Bulger, J., MacDonald, U., Olson, R., Beanan, J., Russo, T. A.

Hypervirulent Klebsiella pneumoniae (hvKP) is an emerging pathotype that is capable of causing tissue-invasive, organ and life threatening infections in healthy individuals from the community. Knowledge on the virulence factors specific to hvKP is limited. In this report we describe a new factor (PEG344) that increases the virulence of the hvKP strain hvKP1. peg344 is present on the hvKP1 virulence plasmid, is broadly prevalent among hvKP strains, and has increased RNA abundance when grown in human ascites. An isogenic derivative of hvKP1 (hvKP1peg344) was constructed and compared with its wild-type parent in in vitro, ex vivo, and infection model studies. Both survival and competition experiments with outbred CD1 mice demonstrated that PEG344 was required for full virulence after pulmonary challenge, but interestingly, not after subcutaneous challenge. In silico analysis suggested that PEG344 serves as an inner membrane transporter. Compared to hvKP1, a small, but significantly significant decrease in growth/survival of hvKP1peg344 was observed in human ascites, but resistance to the bactericidal activity of complement was similar. These data suggested that PEG344 may transport an unidentified growth factor present in ascites. The data presented are important since it expands our limited knowledge base on virulence factors unique to hvKP, which is needed to lay the groundwork for translational approaches to prevent or treat these devastating infections.

Sule, N., Pasupuleti, S., Kohli, N., Menon, R., Dangott, L. J., Manson, M. D., Jayaraman, A.

Enterohemorrhagic E. coli (EHEC) is a commonly occuring foodborne pathogen responsible for numerous multistate outbreaks in the US. It is known to infect the host gastrointestinal tract, specifically in locations associated with lymphoid tissue. These niches serve as sources of enteric neurotransmitters such as epinephrine and norepinephrine that are known to increase virulence in several pathogens, including enterohemorrhagic E. coli. The mechanisms that allow pathogens to target these niches are poorly understood. We previously reported that 3,4-dihydroxymandelic acid (DHMA), a metabolite of norepinephrine produced by E. coli, is a chemoattractant for the non-pathogenic E. coli RP437 strain. Here we report that DHMA is also a chemoattractant for EHEC. In addition, DHMA induces the expression of EHEC virulence genes and increases attachment to intestinal epithelial cells in vitro in a QseC-dependent manner. We also show that DHMA is present in murine gut fecal contents and that its production requires the presence of the commensal microbiota. Based on its ability to both attract and induce virulence gene expression in EHEC, we propose that DHMA acts as a "molecular beacon" to target pathogens to their preferred sites of infection in vivo.IMPORTANCE Enterohemorrhagic E. coli (EHEC) is one of several foodborne pathogens that affect millions of people every year. Such pathogens infect the gut, preferring specific sites such as the gut-associated lymphoid tissue to initiate infection. Previous evidence has shown that norepinephrine, a stress hormone and the predominant neurotransmitter in the sympathetic nervous system that innervates the gut, exacerbates these infections by enhancing the virulence of the pathogens. Our research suggests metabolism of such host molecules by the gut microbiota may promote infections, offering promise of a new target for treatment of foodborne infections.

Burgos, Joaquin; Hernández-Losa, J.; Landolfi, S.; Guelar, A.; Dinares, MªC.; Villar, J.; Navarro, J.; Ribera, E.; Falcó, V.; Curran, A.

Objective: To assess the oncogenic human papillomavirus (HPV) determination and the co-testing HPV and anal cytology value to detect high-grade anal intraepithelial neoplasia (HGAIN) in a cohort of HIV-MSM. Design and Methods: Prospective study of HIV-infected MSM who underwent screening for anal dysplasia. Screening program includes anal cytology, HPV testing, and high-resolution anoscopy (HRA) at each visit. Histological samples were obtained if suspicious lesions were revealed by HRA. Sensitivity and specificity of the different tests were calculated using histological results of HRA-guided biopsy as the reference test for HGAIN diagnosis. Results: From May 2009 to August 2016, 692 HIV-infected MSM underwent 1827 anal cytologies, 1841 HRA examinations and 1607 HPV testing. At first screening visit, anal cytology results were abnormal in 418 (60.4%) of 692 patients, and oncogenic HPV genotypes were found in 482 (79.5%) of 606 patients. Anal cytology showed a sensitivity of 89.2% (95% CI; 80.7-94.2) and a specificity of 44.2% (95% CI; 40.2-48.2) to detect HGAIN. Oncogenic HPV testing had a 90.4% sensitivity (95% CI; 82-86.8) and 24.4% specificity (95% CI; 20.8-28.3). Co-testing showed a 97.4% sensitivity (95% CI; 91-99.3) and 14% specificity (95% CI; 11.2-17.3). In patients with ASCUS on cytology, oncogenic HPV testing had 91.3% sensitivity and 28.3% specificity to detect HGAIN. Conclusions: Abnormal cytology and oncogenic HPV determination showed similar sensitivity for detecting HGAIN. The two test used together improved the sensitivity but with lowered specificity. In our opinion, HPV testing does not improve HGAIN detection and should not replace anal cytology as a standard screening test for HIV-infected MSM. Copyright (C) 2017 Wolters Kluwer Health, Inc.

Abbasi J.

This Medical News article discusses ongoing uncertainties around sepsis management.

Ewelina Gowin, Jacek Wysocki, Micha? Michalak, Danuta Januszkiewicz-Lewandowska

Gourlay, Annabelle J.; Pharris, Anastasia M.; Noori, Teymur; Supervie, Virginie; Rosinska, Magdalena; van Sighem, Ard; Touloumi, Giota; Porter, Kholoud

No abstract available…

Ole Niewoehner

In many prokaryotes, type III CRISPR-Cas systems detect and degrade invasive genetic elements by an RNA-guided, RNA-targeting multisubunit interference complex. The CRISPR-associated protein Csm6 additionally contributes to interference by functioning as a standalone ribonuclease that degrades invader RNA transcripts, but the mechanism linking invader sensing to Csm6 activity is not understood. Here we show that Csm6 proteins are activated through a second messenger generated by the type III interference complex. Upon target RNA binding by the interference complex, its Cas10 subunit converts ATP into a cyclic oligoadenylate product, which allosterically activates Csm6 by binding to its CARF domain. CARF domain mutations that abolish allosteric activation inhibit Csm6 activity in vivo, and mutations in the Cas10 Palm domain phenocopy loss of Csm6. Together, these results point to an unprecedented mechanism for regulation of CRISPR interference that bears striking conceptual similarity to oligoadenylate signalling in mammalian innate immunity.

Friedrich MJ.

Certain species of vaginal bacteria can inhibit the efficacy of the topical microbicide tenofovir, which is used to prevent HIV, by breaking it down before it is absorbed, reports an international team of investigators in Science.