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1. Doppler imaging detects bacterial infection of living tissue

   https://doi.org/10.1038/s42003-020-01550-8  

   Choi, Honggu ; Li, Zhe ; Hua, Zhen ; Zuponcic, Jessica ; Ximenes, Eduardo ; Turek, John J. ; Ladisch, Michael R. ; Nolte, David D. ( February 2021 , Communications Biology)

   Living 3D in vitro tissue cultures, grown from immortalized cell lines, act as living sentinels as pathogenic bacteria invade the tissue. The infection is reported through changes in the intracellular dynamics of the sentinel cells caused by the disruption of normal cellular function by the infecting bacteria. Here, the Doppler imaging of infected sentinels shows the dynamic characteristics of infections. InvasiveSalmonella entericaserovar Enteritidis andListeria monocytogenespenetrate through multicellular tumor spheroids, while non-invasive strains ofEscherichia coliandListeria innocuaremain isolated outside the cells, generating different Doppler signatures. Phase distributions caused by intracellular transport display Lévy statistics, introducing a Lévy-alpha spectroscopy of bacterial invasion. Antibiotic treatment of infected spheroids, monitored through time-dependent Doppler shifts, can distinguish drug-resistant relative to non-resistant strains. This use of intracellular Doppler spectroscopy of living tissue sentinels opens a new class of microbial assay with potential importance for studying the emergence of antibiotic resistance.
2. Targeting the Interplay between Epithelial-to-Mesenchymal-Transition and the Immune System for Effective Immunotherapy

   https://doi.org/10.3390/cancers11050714  

   Soundararajan, Rama ; Fradette, Jared ; Konen, Jessica ; Moulder, Stacy ; Zhang, Xiang ; Gibbons, Don ; Varadarajan, Navin ; Wistuba, Ignacio ; Tripathy, Debasish ; Bernatchez, Chantale ; et al ( May 2019 , Cancers)

   Over the last decade, both early diagnosis and targeted therapy have improved the survival rates of many cancer patients. Most recently, immunotherapy has revolutionized the treatment options for cancers such as melanoma. Unfortunately, a significant portion of cancers (including lung and breast cancers) do not respond to immunotherapy, and many of them develop resistance to chemotherapy. Molecular characterization of non-responsive cancers suggest that an embryonic program known as epithelial-mesenchymal transition (EMT), which is mostly latent in adults, can be activated under selective pressures, rendering these cancers resistant to chemo- and immunotherapies. EMT can also drive tumor metastases, which in turn also suppress the cancer-fighting activity of cytotoxic T cells that traffic into the tumor, causing immunotherapy to fail. In this review, we compare and contrast immunotherapy treatment options of non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We discuss why, despite breakthrough progress in immunotherapy, attaining predictable outcomes in the clinic is mostly an unsolved problem for these tumors. Although these two cancer types appear different based upon their tissues of origin and molecular classification, gene expression indicate that they possess many similarities. Patient tumors exhibit activation of EMT, and resulting stem cell properties in both thesemore »cancer types associate with metastasis and resistance to existing cancer therapies. In addition, the EMT transition in both these cancers plays a crucial role in immunosuppression, which exacerbates treatment resistance. To improve cancer-related survival we need to understand and circumvent, the mechanisms through which these tumors become therapy resistant. In this review, we discuss new information and complementary perspectives to inform combination treatment strategies to expand and improve the anti-tumor responses of currently available clinical immune checkpoint inhibitors.« less
3. Comparative genomics of Acinetobacter baumannii and therapeutic bacteriophages from a patient undergoing phage therapy

   https://doi.org/10.1038/s41467-022-31455-5  

   Liu, Mei ; Hernandez-Morales, Adriana ; Clark, James ; Le, Tram ; Biswas, Biswajit ; Bishop-Lilly, Kimberly A. ; Henry, Matthew ; Quinones, Javier ; Voegtly, Logan J. ; Cer, Regina Z. ; et al ( June 2022 , Nature Communications)

