Strong HLA class I--restricted T cell responses in dengue hemorrhagic fever: a double-edged sword?

Dengue is an increasingly important cause of morbidity and mortality in the tropics, but vaccine development has been impeded by a poor understanding of disease pathogenesis and, in particular, of immunologic enhancement. In a large case-control study of Vietnamese patients with dengue hemorrhagic fever (DHF), variation at the HLA-A locus was significantly associated with susceptibility to DHF (P=.02), and specific HLA-A susceptibility and resistance alleles were identified. HLA-A-specific epitopes were predicted from binding motifs, and ELISPOT analyses of patients with DHF revealed high frequencies of circulating CD8 T lymphocytes that recognized both serotype-specific and -cross-reactive dengue virus epitopes. Thus, strong CD8 T cell responses are induced by natural dengue virus infection, and HLA class I genetic variation is a risk factor for DHF. These genetic and immunologic data support both protective and pathogenic roles for dengue virus-specific CD8 T cell responses in severe disease. The potentially pathogenic role of serotype-cross-reactive CD8 T cells poses yet another obstacle to successful dengue vaccine development.

Typhoid fever and genetic polymorphisms at the natural resistance-associated macrophage protein 1.

Control of Salmonella enterica serovar Typhimurium (S. typhimurium) infection in the mouse model of typhoid fever is critically dependent on the natural resistance-associated macrophage protein 1 (Nramp1). In this study, we examined the role of genetic polymorphisms in the human homologue, NRAMP1, in resistance to typhoid fever in southern Vietnam. Patients with blood-culture-confirmed typhoid fever and healthy control subjects were genotyped for 6 polymorphic markers within and near NRAMP1 on chromosome 2q35. Four single base-pair polymorphisms (274 C/T, 469+14 G/C, 1465-85 G/A, and D543N), a (GT)(n) repeat in the promoter region of NRAMP1 and D2S1471, and a microsatellite marker approximately 130-kb downstream of NRAMP1 were examined. The allelic and genotypic frequencies for each polymorphism were compared in case patients and control subjects. No allelic association was identified between the NRAMP1 alleles and typhoid fever susceptibility. In addition, neither homozygotes nor heterozygotes for any NRAMP1 variants were at increased risk of typhoid fever.

Genes of the class II and class III major histocompatibility complex are associated with typhoid fever in Vietnam.

The influence of genes of the major histocompatibility complex (MHC) class II and class III loci on typhoid fever susceptibility was investigated. Individuals with blood culture-confirmed typhoid fever and control subjects from 2 distinct geographic locations in southern Vietnam were genotyped for HLA-DRB1 and HLA-DQB1 alleles, the gene that encodes tumor necrosis factor (TNF)-alpha (TNFA [-238] and TNFA [-308]), the gene that encodes lymphotoxin-alpha, and alleles of the TNF-alpha microsatellite. HLA-DRB1*0301/6/8, HLA-DQB1*0201-3, and TNFA*2 (-308) were associated with susceptibility to typhoid fever, whereas HLA-DRB1*04, HLA-DQB1*0401/2, and TNFA*1 (-308) were associated with disease resistance. The frequency of all possible haplotypes of the 3 individually associated loci were estimated and were found to be significantly different in typhoid case patients and control subjects (chi2=55.56, 32 df; P=.006). Haplotypes that were either protective (TNFA*1 [-308].DRB1*04) or predisposed individuals to typhoid fever (TNFA*2 [-308].DRB1*0301) were determined. This report identifies a genetic association in humans between typhoid fever and MHC class II and III genes.

Molecular typing of multiple-antibiotic-resistant Salmonella enterica serovar Typhi from Vietnam: application to acute and relapse cases of typhoid fever.

The rate of multiple-antibiotic resistance is increasing among Salmonella enterica serovar Typhi strains in Southeast Asia. Pulsed-field gel electrophoresis (PFGE) and other typing methods were used to analyze drug-resistant and -susceptible organisms isolated from patients with typhoid fever in several districts in southern Vietnam. Multiple PFGE and phage typing patterns were detected, although individual patients were infected with strains of a single type. The PFGE patterns were stable when the S. enterica serovar Typhi strains were passaged many times in vitro on laboratory medium. Paired S. enterica serovar Typhi isolates recovered from the blood and bone marrow of individual patients exhibited similar PFGE patterns. Typing of S. enterica serovar Typhi isolates from patients with relapses of typhoid indicated that the majority of relapses were caused by the same S. enterica serovar Typhi strain that was isolated during the initial infection. However, some individuals were infected with distinct and presumably newly acquired S. enterica serovar Typhi isolates.

Electrocardiographic monitoring in severe falciparum malaria.

Electrocardiographic monitoring over 24 h was performed with 53 patients with severe Plasmodium falciparum malaria (11 adults and 42 children) to assess the frequency of unrecognized cardiac arrhythmias. Nine patients (17%) died, 5 during the monitoring period and 4 afterwards. Pauses lasting 2-3 s were observed in 3 children, a single couplet in one, and a further child experienced frequent supraventricular ectopic beats which had not been detected clinically. In none of the patients who died could death be attributed to cardiac arrhythmia. Furthermore, no abnormality was detected which could have resulted from the often large doses of quinine, chloroquine or the artemisinin derivatives used for treatment. These results suggest that the heart is remarkably resilient even in the face of heavy parasite sequestration and other vital organ dysfunction, and that deaths from cardiac arrhythmias in severe malaria are rare. The need for routine cardiac monitoring of patients with severe and complicated P. falciparum malaria is questionable.