\u3ci\u3eCandida albicans ISW2 Regulates\u3c/i\u3e Chlamydospore Suspensor Cell Formation and Virulence \u3ci\u3eIn Vivo\u3c/i\u3e in a Mouse Model of Disseminated Candidiasis

Formation of chlamydospores by Candida albicans was an established medical diagnostic test to confirm candidiasis before the molecular era. However, the functional role and pathological relevance of this in vitro morphological transition to pathogenesis in vivo remain unclear. We compared the physical properties of in vitro-induced chlamydospores with those of large C. albicans cells purified by density gradient centrifugation from Candida infected mouse kidneys. The morphological and physical properties of these cells in kidneys of mice infected intravenously with wild type C. albicans confirmed that chlamydospores can form in infected kidneys. A previously reported chlamydospore-null Δisw2/ Δisw2 mutant was used to investigate its role in virulence and chlamydospore induction. Virulence of the Δisw2/Δisw2 mutant strain was reduced 3.4-fold compared to wild type C. albicans or the ISW2 reconstituted strain. Altered host inflammatory reactions to the null mutant further indicate that ISW2 is a virulence factor in C. albicans. ISW2 deletion abolished chlamydospore formation within infected mouse kidneys, whereas the reconstituted strain restored chlamydospore formation in kidneys. Under chlamydospore inducing conditions in vitro, deletion of ISW2 significantly delayed chlamydospore formation, and those late induced chlamydospores lacked associated suspensor cells while attaching laterally to hyphae via novel spore-hypha septa. Our findings establish the induction of chlamydospores by C. albicans during mouse kidney colonization. Our results indicate that ISW2 is not strictly required for chlamydospores formation but is necessary for suspensor cell formation. The importance of ISW2 in chlamydospore morphogenesis and virulence may lead to additional insights into morphological differentiation and pathogenesis of C. albicans in the host microenvironment

\u3ci\u3eCandida albicans ISW2 Regulates\u3c/i\u3e Chlamydospore Suspensor Cell Formation and Virulence \u3ci\u3eIn Vivo\u3c/i\u3e in a Mouse Model of Disseminated Candidiasis

Formation of chlamydospores by Candida albicans was an established medical diagnostic test to confirm candidiasis before the molecular era. However, the functional role and pathological relevance of this in vitro morphological transition to pathogenesis in vivo remain unclear. We compared the physical properties of in vitro-induced chlamydospores with those of large C. albicans cells purified by density gradient centrifugation from Candida infected mouse kidneys. The morphological and physical properties of these cells in kidneys of mice infected intravenously with wild type C. albicans confirmed that chlamydospores can form in infected kidneys. A previously reported chlamydospore-null Δisw2/ Δisw2 mutant was used to investigate its role in virulence and chlamydospore induction. Virulence of the Δisw2/Δisw2 mutant strain was reduced 3.4-fold compared to wild type C. albicans or the ISW2 reconstituted strain. Altered host inflammatory reactions to the null mutant further indicate that ISW2 is a virulence factor in C. albicans. ISW2 deletion abolished chlamydospore formation within infected mouse kidneys, whereas the reconstituted strain restored chlamydospore formation in kidneys. Under chlamydospore inducing conditions in vitro, deletion of ISW2 significantly delayed chlamydospore formation, and those late induced chlamydospores lacked associated suspensor cells while attaching laterally to hyphae via novel spore-hypha septa. Our findings establish the induction of chlamydospores by C. albicans during mouse kidney colonization. Our results indicate that ISW2 is not strictly required for chlamydospores formation but is necessary for suspensor cell formation. The importance of ISW2 in chlamydospore morphogenesis and virulence may lead to additional insights into morphological differentiation and pathogenesis of C. albicans in the host microenvironment

Fungal CNS Infections in Africa: The Neuroimmunology of Cryptococcal Meningitis

Cryptococcal meningitis (CM) is the leading cause of central nervous system (CNS) fungal infections in humans, with the majority of cases reported from the African continent. This is partly due to the high burden of HIV infection in the region and reduced access to standard-of-care including optimal sterilising antifungal drug treatments. As such, CM is responsible for 10-15% of all HIV-related mortality, with a large proportion being preventable. Immunity to the causative agent of CM, Cryptococcus neoformans, is only partially understood. IFNγ producing CD4+ T-cells are required for the activation of myeloid cells, especially macrophages, to enable fungal killing and clearance. However, macrophages may also act as a reservoir of the fungal yeast cells, shielding them from host immune detection thus promoting latent infection or persistent chronic inflammation. In this chapter, we review the epidemiology and pathogenesis of CNS fungal infections in Africa, with a major focus on CM, and the antifungal immune pathways operating to protect against C. neoformans infection. We also highlight the areas of research and policy that require prioritisation to help reduce the burden of CNS fungal diseases in Africa

Pregnancy Outcome in Women With APECED (APS-1) : A Multicenter Study on 43 Females With 83 Pregnancies

