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Transformin Growth Factor-β
Published in Jason Kelley, Cytokines of the Lung, 2022
Most striking is the extent to which the amino acid sequence of TGF-β1, the first recognized form of TGF-β, is preserved across species. TGF-β1 molecules from human, primate, porcine, and bovine sources are completely identical in amino acid sequence. This absolute conservation of sequence across species suggests an essential selective pressure against mutational variation. Given this close homology, it seems most paradoxical that there should be multiple forms of TGF-β, termed TGF-β2, 3, 4, and 5. TGF-β2 exhibits only about 70% sequence homology to TGF-β1 (Cheifetz et al., 1987). It has an overlapping range of biological actions to TGF-β1. Like TGF-β1, the amino acid sequence of TGF-β2 is closely conserved across species and tissues. A minor heterodimeric form, TGF-β1·2, consisting of one β1 and one β2 chain, has also been described. TGF-β2 has been isolated from porcine platelets and bovine bone, as well as from human tissue sources. Although both TGF-β1 and TGF-β2 are produced in many species, they appear to be relatively tissue-specific in their distribution.
Introduction to Infection, Resistance, and Immunity
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Efficient public and personal health measures limit the spread of disease between individuals in a community and can determine the profile of pathogens that circulate in the community. Under these conditions highly pathogenic organisms that kill their hosts before they are transmitted to a new host are selected against. In contrast, less pathogenic organisms that establish chronic infections may continue to be propagated. The circulation of weakly pathogenic organisms within a host communi ty may actually induce immunity that is effective against virulent variants, and therefore suppress the appearance of these variants within the community. When public and personal health practices fail to prevent infection, disease may be controlled by chemotherapeutic agents. However, the treatment regimes that we use to control environmental pathogens also exert selective pressures on those pathogens. Antibiotic-resistant bacteria and drug-resistant parasites have been selected by decades of use of prophylactic and therapeutic agents by ourselves and the world community. This often results from the use of drugs at doses, or in dose regimes, that alleviate disease symptoms but fail to kill all of the causative organisms.
Infections in the ICU
Published in Firza Alexander Gronthoud, Practical Clinical Microbiology and Infectious Diseases, 2020
Antibiotic resistance is more common in the ICU. Critically ill patients are more likely to have frequent exposure to antibiotics, which increases risk of multidrug-resistant infections through selection pressure. Consequently, there is also a reduced gut colonization resistance and increased colonization pressure in the ICU (see Chapter 1.1, ‘Pillars of Infection Management’). Other factors associated with resistance are duration of hospitalization, use of invasive devices and immunosuppression and foreign travel. Especially with increased medical tourism, patients are more likely to harbour multidrug-resistant organisms.
Potential therapeutic targets for Mpox: the evidence to date
Published in Expert Opinion on Therapeutic Targets, 2023
Siddappa N Byrareddy, Kalicharan Sharma, Shrikesh Sachdev, Athreya S. Reddy, Arpan Acharya, Kaylee M. Klaustermeier, Christian L Lorson, Kamal Singh
The structure of F13L or its orthologs has not been solved. However, a homology-derived model of MPXV C19L using the crystal structure of Phospholipase D from Streptomyces sp. as a template (PDB entry 1V0W) [100] shows that there is only one pocket in Streptomyces sp. Phospholipase D or in the C19L homology model (generated using Modeller [101]), where Tecovirimat can be docked with a minimal conformational change in the protein. The best docked pose obtained based on the ‘Glide’ score (Schrödinger LLC, NY) is shown in Figure 5. Most of the resistance mutations are around the docked Tecovirimat. Three mutations emerged in the 2022 outbreak: V5A, S250N, and E353K (our unpublished results). The selection pressure of these mutations remains unknown. One of these mutations, S250N is in the vicinity of docked Tecovirimat (Figure 5). It is possible that S250N may impart some resistance to Tecovirimat. A prodrug of Tecovirimat, NIOCH-14 has been reported to have comparable efficacy in the animal models [102–104].
Flagellum and toxin phase variation impacts intestinal colonization and disease development in a mouse model of Clostridioides difficile infection
Published in Gut Microbes, 2022
Dominika Trzilova, Mercedes A. H. Warren, Nicole C. Gadda, Caitlin L. Williams, Rita Tamayo
Many bacterial species employ phase variation to generate phenotypic heterogeneity within a clonal population. Bacteria frequently encounter selective pressures in their environment, and phenotypic heterogeneity helps ensure survival by creating subpopulations that are differentially equipped to overcome these pressures.1 Phase variation typically affects the production of surface factors that directly interface with the bacterium’s environment, such as flagella, pili, and exopolysaccharides. Both mucosal pathogens and commensal species employ phase variation to balance the fitness advantages conferred by these structures with the costs of producing them; in a host environment, the ability to phase vary can promote immune evasion and persistence in the host.2 Phase variation can be achieved by multiple epigenetic and genetic mechanisms, including DNA modification by methylation, slipped-strand mispairing, homologous recombination, and site-specific recombination.1,3
Reverse engineering approach: a step towards a new era of vaccinology with special reference to Salmonella
Published in Expert Review of Vaccines, 2022
Shania Vij, Reena Thakur, Praveen Rishi
The benefits provided by the clinical implementation of vaccines to prevent infections caused by antibiotic-resistant bacteria are indispensable (Figure 1). Upon exposure, vaccination leads to the neutralization of the pathogen, sometimes even before the development of clinical symptoms. On the contrary, antimicrobial therapy is prescribed after the onset of clinical symptoms. Thus, vaccination could bring down the economic burden on the healthcare systems posed by diagnosis followed by treatment of antibiotic-resistant infections significantly [22]. Additionally, vaccines play a crucial role in curbing the emergence and dissemination of antimicrobial resistance by several pathways. For instance, vaccination prevents the establishment of infection by antibiotic-resistant strains because of the generation of herd immunity. In addition to reducing the possibility of selection of antibiotic-resistant strains in the clinical as well as environmental settings, vaccination also averts the establishment of sensitive strains which require antimicrobial therapy, hence taking care of the selection pressure posed by antibiotics. Moreover, vaccination can also reduce the selective pressure mediated by antibiotic therapy on commensal bacteria such as gut microbiota, which also has been suggested as the reservoir of antibiotic resistance determinants [23].