Genetic control of susceptibility of mice to infection with E. histolytica

Genetic susceptibility to Entamoeba histolytica infection in nine inbred strains and one outbred strain of mice was studied. The number of E. histolytica trophozoites in the ceca of the mice was examined 5 days after intracecal inoculation of axenic amoebae. C3H/HeCr, BALB/c, NZB/BIN, B10.A, DBA/2 and C57BL/6 were susceptible whereas A/J, CE, DBA/1 and CD-1 mouse strains were relatively resistant. Examination of F1 hybrid animals derived from susceptible B10.A and resistant A/J strains of mice showed that susceptibility was dominant over resistance. Segregation analysis of backcross and F2 progeny derived from the same progenitor strains is compatible with the hypothesis that susceptibility to E. histolytica infection in mice is controlled by a single, dominant gene which has been designated Enh. No association was found between the H-2 haplotype and the trait of susceptibility to amoebiasis, indicating that the major histocompatibility complex does not play a major role in regulating the early phase of the response to infection with E. histolytica.     

A nursery outbreak of group A streptococcal infection

We report an outbreak of 23 neonatal group A streptococcal infections including two cases of septicaemia in a nursery for the newborn. At the same time, 19 mothers had puerperal endometritis. The outbreak lasted for about 2 months and could not be eradicated by ordinary hygienic measures. In a colonisation study, 19 of 90 umbilical stumps studied on the day of discharge from hospital harboured group A streptococci, all of the same epidemic strain T28 provisional M-type 2841/opacity factor positive (T28/MPT2841/OF+). Chlorhexidine gluconate was therefore applied daily to the umbilical stumps. The outbreak came to an end with the introduction of this procedure. The time interval between delivery and recognition of infection was shorter in infants than in mothers. There were also only two infected mother-infant pairs. Taken together, this suggests that infected umbilical stumps on symptomless infants were a likely source of the maternal infections. Throughout 1 year from the introduction of the chlorhexidine treatment, we have not seen a case of group A streptococcal infection in neonates. Surveillance cultures from umbilical cords after the outbreak have also been negative. We conclude that bacteriological surveillance of umbilical stumps is valuable in recognising an outbreak and should be seriously considered when a group A streptococcal infection has been recorded in a nursery.     

Genetic susceptibility to neonatal infection

PURPOSE OF REVIEW: To review current data on genetic factors contributing to the striking susceptibility of neonates to infectious diseases and other adverse outcomes. RECENT FINDINGS: Although few studies address genetic determinants of neonatal infectious disease susceptibility, several variants in genes involved in the innate immune response have been associated with differential risk for neonatal infection. The most consistent results relate to polymorphisms of tumour necrosis factor-alpha, whereas other gene polymorphisms, such as those of interleukin-6, have yielded conflicting findings. Similar genetic factors may be involved in other inflammatory neonatal diseases. Recent data suggest that genetic variation may influence the pace of immunologic maturation. SUMMARY: Despite the enormous human and financial costs of infection for neonatal mortality and morbidity worldwide, it remains unclear why neonates are so susceptible. Genetic epidemiologic studies may assist in the identification of critical protective and pathogenic pathways. Despite the current relative lack of robust data, such studies are likely to facilitate the development of interventions that ultimately decrease the significant morbidity and mortality of this highly vulnerable population.     

Critical role of the group A streptococcal capsule in pharyngeal colonization and infection in mice.

To study the role of the group A streptococcal capsule in pharyngeal colonization, we used two acapsular mutants derived from a type 24 strain of group A Streptococcus by transposon mutagenesis. One mutant had a stable acapsular phenotype due to a transposon-associated chromosomal deletion of essential capsule synthetic genes, while the second mutant could revert to the encapsulated phenotype at a low frequency (< 10(-4)) upon spontaneous excision of the transposon from the capsule-synthesis region of the chromosome. Both acapsular mutants were sensitive to phagocytic killing in vitro and had reduced virulence in mice after intraperitoneal challenge. Mice inoculated intranasally with the stable acapsular mutant rapidly cleared the organisms from the pharynx, and no mice died. In contrast, throat cultures of animals challenged with the revertible mutant yielded many encapsulated revertants, and mortality was similar to that of animals challenged with the parent strain. The rapid emergence of a population of encapsulated revertants in the pharynx implies that the capsule conferred a powerful selective advantage in this environmental niche. Together with the complete avirulence of the stable acapsular mutant, these observations indicate that the hyaluronic acid capsule plays a critical role in colonization and infection of the pharynx by group A streptococci.     

