The drive to withstand environmental stresses and defend against invasion is a universal trait extant in all forms of life. While numerous canonical signaling cascades have been characterized in detail, it remains unclear how these pathways interface to generate coordinated responses to diverse stimuli. To dissect these connections, we follow heparanase (HPSE), a protein best known for its endoglycosidic activity at the extracellular matrix but recently recognized to drive various forms of late stage disease through unknown mechanisms. Using herpes simplex virus-1 (HSV-1) infection as a model cellular perturbation, we demonstrate that HPSE acts beyond its established enzymatic role to restrict multiple forms of cell-intrinsic defense and facilitate host cell reprogramming by the invading pathogen. We reveal that cells devoid of HPSE are innately resistant to infection and counteract viral takeover through multiple amplified defense mechanisms. With a unique grasp of the fundamental processes of transcriptional regulation and cell death, HPSE represents a potent cellular intersection with broad therapeutic potential.
Alex Agelidis, Benjamin A. Turturice, Rahul K. Suryawanshi, Tejabhiram Yadavalli, Dinesh Jaishankar, Joshua Ames, James Hopkins, Lulia Koujah, Chandrashekhar D. Patil, Satvik R. Hadigal, Evan J. Kyzar, Anaamika Campeau, Jacob M. Wozniak, David J. Gonzalez, Israel Vlodavsky, Jin-ping Li, David L. Perkins, Patricia W. Finn, Deepak Shukla
BACKGROUND Identifying factors conferring responses to therapy in cancer is critical to select the best treatment for patients. For immune checkpoint inhibition (ICI) therapy, mounting evidence suggests that the gut microbiome can determine patient treatment outcomes. However, the extent to which gut microbial features are applicable across different patient cohorts has not been extensively explored.METHODS We performed a meta-analysis of 4 published shotgun metagenomic studies (Ntot = 130 patients) investigating differential microbiome composition and imputed metabolic function between responders and nonresponders to ICI.RESULTS Our analysis identified both known microbial features enriched in responders, such as Faecalibacterium as the prevailing taxa, as well as additional features, including overrepresentation of Barnesiella intestinihominis and the components of vitamin B metabolism. A classifier designed to predict responders based on these features identified responders in an independent cohort of 27 patients with the area under the receiver operating characteristic curve of 0.625 (95% CI: 0.348–0.899) and was predictive of prognosis (HR = 0.35, P = 0.081).CONCLUSION These results suggest the existence of a fecal microbiome signature inherent across responders that may be exploited for diagnostic or therapeutic purposes.FUNDING This work was funded by the Knut and Alice Wallenberg Foundation, BioGaia AB, and Cancerfonden.
Angelo Limeta, Boyang Ji, Max Levin, Francesco Gatto, Jens Nielsen
Infections caused by multi-drug resistant Staphylococcus aureus, especially MRSA, are responsible for high mortality and morbidity worldwide. Resistant lineages were previously confined to hospitals, but are now also causing infections among healthy individuals in the community. It is therefore imperative to explore therapeutic avenues that are less prone to raise drug resistance compared to today’s antibiotics. An opportunity to achieve this ambitious goal could be provided by targeted antimicrobial photodynamic therapy (aPDT), which relies on the combination of a bacteria-specific targeting agent and light-induced generation of reactive oxygen species by an appropriate photosensitizer. Here we conjugated the near-infrared photosensitizer IRDye700DX to a fully human monoclonal antibody, specific for the invariantly expressed staphylococcal antigen IsaA. The resulting immunoconjugate 1D9-700DX was characterized biochemically and in preclinical infection models. As demonstrated in vitro, in vivo, and in a human post-mortem orthopedic implant infection model, targeted aPDT with 1D9-700DX is highly effective. Importantly, combined with the non-toxic aPDT-enhancing agent potassium iodide, 1D9-700DX overcomes the antioxidant properties of human plasma and fully eradicates high titers of MRSA. We show that the developed immunoconjugate 1D9-700DX targets MRSA and kills it upon illumination with red light, without causing collateral damage to human cells.
Mafalda Bispo, Andrea Anaya-Sanchez, Sabrina Suhani, Elisa J.M. Raineri, Marina López-Álvarez, Marjolein Heuker, Wiktor Szymański, Francisco Romero Pastrana, Girbe Buist, Alexander R. Horswill, Kevin P. Francis, Gooitzen M. van Dam, Marleen van Oosten, Jan Maarten van Dijl
Severe burn injury induces gut barrier dysfunction and subsequently a profound systemic inflammatory response. In the present study, we examined the role of the small intestinal brush border enzyme, intestinal alkaline phosphatase (IAP), in preserving gut barrier function and preventing systemic inflammation after burn wound infection in mice. Mice were subjected to a 30% total body surface area dorsal burn with or without intradermal injection of Pseudomonas aeruginosa. Mice were gavaged with 2000 units of IAP or vehicle at 3 and 12 hours after the insult. We found that both endogenously produced and exogenously supplemented IAP significantly reduced gut barrier damage, decreased bacterial translocation to the systemic organs, attenuated systemic inflammation, and improved survival in this burn wound infection model. IAP attenuated liver inflammation and reduced the proinflammatory characteristics of portal serum. Furthermore, we found that intestinal luminal contents of burn wound–infected mice negatively impacted the intestinal epithelial integrity compared with luminal contents of control mice and that IAP supplementation preserved monolayer integrity. These results indicate that oral IAP therapy may represent an approach to preserving gut barrier function, blocking proinflammatory triggers from entering the portal system, preventing gut-induced systemic inflammation, and improving survival after severe burn injuries.
