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Cryptococcosis is a life-threatening opportunistic infection caused by Cryptococcus gattii and Cryptococcus neoformans. It affects both immunocompetent and immunosuppressed hosts. Disseminated cryptococcal infection is rare in immunocompetent patients, but the cryptococcal disease's neurological sequelae may be more prominent in this group. We present a case of a 58-year-old male patient with medical comorbidities of monoclonal gammopathy of undetermined significance (MGUS) and polycythemia vera. The patient presented with gradual worsening of mental status over one week. He was found to have Cryptococcus neoformans meningoencephalitis and fungemia. The patient received two weeks of liposomal amphotericin B (LAmB) and flucytosine with excellent clinical response. He was discharged on high dose fluconazole, and he returned to the hospital in one week with new-onset hemiplegia and cryptococcomas on imaging. Prolonged intravenous (IV) treatment of six weeks duration resulted in significant clinical improvement and disease-free state at two years follow-up. This article aims to stress the importance of individualized prolonged IV treatment with liposomal amphotericin B and flucytosine despite good initial response in patients with polycythemia vera and MGUS. This is the first reported case of cryptococcal disease, to the best of our knowledge, in a patient with MGUS and the third case of cryptococcal infection in patients with polycythemia vera in a non-HIV non-transplant state. Prolonged individualized IV treatment should be considered in immunocompetent patients with the above conditions, as this condition, if not adequately treated and relapses, lead to high morbidity and mortality.

Rationale: Cryptococcal infections commonly occur in immunosuppressed patients and are uncommon in immunocompetent persons. Patient concerns: A 32 year old lady, active smoker presented with right chest pain, dry cough and loss of weight. Initial chest radiograph showed a lobulated lung mass in the right lower lobe. She developed headache and right cranial nerve palsy during admission. Various investigations were done including lumbar puncture, brain and chest imaging. Diagnosis: Cryptococcal meningitis with pulmonary cryptococcoma. Interventions: She received five months of effective antifungal treatment; however, the patient did not respond well. Subsequently, removal of pulmonary cryptococcoma was done. Outcomes: Her condition improved and she no longer had any headache. Lessons: Disseminated cryptococcosis is rare in immunocompetent patient. Our case highlights the importance of high index of suspicion and we postulate that lobectomy helped in reducing the cryptococcal burden in her body, thus facilitating better response to antifungal therapy.

The introduction of antiretroviral therapy (ART) may lead to unusual paradoxical and unmasking presentations of opportunistic infections. Intra-abdominal cryptococcosis is a rare manifestation of Cryptococcus. We present the case of an HIV-infected patient on ART, with a history of cryptococcal meningitis who presented with subacute, worsening abdominal pain during immune recovery. This evolved into chronic abdominal pain, with thickened bowel, and abdominal lymphadenopathy, while receiving empiric tuberculosis treatment. At 6-months, he developed intestinal perforation due to a histologically confirmed cryptococcoma.

Phosphate acquisition by fungi is regulated by the phosphate-sensing and acquisition (PHO) signaling pathway. Cryptococcus neoformans disseminates from the lung to the brain and is the commonest cause of fungal meningitis worldwide. To investigate the contribution of PHO signaling to cryptococcal dissemination, we characterized a transcription factor knockout strain (hlh3Δ/pho4Δ) defective in phosphate acquisition. Despite little similarity with other fungal Pho4 proteins, Hlh3/Pho4 functioned like a typical phosphate-responsive transcription factor in phosphate-deprived cryptococci, accumulating in nuclei and triggering expression of genes involved in phosphate acquisition. The pho4Δ mutant strain was susceptible to a number of stresses, the effect of which, except for alkaline pH, was alleviated by phosphate supplementation. Even in the presence of phosphate, the PHO pathway was activated in wild-type cryptococci at or above physiological pH, and under these conditions, the pho4Δ mutant had a growth defect and compromised phosphate uptake. The pho4Δ mutant was hypovirulent in a mouse inhalation model, where dissemination to the brain was reduced dramatically, and markedly hypovirulent in an intravenous dissemination model. The pho4Δ mutant was not detected in blood, nor did it proliferate significantly when cultured with peripheral blood monocytes. In conclusion, dissemination of infection and the pathogenesis of meningitis are dependent on cryptococcal phosphate uptake and stress tolerance at alkaline pH, both of which are Pho4 dependent. IMPORTANCE Cryptococcal meningitis is fatal without treatment and responsible for more than 500,000 deaths annually. To be a successful pathogen, C. neoformans must obtain an adequate supply of essential nutrients, including phosphate, from various host niches. Phosphate acquisition in fungi is regulated by the PHO signaling cascade, which is activated when intracellular phosphate decreases below a critical level. Induction of phosphate acquisition genes leads to the uptake of free phosphate via transporters. By blocking the PHO pathway using a Pho4 transcription factor mutant (pho4Δ mutant), we demonstrate the importance of the pathway for cryptococcal dissemination and the establishment of brain infection in murine models. Specifically, we show that reduced dissemination of the pho4Δ mutant to the brain is due to an alkaline pH tolerance defect, as alkaline pH mimics the conditions of phosphate deprivation. The end result is inhibited proliferation in host tissues, particularly in blood. Podcast: A podcast concerning this article is available.