Antibody response to bacteriophage hyaluronidase in acute glomerulonephritis after group A streptococcal infection

In a test of the hypothesis that lysogeny of group A streptococci by a temperate bacteriophage might confer nephritogenicity, 283 sera from 69 patients were examined for IgG and IgM antibodies to M 49 streptococcal bacteriophage hyaluronidase. The IgG and IgM response to bacteriophage hyaluronidase was greatest in M 49 streptococci-infected individuals with nephritis, but M 49 streptococci-infected subjects without nephritis also had a greater immune response than did subjects infected with serotypes other than M 49. Although antibody to bacterial hyaluronidase was detected in all Streptococcus-infected groups, antibody to M 49 streptococcal bacteriophage hyaluronidase usually was found in only M 49 streptococci-infected patients. Although the greatest IgG and IgM antibody response to bacteriophage hyaluronidase can be demonstrated in individuals with glomerulonephritis, the antibody response does not indicate a direct relation of lysogeny and nephritis because subjects with and without nephritis after M 49 streptococcal infection all had a significant rise in antibody titer.     

Genetic control of non obese diabetic mice susceptibility to high-dose streptozotocin-induced diabetes

Aims/hypothesis Streptozotocin is a monofunctional alkylating agent that induces diabetes in a large variety of mammals. While multiple low doses of streptozotocin induce immune-mediated diabetes, a single high dose of streptozotocin causes a strictly toxic diabetes. Among mouse strains, non-obese diabetic (NOD) mice are characterized by an extreme susceptibility to high dose of streptozotocin-induced diabetes whereas C3H/Or mice are particularly resistant. We hypothesized that NOD genes involved in high dose streptozotocin-induced diabetes could be also involved in the autoimmune destruction of pancreatic beta cells that characterizes this mouse strain which is a model of Type 1 diabetes.Methods We carried out a whole genome linkage scan on a population of (C3H/Or × NOD) × NOD backcross 1 mice in order to identify the genetic loci involved in NOD susceptibility to high dose of streptozotocin-induced diabetes.Results Two loci, in chromosome 9 (D9Mit135 marker, 48 cM) and in chromosome 11 (D11Mit286 marker, 52 cM), were associated with NOD susceptibility to high dose streptozotocin-induced diabetes, the latter being co-localized with the autoimmune diabetes-predisposing idd4 locus. Moreover, we report here that C57BL/6 mice deficient in Nitric Oxide Synthase 2 were as sensitive as wild-type C57BL/6 mice to high dose streptozotocin-induced diabetes.Conclusion/interpretation Although the Nitric Oxide Synthase 2 (Nos2) gene, localized at 45.6 cM in chromosome 11, is a good candidate gene, our results suggest that Nitric Oxide Synthase 2 activation might not be a crucial event for streptozotocin-induced destruction of pancreatic beta cells.Abbreviations BC backcross - HDS high dose of streptozotocin - MLDS Multiple low doses of streptozotocin - NO nitric oxide - NOD non obese diabetic - NOS nitric oxide synthase - PARP poly (ADP-ribose) polymerase - STZ streptozotocin     

Genetic control of susceptibility to osteoporosis

Osteoporosis is a common disease with a strong genetic component. Twin studies have shown that genetic factors play an important role in regulating bone mineral density (BMD), ultrasound properties of bone, skeletal geometry, and bone turnover as well as contributing to the pathogenesis of osteoporotic fracture itself. These phenotypes are determined by the combined effects of several genes and environmental influences, but occasionally, osteoporosis or unusually high bone mass can occur as the result of mutations in a single gene. Examples are the osteoporosis-pseudoglioma syndrome, caused by inactivating mutations in the lipoprotein receptor-related protein 5 gene and the high bone mass syndrome, caused by activating mutations of the same gene. Genome-wide linkage studies in man have identified loci on chromosomes 1p36, 1q21, 2p21, 5q33-35, 6p11-12, and 11q12-13 that show definite or probable linkage to BMD, but so far, the causative genes remain to be identified. Linkage studies in mice have similarly identified several loci that regulate BMD, and a future challenge will be to investigate the syntenic loci in humans. A great deal of research has been done on candidate genes; among the best studied are the vitamin D receptor and the collagen type I alpha 1 gene. Polymorphisms of vitamin D receptor have been associated with bone mass in several studies, and there is evidence to suggest that this association may be modified by dietary calcium and vitamin D intake. A functional polymorphism affecting an Sp1 binding site has been identified in the collagen type I alpha 1 gene that predicts osteoporotic fractures independently of bone mass by influencing collagen gene regulation and bone quality. An important problem with most candidate gene studies is small sample size, and this has led to conflicting results in different populations. Some researchers are exploring the use of meta-analysis to try and address this issue and gain an accurate estimate of effect size for different polymorphisms in relation to relevant clinical endpoints, such as BMD and fracture. From a clinical standpoint, advances in knowledge about the genetic basis of osteoporosis are important, because they offer the prospect of developing genetic markers for the assessment of fracture risk and the opportunity to identify molecules that will be used as targets for the design of new drugs for the prevention and treatment of bone disease.     

