The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. Bacterial co-infections are associated with unfavourable ...outcomes in respiratory viral infections; however, microbiological and antibiotic data related to COVID-19 are sparse. Adequate use of antibiotics in line with antibiotic stewardship (ABS) principles is warranted during the pandemic. We performed a retrospective study of clinical and microbiological characteristics of 140 COVID-19 patients admitted between February and April 2020 to a German University hospital, with a focus on bacterial co-infections and antimicrobial therapy. The final date of follow-up was 6 May 2020. Clinical data of 140 COVID-19 patients were recorded: The median age was 63.5 (range 17–99) years; 64% were males. According to the implemented local ABS guidelines, the most commonly used antibiotic regimen was ampicillin/sulbactam (41.5%) with a median duration of 6 (range 1–13) days. Urinary antigen tests for
Legionella pneumophila
and
Streptococcus peumoniae
were negative in all cases. In critically ill patients admitted to intensive care units (
n
= 50), co-infections with
Enterobacterales
(34.0%) and
Aspergillus fumigatus
(18.0%) were detected. Blood cultures collected at admission showed a diagnostic yield of 4.2%. Bacterial and fungal co-infections are rare in COVID-19 patients and are mainly prevalent in critically ill patients. Further studies are needed to assess the impact of antimicrobial therapy on therapeutic outcome in COVID-19 patients to prevent antimicrobial overuse. ABS guidelines could help in optimising the management of COVID-19. Investigation of microbial patterns of infectious complications in critically ill COVID-19 patients is also required.
Background Schistosomiasis, a chronic helminth infection, elicits distinct immune responses within the host, ranging from an initial TH 1 and subsequent TH 2 phase to a regulatory state, and is ...associated with dampened allergic reactions within the host. Objective We sought to evaluate whether non-transplacental helminth infection during pregnancy alters the offspring's susceptibility to allergy. Methods Ovalbumin-induced allergic airway inflammation was analyzed in offspring from Schistosoma mansoni –infected mothers mated during the TH 1, TH 2, or regulatory phase of infection. Embryos derived from in vitro fertilized oocytes of acutely infected females were transferred into uninfected foster mice to determine the role of placental environment. The fetomaternal unit was further characterized by helminth-specific immune responses and microarray analyses. Eventually, IFN-γ–deficient mice were infected to evaluate the role of this predominant cytokine on the offspring's allergy phenotype. Results We demonstrate that offspring from schistosome-infected mothers that were mated in the TH 1 and regulatory phases, but not the TH 2 immune phase, are protected against the onset of allergic airway inflammation. Interestingly, these effects were associated with distinctly altered schistosome-specific cytokine and gene expression profiles within the fetomaternal interface. Furthermore, we identified that it is not the transfer of helminth antigens but rather maternally derived IFN-γ during the acute phase of infection that is essential for the progeny's protective immune phenotype. Conclusion Overall, we present a novel immune phase–dependent coherency between the maternal immune responses during schistosomiasis and the progeny's predisposition to allergy. Therefore, we propose to include helminth-mediated transmaternal immune modulation into the expanded hygiene hypothesis.
COVID-19 has so far affected more than 250 million individuals worldwide, causing more than 5 million deaths. Several risk factors for severe disease have been identified, most of which coincide with ...advanced age. In younger individuals, severe COVID-19 often occurs in the absence of obvious comorbidities. Guided by the finding of cytomegalovirus (CMV)-specific T cells with some cross-reactivity to SARS-CoV-2 in a COVID-19 intensive care unit (ICU) patient, we decided to investigate whether CMV seropositivity is associated with severe or critical COVID-19. Herpes simplex virus (HSV) serostatus was investigated as control.
National German COVID-19 bio-sample and data banks were used to retrospectively analyze the CMV and HSV serostatus of patients who experienced mild (n = 101), moderate (n = 130) or severe to critical (n = 80) disease by IgG serology. We then investigated the relationship between disease severity and herpesvirus serostatus via statistical models.
Non-geriatric patients (< 60 years) with severe COVID-19 were found to have a very high prevalence of CMV-seropositivity, while CMV status distribution in individuals with mild disease was similar to the prevalence in the German population; interestingly, this was not detectable in older patients. Prediction models support the hypothesis that the CMV serostatus, unlike HSV, might be a strong biomarker in identifying younger individuals with a higher risk of developing severe COVID-19, in particular in absence of other co-morbidities.
