A selection of 43 Candida albicans isolates, chosen to represent the four major strain clades of the species and also intraclade diversity, was screened for their virulence in the murine intravenous challenge model of C. albicans infection, for a range of properties measurable in vitro that might relate to virulence, and for the numbers of midrepeat sequences in genes of the ALS and HYR families. Heterozygosity at the mating type locus and low whole-cell acid phosphatase activity and growth rate at 40°C were found to be significantly positively associated with the most virulent isolates. Acid phosphatase activity and growth in 2 M NaCl were statistically significant variables between clades by univariate analysis. Isolates in different clades also differed significantly in midrepeat sequence alleles of ALS2, ALS4, ALS6, ALS7, ALS9, HYR1, and HYR2. There was no association between the midrepeat alleles of any ALS or HYR gene and the virulence of isolates to mice. Genome-wide transcript profiles of 20 isolates (5 per clade) grown under two conditions showed considerable variation between individual isolates, but only a small number of genes showed statistically significant differential gene expression between clades. Analysis of the expression profiles by overall strain virulence revealed 18 open reading frames differing significantly between isolates of high, intermediate, and low virulence. Four of these genes encoded functions related to phosphate uptake and metabolism. This finding and the significant association between whole-cell acid phosphatase activity and virulence led us to disrupt PHO100, which encodes a predicted periplasmic acid phosphatase. The pho100⌬ mutant was mildly but significantly attenuated in terms of survival curves in the mouse model. The study has extended the range of properties known to differ between C. albicans clades and suggests a possible but minor role of phosphate metabolism in the virulence of the species.
ThecellwallproteinsoffungiaremodifiedbyN-andO-linkedmannosylation and phosphomannosylation, resulting in changes to the physicalandimmunologicalpropertiesofthecell.Glycosylationofcell wall proteins involves the activities of families of endoplasmic reticulum and Golgi-located glycosyl transferases whose activities are difficult to infer through bioinformatics. The Candida albicans MNT1/ KRE2 mannosyl transferase family is represented by five members. We showed previously that Mnt1 and Mnt2 are involved in O-linked mannosylation and are required for virulence. Here, the role of C. albicans MNT3, MNT4, and MNT5 was determined by generating single and multiple MnT⌬null mutants and by functional complementation experiments in Saccharomyces cerevisiae. CaMnt3, CaMnt4, and CaMnt5 did not participate in O-linked mannosylation, but CaMnt3 and CaMnt5 had redundant activities in phosphomannosylation and were responsible for attachment of approximately half of the phosphomannan attached to N-linked mannans. CaMnt4 and CaMnt5 participated in N-mannan branching. Deletion of CaMNT3, CaMNT4, and CaMNT5 affected the growth rate and virulence of C. albicans, affected the recognition of the yeast by human monocytes and cytokine stimulation, and led to increased cell wall chitin content and exposure of -glucan at the cell wall surface. Therefore, the MNT1/KRE2 gene family participates in three types of protein mannosylation in C. albicans, and these modifications play vital roles in fungal cell wall structure and cell surface recognition by the innate immune system.The human pathogen Candida albicans is the most frequent cause of systemic candidosis, which is a common, life-threatening infection in immunocompromised patients (1). The C. albicans cell wall is a robust yet dynamic structure that protects the cell from changes in the extracellular environment. It is the immediate contact point with host cells and contains antigenic determinants, glycoproteins involved in the adhesion to host tissues, and most of the pathogen-associated molecular patterns that are recognized by host immune system (2). The wall is organized in an inner skeletal layer comprising chitin, 1,3-and 1,6-glucans, and an outer layer that is dominated by highly glycosylated proteins (3). These proteins are post-translationally modified with N-and/or O-linked mannans, both of which can be further elaborated with oligomannosides that are attached via phosphodiester linkages (phosphomannans). Mannans have important roles in cell wall integrity, adhesion to host cells and tissues, virulence, and the establishment of a response by immune cells (2, 4 -10). The O-and N-linked mannans, along with -glucans, represent the main C. albicans pathogen-associated molecular patterns recognized by the innate immune system (2, 11-13).Mannan biosynthesis has been carefully characterized in Saccharomyces cerevisiae, and the main features of the pathways involved in the construction of these oligosaccharides are conserved in C. albicans. However, N-and O-linked mannans of C. al...