Fatemeh Adiliaghdam, Paul Cavallaro, Vidisha Mohad, Marianna Almpani, Florian Kühn, Mohammad Hadi Gharedaghi, Mehran Najibi, Laurence G. Rahme, Richard A. Hodin
ABSTRACTWith the effectiveness of antimicrobials declining as antimicrobial resistance continues to threaten public health, we must look to alternative strategies for the treatment of infections. In this study, we investigated an innovative ‘drug-free’ dual-wavelength irradiation approach that combines two wavelengths of light, 460 nm and 405 nm, against methicillin resistant Staphylococcus aureus (MRSA). MRSA was initially irradiated with 460 nm light (90-360 J/cm2) and subsequently irradiated with aliquots of 405 nm light (54-324 J/cm2). For in vivo studies, mouse skin was abraded and infected with approximately 107 CFU of MRSA and incubated for 3 hours before irradiating with 460 nm (360 J/cm2) and 405 nm (342 J/cm2). Naïve mouse skin was also irradiated to investigate apoptosis. We found that staphyloxanthin, the carotenoid pigment in MRSA cells, promoted resistance to the antimicrobial effects of 405 nm light. In addition, we found that the photolytic effect of 460 nm light on staphyloxanthin attenuated resistance of MRSA to 405 nm light inactivation. Irradiation of 460 nm alone did not elicit any antimicrobial effect on MRSA. In a proof-of-principle mouse skin abrasion infection model, we observed significant inactivation of MRSA by the dual-wavelength irradiation approach. However, when either wavelength of light was administered alone, no significant decrease in bacterial viability was observed. Moreover, exposure of the dual-wavelength irradiation to naïve mouse skin did not result in any visible apoptosis.In conclusion, dual-wavelength irradiation strategy may offer an innovative, effective and safe approach for the treatment of skin infections caused by MRSA.
Leon G. Leanse, Xueping Sharon Goh, Ji-Xin Cheng, David Hooper, Tianhong Dai
Inflammation is a major risk factor of morbidity and mortality in older adults. Although its precise etiology is unknown, low-grade inflammation in older adults is commonly associated with increased intestinal epithelial permeability (leaky gut) and abnormal (dysbiotic) gut microbiota. The increasing older population and lack of treatments to reduce aging-related microbiota dysbiosis, leaky gut and inflammation culminates on a rise in aging-related comorbidities, constituting a significant public health concern. Here we demonstrate that a human-origin probiotic cocktail containing 5-Lactobacillus and 5 Enterococcus strains isolated from healthy infant’s gut prevents high-fat diet (HFD)-induced microbiota dysbiosis, leaky gut, inflammation, metabolic dysfunctions and physical function decline in older mice. Probiotic-modulated gut microbiota primarily reduced leaky gut by increasing tight junctions, which in turn reduced inflammation. Mechanistically, probiotics modulated microbiota in a way to increases bile salt hydrolase activity, which in turn increased taurine abundance in the gut that stimulated tight junctions and suppressed gut leakiness. Further, in Caenorhabditis elegans, taurine increased life span, reduced adiposity and leaky gut, and enhanced physical function. The results suggest that such probiotic therapies could prevent or treat aging-related leaky gut and inflammation in elderly.
Shokouh Ahmadi, Shaohua Wang, Ravinder Nagpal, Bo Wang, Shalini Jain, Atefeh Razazan, Sidharth P. Mishra, Xuewei Zhu, Zhan Wang, Kylie Kavanagh, Hariom Yadav
Relatively little is known about interactions between the airway microbiome and airway host transcriptome in asthma. Since asthma affects and is affected by the entire airway, studying the upper (e.g., nasal) and lower (e.g., bronchial) airways together represents a powerful approach to understanding asthma. Here, we performed a systematic, integrative study of the nasal and bronchial microbiomes and nasal and bronchial host transcriptomes of children with severe persistent asthma and healthy controls. We found that (a) the microbiomes and host transcriptomes of asthmatic children are each distinct by site (nasal versus bronchial); (b) among asthmatic children, Moraxella and Alloiococcus are hub genera in the nasal microbiome, while there are no hubs among bronchial genera; (c) bronchial Actinomyces is negatively associated with bronchial genes for inflammation, suggesting Actinomyces may be protective; (d) compared with healthy children, asthmatic children express more nasal genes for ciliary function and harbor more nasal Streptococcus; and (e) nasal genera such as Corynebacterium are negatively associated with significantly more nasal genes for inflammation in healthy versus asthmatic children, suggesting a potentially stronger protective role for such nasal genera in healthy versus asthmatic children. Our systematic, integrative study provides a window into host-microbiome associations in asthma.