We identified 'CMV-seropositivity' as a potential novel risk factor for severe COVID-19 in non-geriatric individuals in the studied cohorts. More mechanistic analyses as well as confirmation of similar findings in cohorts representing the currently most relevant SARS-CoV-2 variants should be performed shortly.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
T cells expressing anti-CD19 chimeric antigen receptors (CARs) demonstrate impressive efficacy in the treatment of systemic B cell malignancies, including B cell lymphoma. However, their effect on ...primary central nervous system lymphoma (PCNSL) is unknown. Additionally, the detailed cellular dynamics of CAR T cells during their antitumor reaction remain unclear, including their intratumoral infiltration depth, mobility, and persistence. Studying these processes in detail requires repeated intravital imaging of precisely defined tumor regions during weeks of tumor growth and regression. Here, we have combined a model of PCNSL with in vivo intracerebral 2-photon microscopy. Thereby, we were able to visualize intracranial PCNSL growth and therapeutic effects of CAR T cells longitudinally in the same animal over several weeks. Intravenous (i.v.) injection resulted in poor tumor infiltration of anti-CD19 CAR T cells and could not sufficiently control tumor growth. After intracerebral injection, however, anti-CD19 CAR T cells invaded deeply into the solid tumor, reduced tumor growth, and induced regression of PCNSL, which was associated with long-term survival. Intracerebral anti-CD19 CAR T cells entered the circulation and infiltrated distant, nondraining lymph nodes more efficiently than mock CAR T cells. After complete regression of tumors, anti-CD19 CAR T cells remained detectable intracranially and intravascularly for up to 159 d. Collectively, these results demonstrate the great potential of anti-CD19 CAR T cells for the treatment of PCNSL.
Memory differentiation of CD4 and CD8 T-cell populations has been extensively studied and many key molecular players and transcriptional networks have been identified. But how regulatory principles, ...identified on this population level, translate to immune responses that originate from single antigen-specific T cells is only now being elucidated. Here, we provide a short summary of the approaches used for mapping the fate of individual T cells and their progeny in vivo. We then highlight which major questions, with respect to memory T-cell differentiation, have been addressed by studying the development of single-cell-derived T-cell families during infection or vaccination. We discuss how fate decisions of single T cells are modulated by the affinity of their TCR and further shaped through a coregulation of T-cell differentiation and T-cell proliferation. These current findings indicate the early segregation into slowly dividing T central memory precursors (CMPs) and rapidly dividing non-CMPs, as a key event that separates the developmental paths of long- and short-lived T cells.
The majority of approved CAR T cell products are based on the FMC63-scFv directed against CD19. Surprisingly, although antigen binding affinity is a major determinant for CAR function, the affinity ...of the benchmark FMC63-scFv has not been unambiguously determined. That is, a wide range of affinities have been reported in literature, differing by more than 100-fold. Using a range of techniques, we demonstrate that suboptimal experimental designs can cause artefacts that lead to over- or underestimation of the affinity. To minimize these artefacts, we performed SPR with strictly monomeric and correctly folded soluble CD19, yielding an FMC63-scFv affinity of 2-6 nM. Together, apart from analyzing the FMC63-scFv affinity under optimized conditions, we also provide potential explanations for the wide range of published affinities. We expect that this study will be highly valuable for interpretations of CAR affinity-function relationships, as well as for the design of future CAR T cell generations.
For acute medicine physicians, distinguishing between asymptomatic bacteriuria (ABU) and clinically relevant urinary tract infections (UTI) is challenging, resulting in overtreatment of ABU and ...under-recognition of urinary-source bacteraemia without genitourinary symptoms (USB). We conducted a retrospective analysis of ED encounters in a university hospital between October 2013 and September 2018 who met the following inclusion criteria: Suspected UTI with simultaneous collection of paired urinary cultures and blood cultures (PUB) and determination of Procalcitonin (PCT). We sought to develop a simple algorithm based on clinical signs and PCT for the management of suspected UTI. Individual patient presentations were retrospectively evaluated by a clinical "triple F" algorithm (F1 ="fever", F2 ="failure", F3 ="focus") supported by PCT and PUB. We identified 183 ED patients meeting the inclusion criteria. We introduced the term UTI with systemic involvement (SUTI) with three degrees of diagnostic certainty: bacteremic UTI (24.0%; 44/183), probable SUTI (14.2%; 26/183) and possible SUTI (27.9%; 51/183). In bacteremic UTI, half of patients (54.5%; 24/44) presented without genitourinary symptoms. Discordant bacteraemia was diagnosed in 16 patients (24.6% of all bacteremic patients). An alternative focus was identified in 67 patients, five patients presented with S. aureus bacteremia. 