Mortality due to AIDS-related Cryptococcal meningitis (CM) is often >50% in low-middle income countries. Dissemination of CM can result in intracranial mass lesions known as cryptococcoma. Patients who develop cryptococcomas often have worse outcomes when compared to patients with cryptococcosis without cryptococcoma. We describe a cryptococcoma in the central nervous system (CNS) in a Ugandan patient with AIDS, and review the diagnosis and management with special focus on difficulties encountered in low or middle-income countries.

Cryptococcal meningitis is fatal without treatment and responsible for more than 500,000 deaths annually. To be a successful pathogen, C. neoformans must obtain an adequate supply of essential nutrients, including phosphate, from various host niches. Phosphate acquisition in fungi is regulated by the PHO signaling cascade, which is activated when intracellular phosphate decreases below a critical level. Induction of phosphate acquisition genes leads to the uptake of free phosphate via transporters. By blocking the PHO pathway using a Pho4 transcription factor mutant (pho4Δ mutant), we demonstrate the importance of the pathway for cryptococcal dissemination and the establishment of brain infection in murine models. Specifically, we show that reduced dissemination of the pho4Δ mutant to the brain is due to an alkaline pH tolerance defect, as alkaline pH mimics the conditions of phosphate deprivation. The end result is inhibited proliferation in host tissues, particularly in blood., Phosphate acquisition by fungi is regulated by the phosphate-sensing and acquisition (PHO) signaling pathway. Cryptococcus neoformans disseminates from the lung to the brain and is the commonest cause of fungal meningitis worldwide. To investigate the contribution of PHO signaling to cryptococcal dissemination, we characterized a transcription factor knockout strain (hlh3Δ/pho4Δ) defective in phosphate acquisition. Despite little similarity with other fungal Pho4 proteins, Hlh3/Pho4 functioned like a typical phosphate-responsive transcription factor in phosphate-deprived cryptococci, accumulating in nuclei and triggering expression of genes involved in phosphate acquisition. The pho4Δ mutant strain was susceptible to a number of stresses, the effect of which, except for alkaline pH, was alleviated by phosphate supplementation. Even in the presence of phosphate, the PHO pathway was activated in wild-type cryptococci at or above physiological pH, and under these conditions, the pho4Δ mutant had a growth defect and compromised phosphate uptake. The pho4Δ mutant was hypovirulent in a mouse inhalation model, where dissemination to the brain was reduced dramatically, and markedly hypovirulent in an intravenous dissemination model. The pho4Δ mutant was not detected in blood, nor did it proliferate significantly when cultured with peripheral blood monocytes. In conclusion, dissemination of infection and the pathogenesis of meningitis are dependent on cryptococcal phosphate uptake and stress tolerance at alkaline pH, both of which are Pho4 dependent. IMPORTANCE Cryptococcal meningitis is fatal without treatment and responsible for more than 500,000 deaths annually. To be a successful pathogen, C. neoformans must obtain an adequate supply of essential nutrients, including phosphate, from various host niches. Phosphate acquisition in fungi is regulated by the PHO signaling cascade, which is activated when intracellular phosphate decreases below a critical level. Induction of phosphate acquisition genes leads to the uptake of free phosphate via transporters. By blocking the PHO pathway using a Pho4 transcription factor mutant (pho4Δ mutant), we demonstrate the importance of the pathway for cryptococcal dissemination and the establishment of brain infection in murine models. Specifically, we show that reduced dissemination of the pho4Δ mutant to the brain is due to an alkaline pH tolerance defect, as alkaline pH mimics the conditions of phosphate deprivation. The end result is inhibited proliferation in host tissues, particularly in blood. Podcast: A podcast concerning this article is available.