Prevention of group B streptococcal infection in neonates

Most publications on the subject of group B streptococcus since December 1996 have concentrated on supporting and to some degree extending our existing knowledge of the epidemiology of group B streptococcus and of intrapartum antimicrobial prophylaxis, which is the only approach available for reducing the incidence of group B streptococcal infection. Of greatest importance clinically are the reviews and studies on intrapartum antimicrobial prophylaxis, which continue to show that this is a worthwhile intervention as it significantly reduces the incidence of early onset group B streptococcal sepsis. The best approach to the detection of carriage is also covered, as is the changing epidemiology as a result of the implementation of intrapartum antimicrobial prophylaxis in some centres. Finally, the prospect of a vaccine is discussed.     

'Toxic strep syndrome'. A manifestation of group A streptococcal infection

Three patients presented with multisystem disease that shared many of the features of toxic shock syndrome. Bacteriologic and serologic evidence strongly suggested that group A beta-hemolytic Streptococcus had caused the illnesses. Group A streptococcal infection may be an underdiagnosed cause of a toxic streptococcal syndrome, a syndrome of multisystem disease apparently mediated by toxins.     

Explosive pleuritis. Manifestation of group A beta-hemolytic streptococcal infection

Two young adults had clinical and roentgenographic evidence of explosive pleuritis that was caused by group A beta-hemolytic streptococci. Persistent high fever and intense pleuritic pain following severe pharyngitis should suggest streptococcal pleural infection and prompt careful roentgenographic investigation. These cases show that group A beta-hemolytic streptococcal infection can cause explosive pleuritis in the absence of apparent bronchopneumonia.     

Prevention of group B streptococcal infection.

Group B streptococci continue to be major perinatal pathogens, both for mothers and their infants, and are associated with significant morbidity, mortality, and its attendant cost to society. Approaches to prevention are directed toward either eliminating exposure to the organism or enhancing host resistance, that is, chemoprophylaxis and immunoprophylaxis. Intrapartum chemoprophylaxis has been shown to effectively interrupt vertical transmission of group B streptococci from the genitally colonized mother to the infant and to decrease the incidence of both maternal and early-onset neonatal group B streptococcal disease. To avoid unnecessarily exposing large numbers of colonized women to antibiotics, only those with defined risk factors should be selected for intrapartum chemoprophylaxis. This regimen is ampicillin given intravenously, 2 g initially at onset of labor or rupture of membranes, followed by 1 g every 4 hours until delivery. Risk factors include premature onset of labor or rupture of membranes before 37 weeks' gestation, rupture of membranes of more than 12 hours, intrapartum fever, group B streptococcal bacteriuria, or having previously delivered an infant with group B streptococcal disease. Detection of anogenital colonization is accomplished either by culture late in the second or early in the third trimester or by intrapartum group B streptococcal antigen testing of vaginal swabs from those previously culture-negative or not cultured. Although this approach combines the advantages of several proposed strategies, it will still miss those cases of group B streptococcal disease developing in the absence of discernible risk factors. Intrapartum prophylaxis does not prevent late-onset group B streptococcal disease. Prenatal and postnatal chemoprophylaxis have not been shown to be effective. Symptomatic infants born to mothers given chemoprophylaxis should be evaluated for neonatal sepsis and treated accordingly. This approach is also suggested for asymptomatic premature infants, those whose mothers have not received adequate prophylaxis or have previously delivered infants with group B streptococcal disease, and for twin siblings of infants developing group B streptococcal disease. Successful implementation of this approach may be limited by the availability and sensitivity of the rapid antigen test used. Immunoprophylaxis, and active immunization in particular, is the most promising method of preventing perinatal group B streptococcal disease in mothers and their infants, including late-onset disease. Immunization of pregnant women with type III polysaccharide vaccine has resulted in adequate provision of functional antibody to the infants born to responders.(ABSTRACT TRUNCATED AT 400 WORDS)     

