More Like this

1. A hybrid stochastic-deterministic approach to explore multiple infection and evolution in HIV

   https://doi.org/10.1371/journal.pcbi.1009713  

   Kreger, Jesse ; Komarova, Natalia L. ; Wodarz, Dominik ( December 2021 , PLOS Computational Biology)

   Pascual, Mercedes (Ed.)

   To study viral evolutionary processes within patients, mathematical models have been instrumental. Yet, the need for stochastic simulations of minority mutant dynamics can pose computational challenges, especially in heterogeneous systems where very large and very small sub-populations coexist. Here, we describe a hybrid stochastic-deterministic algorithm to simulate mutant evolution in large viral populations, such as acute HIV-1 infection, and further include the multiple infection of cells. We demonstrate that the hybrid method can approximate the fully stochastic dynamics with sufficient accuracy at a fraction of the computational time, and quantify evolutionary end points that cannot be expressed by deterministic models, such as the mutant distribution or the probability of mutant existence at a given infected cell population size. We apply this method to study the role of multiple infection and intracellular interactions among different virus strains (such as complementation and interference) for mutant evolution. Multiple infection is predicted to increase the number of mutants at a given infected cell population size, due to a larger number of infection events. We further find that viral complementation can significantly enhance the spread of disadvantageous mutants, but only in select circumstances: it requires the occurrence of direct cell-to-cell transmission through virological synapses, asmore »well as a substantial fitness disadvantage of the mutant, most likely corresponding to defective virus particles. This, however, likely has strong biological consequences because defective viruses can carry genetic diversity that can be incorporated into functional virus genomes via recombination. Through this mechanism, synaptic transmission in HIV might promote virus evolvability.« less
2. Quantifying the dynamics of viral recombination during free virus and cell-to-cell transmission in HIV-1 infection

   https://doi.org/10.1093/ve/veab026  

   Kreger, Jesse ; Garcia, Josephine ; Zhang, Hongtao ; Komarova, Natalia L ; Wodarz, Dominik ; Levy, David N ( January 2021 , Virus Evolution)

   Abstract Recombination has been shown to contribute to human immunodeficiency virus-1 (HIV-1) evolution in vivo, but the underlying dynamics are extremely complex, depending on the nature of the fitness landscapes and of epistatic interactions. A less well-studied determinant of recombinant evolution is the mode of virus transmission in the cell population. HIV-1 can spread by free virus transmission, resulting largely in singly infected cells, and also by direct cell-to-cell transmission, resulting in the simultaneous infection of cells with multiple viruses. We investigate the contribution of these two transmission pathways to recombinant evolution, by applying mathematical models to in vitro experimental data on the growth of fluorescent reporter viruses under static conditions (where both transmission pathways operate), and under gentle shaking conditions, where cell-to-cell transmission is largely inhibited. The parameterized mathematical models are then used to extrapolate the viral evolutionary dynamics beyond the experimental settings. Assuming a fixed basic reproductive ratio of the virus (independent of transmission pathway), we find that recombinant evolution is fastest if virus spread is driven only by cell-to-cell transmission and slows down if both transmission pathways operate. Recombinant evolution is slowest if all virus spread occurs through free virus transmission. This is due to cell-to-cell transmissionmore »1, increasing infection multiplicity; 2, promoting the co-transmission of different virus strains from cell to cell; and 3, increasing the rate at which point mutations are generated as a result of more reverse transcription events. This study further resulted in the estimation of various parameters that characterize these evolutionary processes. For example, we estimate that during cell-to-cell transmission, an average of three viruses successfully integrated into the target cell, which can significantly raise the infection multiplicity compared to free virus transmission. In general, our study points towards the importance of infection multiplicity and cell-to-cell transmission for HIV evolution.« less
3. The C. elegans SMOC-1 protein acts cell non-autonomously to promote bone morphogenetic protein signaling

   https://doi.org/416669  

   Melisa S. DeGroot, Herong Shi ( February 2019 , Genetics)

   Bone morphogenetic protein (BMP) signaling regulates many different developmental and homeostatic processes in metazoans. The BMP pathway is conserved in Caenorhabditis elegans, and is known to regulate body size and mesoderm development. We have identified the C. elegans smoc-1 (Secreted MOdular Calcium-binding protein-1) gene as a new player in the BMP pathway. smoc-1(0) mutants have a small body size, while overexpression of smoc-1 leads to a long body size and increased expression of the RAD-SMAD (reporter acting downstream of SMAD) BMP reporter, suggesting that SMOC-1 acts as a positive modulator of BMP signaling. Using double-mutant analysis, we showed that SMOC-1 antagonizes the function of the glypican LON-2 and acts through the BMP ligand DBL-1 to regulate BMP signaling. Moreover, SMOC-1 appears to specifically regulate BMP signaling without significant involvement in a TGFβ-like pathway that regulates dauer development. We found that smoc-1 is expressed in multiple tissues, including cells of the pharynx, intestine, and posterior hypodermis, and that the expression of smoc-1 in the intestine is positively regulated by BMP signaling. We further established that SMOC-1 functions cell nonautonomously to regulate body size. Human SMOC1 and SMOC2 can each partially rescue the smoc-1(0) mutant phenotype, suggesting that SMOC-1's function in modulatingmore »BMP signaling is evolutionarily conserved. Together, our findings highlight a conserved role of SMOC proteins in modulating BMP signaling in metazoans.« less
4. TCA and SSRI Antidepressants Exert Selection Pressure for Efflux-Dependent Antibiotic Resistance Mechanisms in Escherichia coli

