The Mnn2 Mannosyltransferase Family Modulates Mannoprotein Fibril Length, Immune Recognition and Virulence of Candida albicans

The fungal cell wall is the first point of interaction between an invading fungal pathogen and the host immune system. The outer layer of the cell wall is comprised of GPI anchored proteins, which are post-translationally modified by both N- and O-linked glycans. These glycans are important pathogen associated molecular patterns (PAMPs) recognised by the innate immune system. Glycan synthesis is mediated by a series of glycosyl transferases, located in the endoplasmic reticulum and Golgi apparatus. Mnn2 is responsible for the addition of the initial α1,2-mannose residue onto the α1,6-mannose backbone, forming the N-mannan outer chain branches. In Candida albicans, the MNN2 gene family is comprised of six members (MNN2, MNN21, MNN22, MNN23, MNN24 and MNN26). Using a series of single, double, triple, quintuple and sextuple mutants, we show, for the first time, that addition of α1,2-mannose is required for stabilisation of the α1,6-mannose backbone and hence regulates mannan fibril length. Sequential deletion of members of the MNN2 gene family resulted in the synthesis of lower molecular weight, less complex and more uniform N-glycans, with the sextuple mutant displaying only un-substituted α1,6-mannose. TEM images confirmed that the sextuple mutant was completely devoid of the outer mannan fibril layer, while deletion of two MNN2 orthologues resulted in short mannan fibrils. These changes in cell wall architecture correlated with decreased proinflammatory cytokine induction from monocytes and a decrease in fungal virulence in two animal models. Therefore, α1,2-mannose of N-mannan is important for both immune recognition and virulence of C. albicans

Purinergic signalling and immune cells

This review article provides a historical perspective on the role of purinergic signalling in the regulation of various subsets of immune cells from early discoveries to current understanding. It is now recognised that adenosine 5'-triphosphate (ATP) and other nucleotides are released from cells following stress or injury. They can act on virtually all subsets of immune cells through a spectrum of P2X ligand-gated ion channels and G protein-coupled P2Y receptors. Furthermore, ATP is rapidly degraded into adenosine by ectonucleotidases such as CD39 and CD73, and adenosine exerts additional regulatory effects through its own receptors. The resulting effect ranges from stimulation to tolerance depending on the amount and time courses of nucleotides released, and the balance between ATP and adenosine. This review identifies the various receptors involved in the different subsets of immune cells and their effects on the function of these cells

Cerebral infarct in children aged zero to fifteen years Infarto cerebral em crianças de zero a quinze anos de idade

Cerebral infarcts in children present peculiar characteristics either due to their diversity of causes or due to the unknown nature of the causes. The etiologies of cerebral infarct were reviewed in children from zero to 15 years old, attended at a tertiary hospital, in Ribeirão Preto (Brazil), from 1990 to 1997, adopting the modified Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria of classification; 1 - Atherosclerosis in large arteries; 2 - Cardioembolic; 3 - Occlusion of small vessels; 4 - Other etiologies; 5 - Undetermined cause. Thirty-nine children were included, 18 males and 21 females, aged 2 months to 15 years, mean age 5.67. The largest group, N=22 (56.4%), included children with ''other etiologies'', 7 of them aged under two years. The most common etiology was dehydration and septic shock leading to brain hypoperfusion and watershed infarcts. Nine (23%) children had ''Undetermined etiology'', 7 (17,9%) cardioembolic subtype and none had atherosclerosis. Laboratory improvement is needed for the large number of patients without a defined cause, and the high proportion of children with dehydration in the group with a determined cause emphasizes the need for preventive health actions among infants and children.<br>Infartos cerebrais em crianças apresentam peculiaridades, como grande variedade de causas e alta freqüência sem etiologia definida. Foram revistos os diagnósticos etiológicos em crianças de zero a 15 anos, atendidas durante o ictus e com imagens cerebrais sugestivas de infarto, entre 1990 e 1997 em hospital terciário de Ribeirão Preto (SP). Adotou-se o critério de classificação modificado do Trial of ORG 10172 in Acute Stroke Treatment (TOAST): 1 - Arterioesclerose de grandes artérias, 2 - Cardioembólico, 3 - Oclusão de pequenos vasos, 4 - Outras etiologias, 5 - Não determinada. Trinta e nove crianças foram incluídas, 18 do sexo masculino e 21 do feminino, com idade variando entre 2 meses e 15 anos e média de 5,67. O maior grupo, com 22 crianças (56,4%), foi o de ''Outras etiologias'', 7 das quais com idades entre 2 meses e um ano. A etiologia mais freqüente foi desidratação e choque séptico, levando a hipoperfusão cerebral e infarto em zonas limítrofes. Nove (23%) com etiologia não determinada constituiram o segundo grupo, 7 (17,9%) apresentaram causas cardioembólicas e nenhum caso foi registrado com arteriosclerose. Ressalta-se a necessidade de investimento laboratorial, considerando-se a alta freqüência de casos sem diagnóstico. O alto número de crianças com infarto decorrente de desidratação requer atenção para ações preventivas em saúde infantil