10 research outputs found
Interferon-driven alterations of the host’s amino acid metabolism in the pathogenesis of typhoid fever
Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host–pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever
MAPR particle filter for AUV sensor fusion
SUT Australasia Perth Branch Offic
Cooperative guidance system for auv docking with an active free-floating docking station
International audienc
Biliary cirrhosis in a child with inherited interleukin-12 deficiency
Interleukin-12 (IL-12) is a key cytokine in the defense against intracellular bacteria notably Mycobacteria and Salmonella species. We report a case of disseminated mycobacterial infection, following BCG vaccination, in a child who later developed tuberculosis. Functional tests and a novel diagnostic polymerase chain reaction (PCR) assay, revealed a loss-of-function deletion in the IL12 gene. Analysis of samples from the parents and siblings of the patient indicated an autosomal recessive inheritance pattern with varying degrees of phenotypic expression in identical genotypes. Interferon-γ (INF-γ) therapy was associated with marked clinical improvement. Biliary cirrhosis, a hitherto unreported complication of IL-12 deficiency, developed later and required liver transplantation. A defect in the IL-12-INF-γ pathway should be suspected in patients presenting with multiple, repeated or persistent infection with intracellular bacteria. The diagnostic work-up and the immuno-genetic assay described here can aid in the quick and reliable diagnosis of IL-12 deficiency resulting from genetic defects and its subsequent management
Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from 30 countries
Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infections were diagnosed in 40 cases, with combined mycobacteriosis and salmonellosis in 36 individuals. BCG disease strongly protected against subsequent EM disease (p = 0.00008). Various other infectious diseases occurred, albeit each rarely, yet candidiasis was reported in 33 of the patients (23%). Ninety-nine patients (70%) survived, with a mean age at last follow-up visit of 12.7 years ± 9.8 years (range, 0.5-46.4 yr). IL-12Rβ1 deficiency is characterized by childhood-onset mycobacteriosis and salmonellosis, rare recurrences of mycobacterial disease, and more frequent recurrence of salmonellosis. The condition has higher clinical penetrance, broader susceptibility to infections, and less favorable outcome than previously thought