Background
Impaired signaling in the IFN-γ/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis.
Objective
We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections.
Methods
PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-γ/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated.
Results
We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-γ–induced gene expression, but we found impaired responses to IFN-γ restimulation.
Conclusion
Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-γ–mediated inflammation.
STAT1 is a key component of Interferon (IFN)-γ and IFN-α signaling and mediates protection against mycobacteria, fungal, viral infections, and cancer. Dominant negative inhibitory as well as gain of function heterozygous STAT1 mutations demonstrate that IFN-γ driven cellular responses need to be tightly regulated to control infections. We describe an autosomal dominant mutation in the SH2 domain of STAT1 that disrupts protein phosphorylation, c.1961 T>A (M654K). The mutant allele does not permit STAT1 phosphorylation, and impairs STAT1 phosphorylation of the wild type allele. Protein dimerization is preserved but DNA binding activity, IFN-γ driven GAS-luciferase activity, and expression of IFN-γ target genes are reduced. IFN-α driven ISRE response, but not IFN-α driven GAS response, are preserved when cells are co-transfected with wild type and the mutant STAT1 constructs. M654K exerts a dominant negative effect on IFN-γ related immunity and is recessive for IFN-α induced immune function.
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Results of QFT-Plus are highly comparable to QFT-GIT. Although there is an indication that a true difference in interferon-γ release between the antigen tubes is associated with recent latent tuberculosis infection, the QFT-Plus could not be used to exclude recent exposure.
Infections in the ICU are often caused by Gram-negative bacteria. When these microorganisms are resistant to third-generation cephalosporines (due to extended-spectrum (ESBL) or AmpC beta-lactamases) or to carbapenems (for example carbapenem producing Enterobacteriales (CPE)), the treatment options become limited. In the last six years, fortunately, there have been new antibiotics approved by the U.S. Food and Drug Administration (FDA) with predominant activities against Gram-negative bacteria. We aimed to review these antibiotics: plazomicin, eravacycline, temocillin, cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, and imipenem/relebactam. Temocillin is an antibiotic that was only approved in Belgium and the UK several decades ago. We reviewed the in vitro activities of these new antibiotics, especially against ESBL and CPE microorganisms, potential side effects, and clinical studies in complicated urinary tract infections (cUTI), intra-abdominal infections (cIAI), and hospital-acquired pneumonia/ventilator-associatedpneumonia (HAP/VAP). All of these new antibiotics are active against ESBL, and almost all of them are active against CPE caused by KPC beta-lactamase, but only some of them are active against CPE due to MBL or OXA beta-lactamases. At present, all of these new antibiotics are approved by the U.S. Food and Drug Administration for cUTI (except eravacycline) and most of them for cIAI (eravacycline, ceftazidime/avibactam, ceftolozane/tazobactam, and imipenem/relebactam) and for HAP or VAP (cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, and imipenem/relebactam).
Background
In the general population, illness after infection with the SARS-CoV-2 Omicron variant is less severe compared with previous variants. Data on the disease burden of Omicron in immunocompromised patients are lacking. We investigated the clinical characteristics and outcome of a cohort of immunocompromised patients with COVID-19 caused by Omicron.
Methods
Solid organ transplant recipients, patients on anti-CD20 therapy, and allogenic hematopoietic stem cell transplantation recipients on immunosuppressive therapy infected with the Omicron variant, were included. Patients were contacted regularly until symptom resolution. Clinical characteristics of consenting patients were collected through their electronic patient files. To identify possible risk factors for hospitalization, a univariate logistic analysis was performed.
Results
A total of 114 consecutive immunocompromised patients were enrolled. Eighty-nine percent had previously received three mRNA vaccinations. While only one patient died, 23 (20%) required hospital admission for a median of 11 days. A low SARS-CoV-2 IgG antibody response (<300 BAU/mL) at diagnosis, higher age, being a lung transplant recipient, more comorbidities and a higher frailty were associated with hospital admission (all p < 0.01). At the end of follow-up, 25% had still not fully recovered. Of the 23 hospitalized patients, 70% had a negative and 92% a low IgG (<300 BAU/mL) antibody response at admission. Sotrovimab was administered to 17 of them, of which one died.
Conclusions
While the mortality in immunocompromised patients infected with Omicron was low, hospital admission was frequent and the duration of symptoms often prolonged. Besides vaccination, other interventions are needed to limit the morbidity from COVID-19 in immunocompromised patients.
We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log
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increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV—CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences—is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence.
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