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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.

A recent meta-analysis found that influenza vaccination is associated with a reduced rate of SARS-CoV-2 infection in most studies, although it does not affect hospital admission or mortality. However, a subgroup analysis showed that this association was not observed in studies conducted in Spain compared to those in Italy, the United States, and Canada. The authors suggest that this difference may be due to unidentified country-specific factors. They also hypothesize that the presence of more aggressive SARS-CoV-2 strains or variants of concern (VOCs) in Italy and Spain may contribute to the differences in infection rates. Further research is needed to determine if the immune response from influenza vaccination provides protection against other viral infections. [Extracted from the article]

Mycobacterium tuberculosis (Mtb)-specific γ9δ2 T cells secrete granzyme A (GzmA) protective against intracellular Mtb growth. However, GzmA-enzymatic activity is unnecessary for pathogen inhibition, and the mechanisms of GzmA-mediated protection remain unknown. We show that GzmA homodimerization is essential for opsonization of mycobacteria, altered uptake into human monocytes, and subsequent pathogen clearance within the phagolysosome. Although monomeric and homodimeric GzmA bind mycobacteria, only homodimers also bind cluster of differentiation 14 (CD14) and Toll-like receptor 4 (TLR4). Without access to surface-expressed CD14 and TLR4, GzmA fails to inhibit intracellular Mtb. Upregulation of Rab11FIP1 was associated with inhibitory activity. Furthermore, GzmA colocalized with and was regulated by protein disulfide isomerase AI (PDIA1), which cleaves GzmA homodimers into monomers and prevents Mtb inhibitory activity. These studies identify a previously unrecognized role for homodimeric GzmA structure in opsonization, phagocytosis, and elimination of Mtb in human monocytes, and they highlight PDIA1 as a potential host-directed therapy for prevention and treatment of tuberculosis, a major human disease. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) causes COVID‐19 and has brought a huge burden in terms of human lives. Strict social distance and influenza vaccination have been recommended to avoid co‐infections between influenza viruses and SARS‐CoV‐2. Scattered reports suggested a protective effect of influenza vaccine on COVID‐19 development and severity. We analyzed 51 studies on the capacity of influenza vaccination to affect infection with SARS‐CoV‐2, hospitalization, admission to Intensive Care Units (ICU), and mortality. All subjects taken into consideration did not receive any anti‐SARS‐CoV‐2 vaccine, although their status with respect to previous infections with SARS‐CoV‐2 is not known. Comparison between vaccinated and not‐vaccinated subjects for each of the four endpoints was expressed as odds ratio (OR), with 95% confidence intervals (CIs); all analyses were performed by DerSimonian and Laird model, and Hartung‐Knapp model when studies were less than 10. In a total of 61 029 936 subjects from 33 studies, influenza vaccination reduced frequency of SARS‐CoV‐2 infection [OR plus 95% CI = 0.70 (0.65−0.77)]. The effect was significant in all studies together, in health care workers and in the general population; distance from influenza vaccination and the type of vaccine were also of importance. In 98 174 subjects from 11 studies, frequency of ICU admission was reduced with influenza vaccination [OR (95% CI) = 0.71 (0.54−0.94)]; the effect was significant in all studies together, in pregnant women and in hospitalized subjects. In contrast, in 4 737 328 subjects from 14 studies hospitalization was not modified [OR (95% CI) = 1.05 (0.82−1.35)], and in 4 139 660 subjects from 19 studies, mortality was not modified [OR (95% CI) = 0.76 (0.26−2.20)]. Our study emphasizes the importance of influenza vaccination in the protection against SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]