One hundred and fifty-eight porcine strains of Pasteurella multocida, recovered primarily from cases of pneumonic pasteurellosis or progressive atrophic rhinitis (PAR) in England and Wales, were characterized by determination of their capsular types, presence or absence of the toxA gene and molecular mass heterogeneity of the heat-modifiable (OmpA) and porin (OmpH) proteins. Eighteen groups (clones) of strains were identified on the basis of specific combinations of capsular type, toxA status and outer-membrane protein (OMP)-type. The data provided evidence that different subpopulations of P. multocida are responsible for pneumonia and PAR in pigs. The majority (88 %) of cases of pneumonia were associated exclusively with non-toxigenic capsular type A strains of OMP-types 1.1, 2.1, 3.1 and 5.1 and capsular type D isolates of OMP-type 6.1. These strains were recovered from widespread geographical locations within England and Wales over a 12-year period and represented mostly single sporadic cases. The association of a small number of P. multocida variants with the majority of cases of porcine pneumonia suggests that these strains are not opportunistic pathogens of low virulence but represent primary pathogens with a relatively high degree of virulence. In contrast, the majority (76 %) of cases of PAR were associated with toxAcontaining capsular type D strains of OMP-type 4.1 and capsular type A and D strains of OMP-type 6.1. Toxigenic capsular type A strains associated with PAR and non-toxigenic capsular type A strains associated with pneumonia represent distinct subpopulations of P. multocida that can be differentiated by their OMP-types. The association of capsular types A and D with strains of the same OMP-types, and the absence and presence of the toxA gene in strains of the same OMP-types, suggest that horizontal transfer of capsular biosynthesis and toxA genes has occurred between strains representing certain subpopulations of P. multocida. INTRODUCTIONPasteurella multocida is the aetiological agent of progressive atrophic rhinitis (PAR) of swine and is of considerable economic importance to the pig-rearing industry throughout the world (Chanter & Rutter, 1989). PAR is characterized by atrophy of the nasal turbinate bones which, in severe cases, can lead to facial distortion. P. multocida strains associated with PAR usually produce a 145-kDa dermonecrotic toxin, which is encoded by the toxA gene (Lax et al., 1990;Buys et al., 1990). This toxin induces osteolysis in the turbinate bones and plays an important role in the pathogenesis of PAR (Kamp & Kimman, 1988). Toxigenic strains associated with PAR are most frequently of capsular type D (Eamens et al., 1988;Foged et al., 1988;Gardner et al., 1994;Lariviere et al., 1992), although toxigenic isolates of capsular type A can also be involved in the disease (Fussing et al., 1999;Sakano et al., 1992). Non-toxigenic P. multocida strains are not usually associated with PAR and confirmation of toxin production is important for the diagnosis and control of the disea...
Mannheimia haemolytica is the etiological agent of pneumonic pasteurellosis of cattle and sheep; two different OmpA subclasses, OmpA1 and OmpA2, are associated with bovine and ovine isolates, respectively. These proteins differ at the distal ends of four external loops, are involved in adherence, and are likely to play important roles in host adaptation. M. haemolytica is surrounded by a polysaccharide capsule, and the degree of OmpA surface exposure is unknown. To investigate surface exposure and immune specificity of OmpA among bovine and ovine M. haemolytica isolates, recombinant proteins representing the transmembrane domain of OmpA from a bovine serotype A1 isolate (rOmpA1) and an ovine serotype A2 isolate (rOmpA2) were overexpressed, purified, and used to generate anti-rOmpA1 and anti-rOmpA2 antibodies, respectively. Immunogold electron microscopy and immunofluorescence techniques demonstrated that OmpA1 and OmpA2 are surface exposed, and are not masked by the polysaccharide capsule, in a selection of M. haemolytica isolates of various serotypes and grown under different growth conditions. To explore epitope specificity, anti-rOmpA1 and anti-rOmpA2 antibodies were cross-absorbed with the heterologous isolate to remove cross-reacting antibodies. These cross-absorbed antibodies were highly specific and recognized only the OmpA protein of the homologous isolate in Western blot assays. A wider examination of the binding specificities of these antibodies for M. haemolytica isolates representing different OmpA subclasses revealed that cross-absorbed anti-rOmpA1 antibodies recognized OmpA1-type proteins but not OmpA2-type proteins; conversely, cross-absorbed antirOmpA2 antibodies recognized OmpA2-type proteins but not OmpA1-type proteins. Our results demonstrate that OmpA1 and OmpA2 are surface exposed and could potentially bind to different receptors in cattle and sheep.
Trichomoniasis is the most common nonviral sexually transmitted disease in humans, but treatment options are limited. Here, we report a resorufin-based drug sensitivity assay for high-throughput microplate-based screening under hypoxic conditions. A 5203-compound enamine kinase library and several specialized compound series were tested for the inhibition of Trichomonas growth at 10 μM with Z′ values of >0.5. Hits were rescreened in serial dilution to establish an IC50 concentration. A series of 7-substituted 7-deazaadenosine analogues emerged as highly potent anti-T. vaginalis agents, with EC50 values in the low double digit nanomolar range. These analogues exhibited excellent selectivity indices. Follow-up medicinal chemistry efforts identified an optimal ribofuranose and C7 substituent. Several nucleosides rapidly cleared cultures of T. vaginalis at a concentrations of just 2 × EC50. Preliminary in vivo evaluation in a murine trichomoniasis model (Tritrichomonas foetus) revealed promising activity upon topical administration, validating purine nucleoside analogues as a new class of antitrichomonal agents.
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