BackgroundThe mouse intravenous challenge model of Candida albicans infection is widely used to determine aspects of host-fungus interaction. We investigated the production of cytokines in the kidneys and spleen of animals up to 48 h after challenge with virulent and attenuated isolates and related these responses to semi-quantitative estimations of histopathological changes in the kidney.Methodology/Principal FindingsProgression of Candida albicans infection of the kidney in response to highly virulent fungal strains was characterized by higher levels of host cellular infiltrate, higher lesion densities and greater quantities of fungal elements at 24 and 48 h, and by higher kidney concentrations of IL-1β, MCP-1, KC, IL-6, G-CSF, TNF, MIP-2 and MIP-1β, among the immune effectors measured. Levels of the chemokine KC as early as 12 h after challenge correlated significantly with all later measurements of lesion severity. Early renal IL-6 and MIP-1β concentrations also correlated with subsequent damage levels, but less significantly than for KC. All chemokines tested appeared in kidney homogenates, while most of the cytokines were undetectable in kidney and spleen homogenates. GM-CSF and IL-10 showed inverse correlations with measures of lesion severity, suggesting these alone may have exerted a defensive role. Spleen levels of KC at all times showed significant associations with kidney lesion measurements.Conclusions/SignificanceElevated chemokine levels, including KC, represent the earliest responses to C. albicans infection in the mouse kidney. Fungal strains of low mouse virulence stimulate a lower innate response and less host infiltrate than more virulent strains. These findings are consistent with immunopathological damage to kidneys in the mouse C. albicans infection model and with growing evidence implicating some TLR pathways as the main point of interaction between fungal surface polysaccharides and leukocytes.
Human T-lymphotropic virus type I (HTLV-I) is associated with adult T-cell leukemia/lymphoma and with a chronic degenerative myelopathy. However, another major type of HTLV, HTLV-H, has been isolated only sporadically, and little is known of disease associations, transmission routes, and risk factors for HTLV-II infection. Recent studies indicate that a high percentage of-certain groups of i.v. drug users and blood donors are infected with HTLV-II.Seroepidemiologic studies have found an elevated rate of seroreactivity to HTLV among Guaymi Indians from Bocas del Toro Province, Panama. To identify the cause of seroreactivity among this unique population we used HTLV-II-specific polymerase chain reaction techniques to detect HTLV genetic sequences from blood leukocytei of three seropositive Guaymi Indians. The HTLV-H primer-amplified polymerase chain reaction products from two of these, subjects were partially sequenced and matched published HTLV-H nucleotide sequences in both p24 gag (94% of 107 bases) andpol (98% of 112 bases) regions. A CD4+ T-lymphocyte line established from one of these same subjects produced HTLV-I1-speciflc proteins when tested in antigen-capture and immunoblot assays, as well as mature HTLV particles. The demonstration of HTLV-ll infection in this geographically and culturally isolated Central American Indian population without' typical risk factors of HTLV infection suggests that HTLV-H infection is endemic in this population and provides an important clue to a potential natural reservoir for this virus.
This cross-sectional study was conducted to describe the epidemiology of epilepsy in Guaymi Indians residing in Changuinola, a small town on Panama's Caribbean coast near Costa Rica. We randomly selected households and attempted to enroll all residents aged less than or equal to 1 year; 337 eligible subjects agreed to participate (93% response rate). We administered a standard neurologic disease screening examination to all subjects and, if any abnormality was found, we administered a standard neurologic evaluation. We detected 19 cases of active epilepsy; the mean age at onset was 12 years, and generalized tonic-clonic seizures were the most common diagnosis (10 of 19, 53%). The prevalence of active epilepsy among Caribbean coastal Guaymi (57/1000) is considerably greater than that in lower class Panama City populations (22/1000) or in other parts of the world. To identify risk factors for epilepsy, we collected epidemiologic data and serum (for Cysticercus antibody) from subjects with active epilepsy and from 44 age/sex-matched controls. Significantly more cases (47%) than controls (6%) had other family members with epilepsy (relative risk, RR = 14); 44% of cases and 13% of controls reported a history of febrile seizures during childhood (RR = 6).
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