Hyperinflammation contributes to lung injury and subsequent acute respiratory distress syndrome (ARDS) with high mortality in patients with severe coronavirus disease 2019 (COVID-19). To understand the underlying mechanisms involved in lung pathology, we investigated the role of the lung-specific immune response. We profiled immune cells in bronchoalveolar lavage fluid and blood collected from COVID-19 patients with severe disease and bacterial pneumonia patients not associated with viral infection. By tracking T cell clones across tissues, we identified clonally expanded tissue-resident memory-like Th17 cells (Trm17 cells) in the lungs even after viral clearance. These Trm17 cells were characterized by a a potentially pathogenic cytokine expression profile of IL17A and CSF2 (GM-CSF). Interactome analysis suggests that Trm17 cells can interact with lung macrophages and cytotoxic CD8+ T cells, which have been associated with disease severity and lung damage. High IL-17A and GM-CSF protein levels in the serum of COVID-19 patients were associated with a more severe clinical course. Collectively, our study suggests that pulmonary Trm17 cells are one potential orchestrator of the hyperinflammation in severe COVID-19.

Th17 cells are most abundant in the gut, where their presence depends on the intestinal microbiota. Here, we examined whether intestinal Th17 cells contribute to extra-intestinal Th17 responses in autoimmune kidney disease. We found high frequencies of Th17 cells in the kidneys of patients with antineutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis. We utilized photoconversion of intestinal cells in Kaede mice to track intestinal T cell mobilization upon glomerulonephritis induction, and we found that Th17 cells egress from the gut in a S1P-receptor-1-dependent fashion and subsequently migrate to the kidney via the CCL20/CCR6 axis. Depletion of intestinal Th17 cells in germ-free and antibiotic-treated mice ameliorated renal disease, whereas expansion of these cells upon Citrobacter rodentium infection exacerbated pathology. Thus, in some autoimmune settings, intestinal Th17 cells migrate into target organs, where they contribute to pathology. Targeting the intestinal Th17 cell "reservoir" may present a therapeutic strategy for these autoimmune disorders.

Although it is well established that microbial infections predispose to autoimmune diseases, the underlying mechanisms remain poorly understood. After infection, tissue-resident memory T (TRM) cells persist in peripheral organs and provide immune protection against reinfection. However, whether TRM cells participate in responses unrelated to the primary infection, such as autoimmune inflammation, is unknown. By using high-dimensional single-cell analysis, we identified CD4+ TRM cells with a TH17 signature (termed TRM17 cells) in kidneys of patients with ANCA-associated glomerulonephritis. Experimental models demonstrated that renal TRM17 cells were induced by pathogens infecting the kidney, such as Staphylococcus aureus, Candida albicans, and uropathogenic Escherichia coli, and persisted after the clearance of infections. Upon induction of experimental glomerulonephritis, these kidney TRM17 cells rapidly responded to local proinflammatory cytokines by producing IL-17A and thereby exacerbate renal pathology. Thus, our data show that pathogen-induced TRM17 cells have a previously unrecognized function in aggravating autoimmune disease.

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Background: To diagnose Pneumocystis jirovecii pneumonia (PCP), PCR testing in bronchoalveolar lavage (BAL) fluid has recently become an alternative to immunofluorescence testing (IFT); however, its diagnostic accuracy is less clear. Objective: To analyze the diagnostic value of a new semiquantitative real-time PCR (RT-PCR) in BAL in a real-life clinical setting. Methods: Retrospective analysis of all RT-PCR results [semiquantitative: negative, weakly positive, and strongly positive; measured in cycle thresholds (Ct)] in BAL in the period between 2010 and 2014. The diagnosis of PCP was defined by clinical, radiological, and laboratory signs and by treatment initiation. Any positive PCR was compared with subsequent IFT. Results: Of 128 patient samples, 32 had PCP. There is a relevant correlation of high significance between positive PCR Ct and IFT (r = -0.7781, p < 0.001), which amounts to about 60% of the variance. Sensitivity, specificity, and positive predictive values (PPV) of any positive RT-PCR were 100, 80, and 63%, respectively. No patient with negative RT-PCR had PCP. Specificity and PPV are 100% in strongly positive RT-PCR, whereas they decrease to 80 and 21% in weakly positive RT-PCR. Conclusion: A negative RT-PCR (Ct >45) rules out PCP. A strongly positive PCR (Ct <31.5) confirms PCP. In these cases, the diagnostic value of the new method is at least equal to the IFT. A weakly positive PCR probably represents pneumocystis colonization and can occur under PCP treatment.