Yoojin Chun, Anh Do, Galina Grishina, Alexander Grishin, Gang Fang, Samantha Rose, Chantal Spencer, Alfin Vicencio, Eric Schadt, Supinda Bunyavanich
Despite an unprecedented 2 decades of success, the combat against malaria — the mosquito-transmitted disease caused by Plasmodium parasites — is no longer progressing. Efforts toward eradication are threatened by the lack of an effective vaccine and a rise in antiparasite drug resistance. Alternative approaches are urgently needed. Repurposing of available, approved drugs with distinct modes of action are being considered as viable and immediate adjuncts to standard antimicrobial treatment. Such strategies may be well suited to the obligatory and clinically silent first phase of Plasmodium infection, where massive parasite replication occurs within hepatocytes in the liver. Here, we report that the widely used antidiabetic drug, metformin, impairs parasite liver stage development of both rodent-infecting Plasmodium berghei and human-infecting P. falciparum parasites. Prophylactic treatment with metformin curtails parasite intracellular growth in vitro. An additional effect was observed in mice with a decrease in the numbers of infected hepatocytes. Moreover, metformin provided in combination with conventional liver- or blood-acting antimalarial drugs further reduced the total burden of P. berghei infection and substantially lessened disease severity in mice. Together, our findings indicate that repurposing of metformin in a prophylactic regimen could be considered for malaria chemoprevention.
Iset Medina Vera, Margarida T. Grilo Ruivo, Leonardo F. Lemos Rocha, Sofia Marques, Sangeeta N. Bhatia, Maria M. Mota, Liliana Mancio-Silva
BACKGROUND Fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridioides difficile infection (rCDI) in adults and children, but donor stool samples are currently screened for only a limited number of potential pathogens. We sought to determine whether putative procarcinogenic bacteria (enterotoxigenic Bacteroides fragilis, Fusobacterium nucleatum, and Escherichia coli harboring the colibactin toxin) could be durably transmitted from donors to patients during FMT.METHODS Stool samples were collected from 11 pediatric rCDI patients and their respective FMT donors prior to FMT as well as from the patients at 2–10 weeks, 10–20 weeks, and 6 months after FMT. Bacterial virulence factors in stool DNA extracts and stool cultures were measured by quantitative PCR: Bacteroides fragilis toxin (bft), Fusobacterium adhesin A (fadA), and Escherichia coli colibactin (clbB).RESULTS Four of 11 patients demonstrated sustained acquisition of a procarcinogenic bacteria. Whole genome sequencing was performed on colony isolates from one of these donor/recipient pairs and demonstrated that clbB+ E. coli strains present in the recipient after FMT were identical to a strain present in the donor, confirming strain transmission. Conversely, 2 patients exhibited clearance of procarcinogenic bacteria following FMT from a negative donor.CONCLUSION Both durable transmission and clearance of procarcinogenic bacteria occurred following FMT, suggesting that additional studies on appropriate screening measures for FMT donors and the long-term consequences and/or benefits of FMT are warranted.FUNDING Crohn’s & Colitis Foundation, the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University School of Medicine, the National Cancer Institute, and the Canadian Institutes of Health Research.
Julia L. Drewes, Alina Corona, Uriel Sanchez, Yunfan Fan, Suchitra K. Hourigan, Melissa Weidner, Sarah D. Sidhu, Patricia J. Simner, Hao Wang, Winston Timp, Maria Oliva-Hemker, Cynthia L. Sears
Previous studies have demonstrated the presence of microbial DNA in the fetal environment. However, it remains unclear whether this DNA represents viable bacteria and how it relates to the maternal microbiota across different body sites. We studied the microbiota of human and mouse dyads to understand these relationships, localize bacteria in the fetus, and demonstrate bacterial viability. In human preterm and full-term mother-infant dyads at the time of Cesarean delivery, the oral cavity and meconium of newborn infants born as early as 24 weeks of gestation contained a microbiota that was predicted to originate from in utero sources including the placenta. Using operative deliveries of pregnant mice under highly controlled, sterile conditions in the laboratory, composition, visualization, and viability of bacteria in the in utero compartment and fetal intestine were demonstrated by 16S rRNA gene sequencing, fluorescence in situ hybridization, and bacterial culture. The composition and predicted source of the fetal gut microbiota shifted between mid- and late gestation. Cultivatable bacteria in the fetal intestine were found during mid-gestation but not late gestation. Our results demonstrate a dynamic, viable mammalian fetal microbiota during in utero development.
Noelle Younge, Jessica R. McCann, Julie Ballard, Catherine Plunkett, Suhail Akhtar, Félix Araújo-Pérez, Amy Murtha, Debra Brandon, Patrick C. Seed
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