   https://doi.org/10.1128/mbio.02191-22  

   Ou, Jin ; Elizalde, Paul ; Guo, Hao-Bo ; Qin, Hong ; Tobe, Brian T.D. ; Choy, John S. ( December 2022 , mBio)

   Bonomo, Robert A. (Ed.)

   ABSTRACT Microbial diversity is reduced in the gut microbiota of animals and humans treated with selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs). The mechanisms driving the changes in microbial composition, while largely unknown, is critical to understand considering that the gut microbiota plays important roles in drug metabolism and brain function. Using Escherichia coli , we show that the SSRI fluoxetine and the TCA amitriptyline exert strong selection pressure for enhanced efflux activity of the AcrAB-TolC pump, a member of the resistance-nodulation-cell division (RND) superfamily of transporters. Sequencing spontaneous fluoxetine- and amitriptyline-resistant mutants revealed mutations in marR and lon, negative regulators of AcrAB-TolC expression. In line with the broad specificity of AcrAB-TolC pumps these mutants conferred resistance to several classes of antibiotics. We show that the converse also occurs, as spontaneous chloramphenicol-resistant mutants displayed cross-resistance to SSRIs and TCAs. Chemical-genomic screens identified deletions in marR and lon, confirming the results observed for the spontaneous resistant mutants. In addition, deletions in 35 genes with no known role in drug resistance were identified that conferred cross-resistance to antibiotics and several displayed enhanced efflux activities. These results indicate that combinations of specific antidepressants and antibiotics may have important effects when bothmore »are used simultaneously or successively as they can impose selection for common mechanisms of resistance. Our work suggests that selection for enhanced efflux activities is an important factor to consider in understanding the microbial diversity changes associated with antidepressant treatments. IMPORTANCE Antidepressants are prescribed broadly for psychiatric conditions to alter neuronal levels of synaptic neurotransmitters such as serotonin and norepinephrine. Two categories of antidepressants are selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs); both are among the most prescribed drugs in the United States. While it is well-established that antidepressants inhibit reuptake of neurotransmitters there is evidence that they also impact microbial diversity in the gastrointestinal tract. However, the mechanisms and therefore biological and clinical effects remain obscure. We demonstrate antidepressants may influence microbial diversity through strong selection for mutant bacteria with increased AcrAB-TolC activity, an efflux pump that removes antibiotics from cells. Furthermore, we identify a new group of genes that contribute to cross-resistance between antidepressants and antibiotics, several act by regulating efflux activity, underscoring overlapping mechanisms. Overall, this work provides new insights into bacterial responses to antidepressants important for understanding antidepressant treatment effects.« less
5. Mutant Evolution in Spatially Structured and Fragmented Expanding Populations

   https://doi.org/10.1534/genetics.120.303422  

   Wodarz, Dominik ; Komarova, Natalia L. ( July 2020 , Genetics)

   Mutant evolution in spatially structured systems is important for a range of biological systems, but aspects of it still require further elucidation. Adding to previous work, we provide a simple derivation of growth laws that characterize the number of mutants of different relative fitness in expanding populations in spatial models of different dimensionalities. These laws are universal and independent of "microscopic" modeling details. We further study the accumulation of mutants and find that with advantageous and neutral mutants, more of them are present in spatially structured, compared to well-mixed colonies of the same size. The behavior of disadvantageous mutants is subtle: if they are disadvantageous through a reduction in division rates, the result is the same, and it is the opposite if the disadvantage is due to a death rate increase. Finally, we show that in all cases, the same results are observed in fragmented, non-spatial patch models. This suggests that the patterns observed are the consequence of population fragmentation, and not spatial restrictions per se. We provide an intuitive explanation for the complex dependence of disadvantageous mutant evolution on spatial restriction, which relies on desynchronized dynamics in different locations/patches, and plays out differently depending on whether the disadvantage ismore »due to a lower division rate or a higher death rate. Implications for specific biological systems, such as the evolution of drug-resistant cell mutants in cancer or bacterial biofilms, are discussed.« less