Intersection of phosphate transport, oxidative stress and TOR signalling in Candida albicans virulence

Phosphate is an essential macronutrient required for cell growth and division. Pho84 is the major high-affinity cell-surface phosphate importer of Saccharomyces cerevisiae and a crucial element in the phosphate homeostatic system of this model yeast. We found that loss of Candida albicans Pho84 attenuated virulence in Drosophila and murine oropharyngeal and disseminated models of invasive infection, and conferred hypersensitivity to neutrophil killing. Susceptibility of cells lacking Pho84 to neutrophil attack depended on reactive oxygen species (ROS): pho84-/- cells were no more susceptible than wild type C. albicans to neutrophils from a patient with chronic granulomatous disease, or to those whose oxidative burst was pharmacologically inhibited or neutralized. pho84-/- mutants hyperactivated oxidative stress signalling. They accumulated intracellular ROS in the absence of extrinsic oxidative stress, in high as well as low ambient phosphate conditions. ROS accumulation correlated with diminished levels of the unique superoxide dismutase Sod3 in pho84-/- cells, while SOD3 overexpression from a conditional promoter substantially restored these cells’ oxidative stress resistance in vitro. Repression of SOD3 expression sharply increased their oxidative stress hypersensitivity. Neither of these oxidative stress management effects of manipulating SOD3 transcription was observed in PHO84 wild type cells. Sod3 levels were not the only factor driving oxidative stress effects on pho84-/- cells, though, because overexpressing SOD3 did not ameliorate these cells’ hypersensitivity to neutrophil killing ex vivo, indicating Pho84 has further roles in oxidative stress resistance and virulence. Measurement of cellular metal concentrations demonstrated that diminished Sod3 expression was not due to decreased import of its metal cofactor manganese, as predicted from the function of S. cerevisiae Pho84 as a low-affinity manganese transporter. Instead of a role of Pho84 in metal transport, we found its role in TORC1 activation to impact oxidative stress management: overexpression of the TORC1-activating GTPase Gtr1 relieved the Sod3 deficit and ROS excess in pho84-/- null mutant cells, though it did not suppress their hypersensitivity to neutrophil killing or hyphal growth defect. Pharmacologic inhibition of Pho84 by small molecules including the FDA-approved drug foscarnet also induced ROS accumulation. Inhibiting Pho84 could hence support host defenses by sensitizing C. albicans to oxidative stress

Worldwide Survey of COVID-19-Associated Arrhythmias

Background: Coronavirus disease 2019 (COVID-19) has led to over 1 million deaths worldwide and has been associated with cardiac complications including cardiac arrhythmias. The incidence and pathophysiology of these manifestations remain elusive. In this worldwide survey of patients hospitalized with COVID-19 who developed cardiac arrhythmias, we describe clinical characteristics associated with various arrhythmias, as well as global differences in modulations of routine electrophysiology practice during the pandemic. Methods: We conducted a retrospective analysis of patients hospitalized with COVID-19 infection worldwide with and without incident cardiac arrhythmias. Patients with documented atrial fibrillation, atrial flutter, supraventricular tachycardia, nonsustained or sustained ventricular tachycardia, ventricular fibrillation, atrioventricular block, or marked sinus bradycardia (heart rate<40 bpm) were classified as having arrhythmia. Deidentified data was provided by each institution and analyzed. Results: Data were collected for 4526 patients across 4 continents and 12 countries, 827 of whom had an arrhythmia. Cardiac comorbidities were common in patients with arrhythmia: 69% had hypertension, 42% diabetes, 30% had heart failure, and 24% had coronary artery disease. Most had no prior history of arrhythmia. Of those who did develop an arrhythmia, the majority (81.8%) developed atrial arrhythmias, 20.7% developed ventricular arrhythmias, and 22.6% had bradyarrhythmia. Regional differences suggested a lower incidence of atrial fibrillation in Asia compared with other continents (34% versus 63%). Most patients in North America and Europe received hydroxychloroquine, although the frequency of hydroxychloroquine therapy was constant across arrhythmia types. Forty-three percent of patients who developed arrhythmia were mechanically ventilated and 51% survived to hospital discharge. Many institutions reported drastic decreases in electrophysiology procedures performed. Conclusions: Cardiac arrhythmias are common and associated with high morbidity and mortality among patients hospitalized with COVID-19 infection. There were significant regional variations in the types of arrhythmias and treatment approaches