Antimicrobial susceptibility of viridans group streptococcal blood isolates to eight antimicrobial agents

A total of 155 viridans group streptococci blood culture isolates identified by the Rapid ID32 Strep system were tested for their minimum inhibitory concentrations (MICs) to penicillin, amoxicillin, ceftriaxone, erythromycin, clindamycin, rifampicin, vancomycin and teicoplanin using the E-test. The following species were identified: S. oralis (n = 67), S. mitis (n = 66), S. sanguis (n = 7), S. salivarius (n = 5), S. parasanguis (n = 4), S. gordonii (n = 3) and S. mutans (n = 3). S. oralis and S. mitis demonstrated the highest levels of resistance to the agents tested. There were 27% of S. oralis isolates resistant to pencillin, 51% resistant to erythromycin and 6% resistant to clindamycin. For S. mitis 11% were resistant to penicillin, 40% resistant to erythromycin and 3% resistant to clindamycin. Penicillin resistant isolates (MIC > or = 2 mg/l) also demonstrated decreased susceptibility to other antimicrobial agents tested in this study. High level resistance (MIC > or = 2 mg/l) to ceftriaxone was found in 12 isolates. The isolates identified as ceftriaxone resistant comprised S. oralis (n = 7), S. mitis (n = 4) and S. parasanguis (n = 1). This study has highlighted the difference in susceptibility between different species of viridans group streptococci. These findings are of concern in the light of spread of antibiotic resistance genes from S. oralis and S. mitis to the more invasive pneumococcus.     

An outbreak of group A streptococcal skin infection: control by source isolation and teicoplanin therapy

Streptococcus pyogenes is a potential cause of serious infections in plastic surgery and burns units. We report an outbreak of this organism in one such unit, which was successfully managed by closing the ward, and treating infected patients with a new antibiotic, teicoplanin.     

Perimyocarditis following streptococcal group A infection: From clinical cases to bioinformatics analysis

BackgroundStreptococcal infection is known to be associated with non-suppurative complications, including rheumatic fever. A less well recognized complication is perimyocarditis.MethodsWe report 4 cases of myocarditis in young males associated with acute streptoccal infection. Following this clinical observation we employed bioinformatic techniques to identify common epitopes between Streptococcus group A and human muscle proteins. We used Blast to search all the proteome (1697 proteins) of the Streptococcus pyogenes M1 GAS against the human proteome of 34,180 proteins.Results4 patients with streptococcal A related myocarditis were treated and made a complete recovery. One cardiac protein, ATP2A2 (NP_733765.1)), a cardiac Ca2+ ATPase, shared an epitope with Streptococcus group A and a high probability of being presented on a MHC Class II molecule.ConclusionStreptococcal myocarditis may be a commoner entity than previously appreciated. Bioinformatic techniques have identified a suspected common epitope between the streptococcal proteins and a cardiac Ca2+ ATPase.     

Enhanced susceptibility to superantigen-associated streptococcal sepsis in human leukocyte antigen-DQ transgenic mice

Bacterial superantigens are believed to cause septic shock, although, because of the lack of superantigen-sensitive infection models, proof that superantigenicity underlies shock pathogenesis is lacking. This work demonstrates a clear superantigen effect in septic shock resulting from bacterial infection. Transgenic expression of human leukocyte antigen (HLA)-DQ, but not HLA-DR, specifically augments lymphocyte responses to streptococcal pyrogenic exotoxin A (SPEA). HLA-DQ transgenic mice had increased mortality after administration of SPEA or infection with Streptococcus pyogenes. Immune activation during infection was HLA-DQ transgene-dependent and was manifested by Vbeta-specific T cell repertoire changes and widespread lymphoblastic tissue infiltration. Unlike earlier models, which used toxin-induced shock, these T cell superantigen responses and lymphoblastoid changes were observed during invasive streptococcal sepsis. Lymphoid activation was undetectable in HLA-DQ mice infected with an isogenic SPEA(-) strain, which proves that a single superantigen can play a role in sepsis pathogenesis.