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

Oral care of HIV-infected patients: the knowledge and attitudes of South African dentists.

As the numbers of people with HIV infection and AIDS increase, so will the contribution required from the dental practitioners. A postal questionnaire survey was therefore conducted among dental practitioners in South Africa to determine their knowledge and attitudes towards HIV infection and the issues it raises for them. Although a majority of dentists were aware of the facts related to AIDS, and the spread and oral manifestations of HIV infection, there were considerable gaps in their knowledge with regard to the dental management of infected patients. Only 45 per cent were prepared to be engaged in the continued care of HIV-infected patients while contradicting opinions were expressed on the risk of HIV transmission in dentistry and attitudes towards HIV seropositive patients and staff. Further educational efforts on HIV infection and its implications in dentistry should be directed towards dentists in South Africa. | As the number of people with HIV infection increases, dental practitioners will be required to enhance their knowledge of the disease and its oral manifestations. In this study, a questionnaire was mailed to 1000 dentists randomly selected from the Dentists' Register of South Africa. After 2 mailings, a total of 408 responses were returned. HIV transmission in the dental clinic was rated as very likely by 30%, likely by 41%, unlikely by 12%, and extremely unlikely by 9%. Oral candidiasis, Kaposi's sarcoma, and herpes infection were correctly identified by the majority of respondents as the most common oral manifestations of AIDS. 71% of dentists felt they had acquired adequate knowledge of HIV/AIDS, primarily from journals. 95% routinely wore gloves, masks, and eye protection. 57% had a policy for the treatment of HIV-positive patients and 19% had actually treated such patients. 91% believed that all HIV-positive patients should be notified to a government body and 76% thought such patients should carry an identity card noting their HIV status. Only 45% were willing to be engaged in the continued care of AIDS patients and 83% believed a small group of dentists with specialized training should be responsible for the care of these patients. 69% reported their patients had expressed concerns about contracting AIDS through dental procedures and asked questions about sterilization practices. Finally, 63% believed that HIV seropositivity was not sufficient grounds for dismissal of dentists from practice.link_to_subscribed_fulltex

Oral cytology in cannabis smokers

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