Early and Rapid Identification of COVID-19 Patients with Neutralizing Type I Interferon Auto-antibodies

Journal of Clinical Immunology - Six to 19% of critically ill COVID-19 patients display circulating auto-antibodies against type I interferons (IFN-AABs). Here, we establish a clinically applicable...     

Enolase 1 of Candida albicans binds human CD4+ T cells and modulates naïve and memory responses

To obtain a better understanding of the biology behind life-threatening fungal infections caused by Candida albicans, we recently conducted an in silico screening for fungal and host protein interaction partners. We report here that the extracellular domain of human CD4 binds to the moonlighting protein enolase 1 (Eno1) of C. albicans as predicted bioinformatically. By using different anti-CD4 monoclonal antibodies, we determined that C. albicans Eno1 (CaEno1) primarily binds to the extracellular domain 3 of CD4. Functionally, we observed that CaEno1 binding to CD4 activated lymphocyte-specific protein tyrosine kinase (LCK), which was also the case for anti-CD4 monoclonal antibodies tested in parallel. CaEno1 binding to naïve human CD4⁺ T cells skewed cytokine secretion toward a Th2 profile indicative of poor fungal control. Moreover, CaEno1 inhibited human memory CD4⁺ T-cell recall responses. Therapeutically, CD4⁺ T cells transduced with a p41/Crf1-specific T-cell receptor developed for adoptive T-cell therapy were not inhibited by CaEno1 in vitro. Together, the interaction of human CD4⁺ T cells with CaEno1 modulated host CD4⁺ T-cell responses in favor of the fungus. Thus, CaEno1 mediates not only immune evasion through its interference with complement regulators but also through the direct modulation of CD4⁺ T-cell responses.     

Influence of neonatal sympathectomy on proximal renal resistance artery function in spontaneously hypertensive rats

Renal transplantation experiments have shown that the kidney contributes to chronic sympathectomy-induced arterial pressure reduction in spontaneously hypertensive rats (SHR). The underlying mechanisms are currently unclear but may include alterations in the function of small renal arteries. Neonatal SHR were sympathectomized by intraperitoneal guanethidine injections and removal of adrenal medullary tissue. Controls were sham- or hydralazine-treated. At 12 weeks of age, distal interlobar artery segments were investigated using small-vessel wire myography. Vessels from sympathectomized animals showed increased sensitivity to noradrenaline (NE). Vasopressin- and endothelin-1-induced vasoconstriction was similar in all groups (as reflected by the pD₂, i.e. –logEC₅₀, where EC₅₀ is the molar concentration of agonist eliciting a half-maximal response). Maximum vasopressin-induced tension was similar in all groups while endothelin-1-induced maximum tension was significantly higher in sympathectomized than in sham-treated SHR. The sensitivity of NE-induced vasoconstriction to extracellular Ca²⁺ did not differ between groups while sensitivity to L-type Ca²⁺ channel activation was significantly higher in both sympathectomized and hydralazine-treated animals than in sham-treated animals. Endothelium-dependent and independent vasodilation were similar in all groups. Sequential blockade of NO-synthase and cyclooxygenase had similar effects in all groups. In conclusion, neonatal sympathectomy does not induce any changes in the function of isolated proximal renal resistance arteries from SHR that could explain the blood pressure lowering effect of a kidney graft from sympathectomized SHR.     

Studies on the relevance of microtubules and of microfilament-dependent processes for triggering lymphocyte activation

The effects of Isoptin i) on isolated microtubules, ii) on the anti-immunoglobulin and the Concanavalin A induced changes in the plasma membrane topography of murine lymphocytes and iii) on murine lymphocyte activation by lipopolysaccharide and by Concanavalin A was investigated. Isoptin and lidocaine (a local anaestetic) inhibited repolymerisation of tubulin into microtubules and induced depolymerisation of microtubules. Isoptin and lidocaine inhibited competitively binding of colchicine (a classical microtubules disrupting agent) to tubulin. Isoptin induced changes in the plasma membrane topography resembling effects caused by local anaesthetics or by a combination of colchicine and cytochalasin B (an agent affecting microfilament function). Isoptin, lidocaine, colchicine and hydroxyurea when present in the culture medium during the whole incubation period inhibited DNA synthesis induced by lipopolysaccharide or Concanavalin A. RNA synthesis was completely inhibited by lidocaine but not by Isoptin or by colchicine. If Isoptin, colchicine or hydroxyurea were removed from the culture medium at 20 h of culture period, the cells immediately started to incorporate 3H-Thymidine. The inhibitory action of lidocaine was irreversible. These results show that Isoptin, a drug which depolymerizes microtubules in vitro and disturbs the mitogen induced changes in plasma membrane topography of lymphocytes (believed to be controlled by microtubules and microfilaments), does not abolish commitment of the cells for DNA synthesis.     

Location of residence and mortality for patients diagnosed with Fournier’s gangrene

IntroductionFournier’s gangrene (FG) is a necrotizing infection of the genitalia. Time from to surgical intervention is a critical determinant of prognosis. We sought to investigate whether patients from rural locations have worse clinical outcomes given distance from a tertiary center.MethodsThe Manitoba Intensive Care Unit (ICU) registry includes patients who have been admitted into ICUs across Manitoba. We identified patients admitted with FG from February 1999 to October 2019. Age, gender, Charlson comorbidity index (CCI), presence of colostomy and scrotal debridement, length of stay (LOS), and mortality outcomes were obtained. Patients were categorized as being rural or urban.ResultsFrom 1999–2019, a total of 79 patients were admitted with FG. The median age was 60 years [interquartile range [IQR] 48–67). The mortality rate during hospitalization was 16.5%. There was no statistically significant difference in the number of deaths for patients from urban vs. rural dwellings (9/47 [19.1%] vs. 4/32 [12.5%], p=0.434]. A comparison of the 66 (83.5%) patients that survived and the 13 (16.5%) that died during ICU hospitalization demonstrated no difference in age, gender, CCI, presence of colostomy, and rates of scrotal re-debridement (p>0.05). Multivariable analysis demonstrated that living in a rural area was not associated with increased mortality (odds ratio 0.64, 95% confidence interval 00.16–2.57, p=0.527).ConclusionsLocation of residence was not predictive of death from FG. In addition, baseline characteristics such as age, gender, CCI, surgical interventions, or LOS were not found to be associated with mortality.