Staphylococcus aureus is frequently detected in patients with sepsis and thus represents a major health burden worldwide. CD4+ T helper cells are involved in the immune response to S. aureus by supporting antibody production and phagocytosis. In particular, Th1 and Th17 cells secreting IFN-γ and IL-17A, are involved in the control of systemic S. aureus infections in humans and mice. To investigate the role of T cells in severe S. aureus infections, we established a mouse sepsis model in which the kidney was identified to be the organ with the highest bacterial load and abundance of Th17 cells. In this model, IL-17A but not IFN-γ was required for bacterial control. Using Il17aCre × R26YFP mice we could show that Th17 fate cells produce Th17 and Th1 cytokines, indicating a high degree of Th17 cell plasticity. Single cell RNA-sequencing of renal Th17 fate cells uncovered their heterogeneity and identified a cluster with a Th1 expression profile within the Th17 cell population, which was absent in mice with T-bet/Tbx21-deficiency in Th17 cells (Il17aCre x R26eYFP x Tbx21-flox). Blocking Th17 to Th1 transdifferentiation in Th17 fate cells in these mice resulted in increased S. aureus tissue loads. In summary, we highlight the impact of Th17 cells in controlling systemic S. aureus infections and show that T-bet expression by Th17 cells is required for bacterial clearance. While targeting the Th17 cell immune response is an important therapeutic option in autoimmunity, silencing Th17 cells might have detrimental effects in bacterial infections.

γδ T cells are involved in the control of Staphylococcus aureus infection, but their importance in protection compared to other T cells is unclear. We used a mouse model of systemic S. aureus infection associated with high bacterial load and persistence in the kidney. Infection caused fulminant accumulation of γδ T cells in the kidney. Renal γδ T cells acquired tissue residency and were maintained in high numbers during chronic infection. At day 7, up to 50% of renal γδ T cells produced IL-17A in situ and a large fraction of renal γδ T cells remained IL-17A + during chronic infection. Controlled depletion revealed that γδ T cells restricted renal S. aureus replication in the acute infection and provided protection during chronic renal infection and upon reinfection. Our results demonstrate that kidney-resident γδ T cells are nonredundant in limiting local S. aureus growth during chronic infection and provide enhanced protection against reinfection.

Background Chlamydia trachomatis (chlamydia) is a common, frequently asymptomatic, sexually transmitted infection. It can result in severe sequelae, such as ectopic pregnancy and infertility. In Germany, chlamydia is not notifiable. An opportunistic screening program for women < 25 years was introduced in 2008. The aim of this research was to triangulate different data sources to describe the epidemiological situation of chlamydia in Germany and to investigate whether the current target group of the chlamydia screening program aligns with these findings. Methods Urine specimens from participants from population-based health examination surveys of children (2014–17) and adults (2008–11) were tested for chlamydia, using nucleic acid amplification testing. These data were used to generate weighted chlamydia prevalence estimates by age group and sex. Data from a nationwide chlamydia laboratory sentinel system (2014–16) were used to calculate the positive proportion among individuals tested for chlamydia by age, sex and test reason. Results Using data from the population-based surveys, we found a chlamydia prevalence estimate of 2.8% (95% confidence interval (CI) 1.0–7.5%) among all 15- to 17-year-old girls and of 9.6% (95% CI 0.0–23) among those reporting to be sexually active. In adult women, we found the highest prevalence among 18- to 24-year-olds (all: 2.3%; 95% CI 1.0–5.3%; sexually active: 3.1%; 95% CI 1.3–7.0%). In adult men, we found the highest prevalence among 25- to 29-year-olds (all: 3.5%; 95% CI 1.6–7.7%; sexually active: 3.3%; 95% CI 1.3–7.8%). Data from the chlamydia laboratory sentinel showed the highest positive proportion among those opportunistically screened in 19-year-old women (6.1%; 95%- CI 5.9–6.4%), among those screened due to pregnancy in 15-year-old girls (10%; 95% CI 8.5–12%), and among those tested due to symptoms or a positive partner in 19-year-old women (10%; 95% CI 9.8–11%) and 19-year-old men (24%; 95% CI 22–26%). Conclusions Chlamydia seems to mainly affect adolescents and young adults in Germany, with similar overall prevalence in men and women, but with slightly different age distributions. Women at highest risk of chlamydia are covered by the current screening program but given the on-going discussions in high-income countries on cost-effectiveness and benefit-to-harm ratio of these programs, the program-aim needs reconsideration.