Following emergence of the SARS-CoV-2 variant Omicron in November 2021, the dominant BA.1 sub-lineage was replaced by the BA.2 sub-lineage in Denmark. We analysed the first 2,623 BA.2 cases from 29 November 2021 to 2 January 2022. No epidemiological or clinical differences were found between individuals infected with BA.1 versus BA.2. Phylogenetic analyses showed a geographic east-to-west transmission of BA.2 from the Capital Region with clusters expanding after the Christmas holidays. Mutational analysis shows distinct differences between BA.1 and BA.2.
Combination therapy with several antibiotics is one strategy that has been applied in order to limit the spread of antimicrobial resistance. We compared the de novo evolution of resistance during combination therapy with the β-lactam ceftazidime and the fluoroquinolone ciprofloxacin with the resistance evolved after single-drug exposure. Combination therapy selected for mutants that displayed broad-spectrum resistance, and a major resistance mechanism was mutational inactivation of the repressor gene mexR that regulates the multidrug efflux operon mexAB-oprM. Deregulation of this operon led to a broad-spectrum resistance phenotype that decreased susceptibility to the combination of drugs applied during selection as well as to unrelated antibiotic classes. Mutants isolated after single-drug exposure displayed narrow-spectrum resistance and carried mutations in the MexCD-OprJ efflux pump regulator gene nfxB conferring ciprofloxacin resistance, or in the gene encoding the non-essential penicillin-binding protein DacB conferring ceftazidime resistance. Reconstruction of resistance mutations by allelic replacement and in vitro fitness assays revealed that in contrast to single antibiotic use, combination therapy consistently selected for mutants with enhanced fitness expressing broad-spectrum resistance mechanisms.
New lineages of SARS-CoV-2 are of potential concern due to higher transmissibility, risk of severe outcomes, and/or escape from neutralizing antibodies. Lineage B.1.1.7 (the Alpha variant) became dominant in early 2021, but the association between transmissibility and risk factors, such as age of primary case and viral load remains poorly understood. Here, we used comprehensive administrative data from Denmark, comprising the full population (January 11 to February 7, 2021), to estimate household transmissibility. This study included 5,241 households with primary cases; 808 were infected with lineage B.1.1.7 and 4,433 with other lineages. Here, we report an attack rate of 38% in households with a primary case infected with B.1.1.7 and 27% in households with other lineages. Primary cases infected with B.1.1.7 had an increased transmissibility of 1.5–1.7 times that of primary cases infected with other lineages. The increased transmissibility of B.1.1.7 was multiplicative across age and viral load.
Bacteria with increased mutation rates (mutators) are common in chronic infections and are associated with poorer clinical outcomes; especially in the case of Pseudomonas aeruginosa infecting cystic fibrosis (CF) patients. There is however considerable between-patient variation in both P. aeruginosa mutator frequency and the composition of co-infecting pathogen communities, and we investigated whether community context might affect selection of mutators. Using an in vitro CF model community, we show that P. aeruginosa mutators were favoured in the absence of other species but not their presence. This was because there were tradeoffs between adaptation to the biotic and abiotic environments (for example, loss of quorum sensing and associated toxin production was beneficial in the latter but not the former in our in vitro model community) limiting the evolvability advantage of an elevated mutation rate. Consistent with a role of co-infecting pathogens selecting against P. aeruginosa mutators in vivo, we show that the mutation frequency of P. aeruginosa population was negatively correlated with the frequency and diversity of co-infecting bacteria in CF infections. Our results suggest that coinfecting taxa can select against P. aeruginosa mutators, which may have potentially beneficial clinical consequences. MainInteractions with other species can be a key determinant of the rate of evolution 1-3 , as well as potentially imposing indirect selection for mechanisms that increase genetic variation, such as increased recombination rates 4,5 and, in the case of bacteria, increased mutation rates 6,7 . These findings are largely based on coevolutionary interactions between host-parasite pairs. It is unclear how being embedded in a multi-species microbial community affects selection for mutation rates in focal bacterial species. Fluctuations in the densities of community members, as well as coevolutionary changes, may result in continually changing selection pressures 1,2,8 , potentially selecting for bacteria with elevated mutation rates (mutators). Alternatively, mutators may be selected against if interspecific competitors constrain adaptation to other components of the environment, including other community members 6,9 . Furthermore, changes in population size of the focal species caused by interactions with other species could result in both selection for or against mutators 10,11 . Despite most mutations being deleterious or neutral, mutators can occur at high frequencies in natural populations of bacteria [12][13][14][15][16][17][18][19][20] . They can be found at particularly high frequencies in chronic infections [15][16][17][18][19][20] , where they are associated with treatment failure and patient morbidity [21][22][23][24][25][26][27] , especially in cystic fibrosis (CF) chronic lung infections by the opportunistic pathogen P.aeruginosa [24][25][26][27] . The success of mutators in this context is attributed to the ability of mutator alleles to generate, and hitchhike with, beneficial mutations that allow adapta...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.