-17, in any regard, is inaccurate. Our laboratory has shown a lack of any role for IL-17 in the neutrophil response during VVC using genetically deficient mouse strains10Yano J et al.The acute neutrophil response mediated by S100 alarmins during vaginal Candida infections is independent of the Th17-pathway.PLoS One. 2012; 7 (1:CAS:528:DC%2BC38XhsVGhtL3L): e4631110.1371/journal.pone.0046311Crossref PubMed Scopus (76) Google Scholar and Peters and colleagues have confirmed that the IL-17 that is induced during experimental VVC is dispensable in the immunopathogenic response.11Peters BM et al.The interleukin (IL) 17r/IL-22R signaling axis is dispensable for vulvovaginal candidiasis regardless of estrogen status.J. Infect. Dis. 2020; 221 (1:CAS:528:DC%2BB3cXnsVKrtbY%3D): 1554-156310.1093/infdis/jiz649Crossref PubMed Scopus (30) Google Scholar Hence, caution should be taken in the interpretations made in the current manuscript. While we again recognize that the VVC studies in the manuscript are a small portion of an otherwise elegant study describing the developmentally regulated intrauterine γ/δ T cells, the strong inferences made regarding a putative role of γ/δ T cells in protection against VVC by IL-17-dependent neutrophils is unfortunate. These studies may have benefitted from a formal collaboration with colleagues in the field of Candida vaginitis whereby discussions regarding optimal experimental design/methods, choice of fungal strains, and consensus outcome measurements would have enhanced the potential to more adequately address the question(s) being investigated. I wish to thank Junko Yano, PhD (LSUHSC), Mairi Noverr, PhD (Tulane University School of Medicine), and Brian Peters, PhD (University of Tennessee Health Sciences Center) who contributed valuable feedback to this Letter. The author declares no competing interests." @default.
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• W3136688574 title "Caution regarding interpretations of intrauterine γ/δ T cells in protection against experimental vaginal candidiasis" @default.
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