Context: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; also known as autoimmune polyendocrine syndrome type 1) has a severe, unpredictable course. Autoimmunity and disease components may affect fertility and predispose to maternal and fetal complications, but pregnancy outcomes remain unknown. Objective: To assess fetal and maternal outcomes and course of clinical APECED manifestations during pregnancy in women with APECED. Design and Setting: A multicenter registry-based study including 5 national patient cohorts. Patients: 321 females with APECED. Main Outcome Measure: Number of pregnancies, miscarriages, and deliveries. Results: Forty-three patients had altogether 83 pregnancies at median age of 27 years (range, 17-39). Sixty (72%) pregnancies led to a delivery, including 2 stillbirths (2.4%) and 5 (6.0%) preterm livebirths. Miscarriages, induced abortions, and ectopic pregnancies were observed in 14 (17%), 8 (10%), and 1 (1.2%) pregnancies, respectively. Ovum donation resulted in 5 (6.0%) pregnancies. High maternal age, premature ovarian insufficiency, primary adrenal insufficiency, or hypoparathyroidism did not associate with miscarriages. Women with livebirth had, on average, 4 APECED manifestations (range 0-10); 78% had hypoparathyroidism, and 36% had primary adrenal insufficiency. APECED manifestations remained mostly stable during pregnancy, but in 1 case, development of primary adrenal insufficiency led to adrenal crisis and stillbirth. Birth weights were normal in >80% and apart from 1 neonatal death of a preterm baby, no serious perinatal complications occurred. Conclusions. Outcome of pregnancy in women with APECED was generally favorable. However, APECED warrants careful maternal multidisciplinary follow-up from preconceptual care until puerperium.Peer reviewe

Anti-CD45RC antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy-candidiasis- ectodermal dystrophy syndrome

Targeted monoclonal antibody (mAb) therapies show great promise for the treatment of transplant rejection and autoimmune diseases by inducing more specific immunomodulatory effects than broadly immunosuppressive drugs routinely used. We recently described the therapeutic advantage of targeting CD45RC, expressed at high levels by conventional T (Tconv) cells (CD45RC(hi)), their precursors, and terminally differentiated T (TEMRA) cells, but not by regulatory T cells (Tregs; CD45RC(lo/-)). We demonstrated efficacy of anti-CD45RC mAb treatment in transplantation, but its potential has not been examined in autoimmune diseases. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare genetic syndrome caused by loss-of-function mutations of autoimmune regulator (AIRE), a key central tolerance mediator, leading to abnormal autoreactive T cell responses and autoantibody production. Herein, we show that, in a rat model of APECED syndrome, anti-CD45RC mAb was effective for both prevention and treatment of autoimmune manifestations and inhibited autoantibody development. Anti-CD45RC mAb intervention depleted CD45RC(hi) T cells, inhibited CD45RC(hi) B cells, and restored the Treg/Tconv cell ratio and the altered Treg transcriptomic profile. In APECED patients, CD45RC was significantly increased in peripheral blood T cells, and lesioned organs from APECED patients were infiltrated by CD45RC(hi) cells. Our observations highlight the potential role for CD45RC(hi) cells in the pathogenesis of experimental and human APECED syndrome and the potential of anti-CD45RC antibody treatment.Peer reviewe

The fungal peptide toxin Candidalysin activates the NLRP3 inflammasome and causes cytolysis in mononuclear phagocytes

Clearance of invading microbes requires phagocytes of the innate immune system. However, successful pathogens have evolved sophisticated strategies to evade immune killing. The opportunistic human fungal pathogen Candida albicans is efficiently phagocytosed by macrophages, but causes inflammasome activation, host cytolysis, and escapes after hypha formation. Previous studies suggest that macrophage lysis by C. albicans results from early inflammasome-dependent cell death (pyroptosis), late damage due to glucose depletion and membrane piercing by growing hyphae. Here we show that Candidalysin, a cytolytic peptide toxin encoded by the hypha-associated gene ECE1, is both a central trigger for NLRP3 inflammasome-dependent caspase-1 activation via potassium efflux and a key driver of inflammasome-independent cytolysis of macrophages and dendritic cells upon infection with C. albicans. This suggests that Candidalysin-induced cell damage is a third mechanism of C. albicans-mediated mononuclear phagocyte cell death in addition to damage caused by pyroptosis and the growth of glucose-consuming hyphae

CARD9⁺ microglia promote antifungal immunity via IL-1β- and CXCL1-mediated neutrophil recruitment

This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Disease, National Institutes of Health, as well as NIH grants awarded to TMH (R01 093808), SGF (R01AI124566) and SRL (R01CA161373). Additional funding was provided by the Burroughs Wellcome Fund (awarded to TMH), the Wellcome Trust (102705, 097377; awarded to GDB), the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1; awarded to GDB). The authors additionally thank Celeste Huaman for care and screening of the Malt1 793 -/- mice.Peer reviewedPostprin

Emerging Infections and Pertinent Infections Related to Travel for Patients with Primary Immunodeficiencies

Erratum: J Clin Immunol. 2017 Oct;37(7):693-694. doi: 10.1007/s10875-017-0436-0.In today's global economy and affordable vacation travel, it is increasingly important that visitors to another country and their physician be familiar with emerging infections, infections unique to a specific geographic region, and risks related to the process of travel. This is never more important than for patients with primary immunodeficiency disorders (PIDD). A recent review addressing common causes of fever in travelers provides important information for the general population Thwaites and Day (N Engl J Med 376:548-560, 2017). This review covers critical infectious and management concerns specifically related to travel for patients with PIDD. This review will discuss the context of the changing landscape of infections, highlight specific infections of concern, and profile distinct infection phenotypes in patients who are immune compromised. The organization of this review will address the environment driving emerging infections and several concerns unique to patients with PIDD. The first section addresses general considerations, the second section profiles specific infections organized according to mechanism of transmission, and the third section focuses on unique phenotypes and unique susceptibilities in patients with PIDDs. This review does not address most parasitic diseases. Reference tables provide easily accessible information on a broader range of infections than is described in the text.Peer reviewe