   In 2016, a 68-year-old patient with a disseminated multidrug-resistantAcinetobacter baumanniiinfection was successfully treated using lytic bacteriophages. Here we report the genomes of the nine phages used for treatment and three strains ofA. baumanniiisolated prior to and during treatment. The phages used in the initial treatment are related, T4-like myophages. Analysis of 19A. baumanniiisolates collected before and during phage treatment shows that resistance to the T4-like phages appeared two days following the start of treatment. We generate complete genomic sequences for threeA. baumanniistrains (TP1, TP2 and TP3) collected before and during treatment, supporting a clonal relationship. Furthermore, we use strain TP1 to select for increased resistance to five of the phages in vitro, and identify mutations that are also found in phage-insensitive isolates TP2 and TP3 (which evolved in vivo during phage treatment). These results support that in vitro investigations can produce results that are relevant to the in vivo environment.
4. Genomic evolution of antibiotic resistance is contingent on genetic background following a long-term experiment with Escherichia coli

   https://doi.org/10.1073/pnas.2016886118  

   Card, Kyle J. ; Thomas, Misty D. ; Graves, Jr, Joseph L. ; Barrick, Jeffrey E. ; Lenski, Richard E. ( January 2021 , Proceedings of the National Academy of Sciences)

   Antibiotic resistance is a growing health concern. Efforts to control resistance would benefit from an improved ability to forecast when and how it will evolve. Epistatic interactions between mutations can promote divergent evolutionary trajectories, which complicates our ability to predict evolution. We recently showed that differences between genetic backgrounds can lead to idiosyncratic responses in the evolvability of phenotypic resistance, even among closely relatedEscherichia colistrains. In this study, we examined whether a strain's genetic background also influences the genotypic evolution of resistance. Do lineages founded by different genotypes take parallel or divergent mutational paths to achieve their evolved resistance states? We addressed this question by sequencing the complete genomes of antibiotic-resistant clones that evolved from several different genetic starting points during our earlier experiments. We first validated our statistical approach by quantifying the specificity of genomic evolution with respect to antibiotic treatment. As expected, mutations in particular genes were strongly associated with each drug. Then, we determined that replicate lines evolved from the same founding genotypes had more parallel mutations at the gene level than lines evolved from different founding genotypes, although these effects were more subtle than those showing antibiotic specificity. Taken together with our previous work, we concludemore »that historical contingency can alter both genotypic and phenotypic pathways to antibiotic resistance.

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5. Systemic veterinary drugs for control of the common bed bug, Cimex lectularius, in poultry farms

   https://doi.org/10.1186/s13071-022-05555-6  

   González-Morales, Maria A. ; Thomson, Andrea E. ; Petritz, Olivia A. ; Crespo, Rocio ; Haija, Ahmed ; Santangelo, Richard G. ; Schal, Coby ( November 2022 , Parasites & Vectors)

   The common bed bug,CimexlectulariusL., is a hematophagous ectoparasite that was a common pest in poultry farms through the 1960s. Dichlorodiphenyltrichloroethane (DDT) and organophosphates eradicated most infestations, but concurrent with their global resurgence as human ectoparasites, infestations of bed bugs have been reappearing in poultry farms. Although the impact of bed bugs on chicken health has not been quantified, frequent biting and blood-feeding are expected to cause stress, infections and even anemia in birds. Bed bug control options are limited due to the sensitive nature of the poultry environment, limited products labeled for bed bug control and resistance of bed bug populations to a broad spectrum of active ingredients. Veterinary drugs are commonly used to control endo- and ectoparasites in animals. In this study, we evaluated the effects of two common veterinary drugs on bed bugs by treating the host with systemic antiparasitic drugs.

   We conducted dose–response studies of ivermectin and fluralaner against several bed bug strains using a membrane feeding system. Also, different doses of these drugs were given to chickens and two delivery methods (topical treatment and ingestion) were used to evaluate the efficacy of ivermectin and fluralaner on bed bug mortality.

   Using an artificial feeding system, bothmore »ivermectin and fluralaner caused high mortality in insecticide-susceptible bed bugs, and fluralaner was found to be effective on pyrethroid- and fipronil-resistant bed bugs. Ivermectin was ineffective in chickens either by the topical treatment or ingestion, whereas bed bugs that fed on chickens which had ingested fluralaner suffered high mortality when feeding on these chickens for up to 28 days post treatment.

   These findings suggest that systemic ectoparasitic drugs have great potential for practical use to control bed bug infestations in poultry farms. These findings also demonstrate the efficacy of fluralaner (and potentially other isoxazolines) as a potent new active ingredient for bed bug control.

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