62 patients were diagnosed with possible UTI (n = 20) or ABU (n = 42). Using the proposed "triple F" algorithm, dichotomised PCT of < 0.25 pg/ml had a negative predictive value of 88.7% and 96.2% for bacteraemia und accordant bacteraemia respectively. The application of the algorithm to our cohort could have resulted in 33.3% reduction of BCs. Using the diagnostic categories "possible" or "probable" SUTI as a trigger for initiation of antimicrobial treatment would have reduced or streamlined antimicrobial use in 30.6% and 58.5% of cases, respectively. In conclusion, the "3F" algorithm supported by PCT and PUB is a promising diagnostic and antimicrobial stewardship tool.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Control of human cytomegalovirus (HCMV) depends on CD8+ T cell responses that are shaped by an individual's repertoire of MHC molecules. MHC class I presentation is modulated by a set of HCMV-encoded ...proteins. Here we show that HCMV immunoevasins differentially impair T cell recognition of epitopes from the same viral antigen, immediate-early 1 (IE-1), that are presented by different MHC class I allotypes. In the presence of immunoevasins, HLA-A- and HLA-B-restricted T cell clones were ineffective, but HLA-C*0702-restricted T cell clones recognized and killed infected cells. Resistance of HLA-C*0702 to viral immunoevasins US2 and US11 was mediated by the alpha3 domain and C-terminal region of the HLA heavy chain. In healthy donors, HLA-C*0702-restricted T cells dominated the T cell response to IE-1. The same HLA-C allotype specifically protected infected cells from attack by NK cells that expressed a corresponding HLA-C-specific KIR. Thus, allotype-specific viral immunoevasion allows HCMV to escape control by NK cells and HLA-A- and HLA-B-restricted T cells, while the virus becomes selectively vulnerable to an immunodominant population of HLA-C-restricted T cells. Our work identifies a T cell population that may be of particular efficiency in HCMV-specific immunotherapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To what extent the lineage decisions of activated CD4+ T cells are determined by the quality of T cell receptor (TCR) ligation is incompletely understood. Here, we show that individual T cells ...expressing identical TCRs take highly variable fate decisions despite binding the same ligand. We identify a mathematical model that correctly captures this probabilistic behavior and allows one to formalize changes in TCR signal quality—due to cognate versus altered peptide ligation—as changes of lineage-specific proliferation and differentiation rates. We show that recall responses also adhere to this probabilistic framework requiring recruitment of multiple memory clones to provide reliable differentiation patterns. By extending our framework to simulate hypothetical TCRs of distinct binding strength, we reconstruct primary and secondary response patterns emerging from a polyclonal TCR repertoire in silico. Collectively, these data suggest that individual T cells harboring distinct TCRs generate overlapping primary differentiation patterns that segregate only upon repetitive immunization.
Display omitted
•Single CD4+ T cells take disparate fate decisions despite expressing identical TCRs•A probabilistic model predicts the behavior of single TN and TCM cells•Primary expansion into multiple memory cells enables reliable recall responses•Polyclonal response patterns are predicted to segregate only upon recall
The unique TCR expressed by a CD4+ T cell is thought to closely instruct its behavior in response to antigen encounter. Cho et al. question this deterministic concept by showing that single CD4+ T cells expressing identical TCRs take highly variable fate decisions when exposed to the same antigen in vivo.
Repetitive pathogen exposure leads to the dominant outgrowth of T cell clones with high T cell receptor (TCR) affinity to the relevant pathogen-associated antigens. However, low-affinity clones are ...also known to expand and form immunological memory. While these low-affinity clones contribute less immunity to the original pathogen, their role in protection against pathogens harboring immune escape mutations remains unclear. Based on identification of the TCR repertoire and functionality landscape of naive epitope-specific CD8+ T cells, we reconstructed defined repertoires that could be followed as polyclonal populations during immune responses in vivo. We found that selective clonal expansion is governed by clear TCR avidity thresholds. Simultaneously, initial recruitment of broad TCR repertoires provided a polyclonal niche from which flexible secondary responses to mutant epitopes could be recalled. Elucidating how T cell responses develop “from scratch” is informative for the development of enhanced immunotherapies and vaccines.
Display omitted
•TCR avidity distribution in naive donors is highly skewed•Clonal T cell expansion upon infection is governed by clear TCR avidity thresholds•The cross-reactivity landscape of single TCRs correlates with functional avidity•Recruitment of broad TCR repertoires enables flexible immune responses
High-avidity CD8+ T cells provide protective immunity. However, their recruitment into immune responses alongside lower avidity T cells is not well understood. Straub et al. here show that rare high-avidity clones are selectively expanded from naive precursor repertoires with heterogeneous functionalities. Such polyclonal recruitment enables flexible immune responses against heterologous re-infection.
PDF
