Characterization of phage resistance and phages capable of intestinal decolonization of carbapenem-resistant Klebsiella pneumoniae in mice

Carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged as a severe global health challenge. We isolate and characterize two previously unidentified lytic phages, P24 and P39, with large burst sizes active against ST11 KL64, a major CRKP lineage. P24 and P39 represent species of the genera Przondovirus (Studiervirinae subfamily) and Webervirus (Drexlerviridae family), respectively. P24 and P39 together restrain CRKP growth to nearly 8 h. Phage-resistant mutants exhibit reduced capsule production and decreased virulence. Modifications in mshA and wcaJ encoding capsule polysaccharide synthesis mediate P24 resistance whilst mutations in epsJ encoding exopolysaccharide synthesis cause P39 resistance. We test P24 alone and together with P39 for decolonizing CRKP using mouse intestinal colonization models. Bacterial load shed decrease significantly in mice treated with P24 and P39. In conclusion, we report the characterization of two previously unidentified lytic phages against CRKP, revealing phage resistance mechanisms and demonstrating the potential of lytic phages for intestinal decolonization.

Elucidating design principles for engineering cell-derived vesicles to inhibit SARS-CoV-2 infection

The ability of pathogens to develop drug resistance is a global health challenge. The SARS-CoV-2 virus presents an urgent need wherein several variants of concern resist neutralization by monoclonal antibody therapies and vaccine-induced sera. Decoy nanoparticles (cell-mimicking particles that bind and inhibit virions) are an emerging class of therapeutics that may overcome such drug resistance challenges. To date, we lack quantitative understanding as to how design features impact performance of these therapeutics. To address this gap, here we perform a systematic, comparative evaluation of various biologically-derived nanoscale vesicles, which may be particularly well-suited to sustained or repeated administration in the clinic due to low toxicity, and investigate their potential to inhibit multiple classes of model SARS-CoV-2 virions. A key finding is that such particles exhibit potent antiviral efficacy across multiple manufacturing methods, vesicle subclasses, and virus-decoy binding affinities. In addition, these cell-mimicking vesicles effectively inhibit model SARS-CoV-2 variants that evade monoclonal antibodies and recombinant protein-based decoy inhibitors. This study provides a foundation of knowledge that may guide the design of decoy nanoparticle inhibitors for SARS-CoV-2 and other viral infections.

Current status of therapeutic approaches and vaccines for SARS-CoV-2

SARS-CoV-2, declared a pandemic in March 2020, is the current global health challenge. The global bioburden of this virus is increasing at a rapid pace. Many antiviral drugs and vaccines have been registered for clinical trials because of their inhibitory activity observed in vitro. Currently, five types of vaccines have successfully passed Phase IV clinical trial and are being administered in populations worldwide. A plethora of experimental designs have been proposed worldwide in order to find a safe and efficacious treatment option. Therefore, it is necessary to provide baseline data and information to clinicians and researchers so that they can review the current status of therapeutics and efficacy of already developed vaccines. This review article summarizes all therapeutic options that may help to combat SARS-CoV-2.

Tuberculosis Vaccines: An Update of Recent and Ongoing Clinical Trials

TB remains a global health challenge and, until now, only one licensed vaccine (the BCG vaccine) is available. The main goal of this work is to assess the progress in the development of new TB vaccines and highlight the research in nanovaccines. A review was conducted using a methodology with the appropriate keywords and inclusion and exclusion criteria. The search revealed 37 clinical trials that were further reviewed. The results available have reported good immunogenicity and safety profiles for the vaccines under investigation. Over the last five years, the vaccines, VPM1002 and Vaccae, have moved ahead to phase III clinical trials, with the remaining candidate vaccines progressing in phase I and II clinical trials. RUTI and ID93+GLA-SE involve the use of nanoparticles. This strategy seems promising to improve the delivery, efficacy, cost, and storage conditions of the existing TB vaccines. In conclusion, the use of nanovaccines may be an option for both prevention and treatment. However, further studies are necessary for the development of novel TB vaccines.

Harmony and Tension in Integrating Indigenous Responses to COVID-19 in Uganda

Coronavirus poses a global health challenge. Amidst uncertainties associated with the pandemic, effective response requires multiple stakeholder involvement. The performance of ryemo gemo, an indigenous epidemic control measure among the Acholi in Uganda as part of the response to COVID-19 evoked responses that highlighted both harmony and tension in integrating a traditional response in the national efforts. We review the directives, the cultural context of the practice of ryemo gemo and reactions it evoked on social and print media, and discuss points of convergence and divergence in integrating the traditional practice, and compounding factors of tension. The complexity of the social challenges, the lack of shared worldview in regards to the indigenous measure, cultural disconnect and lack of clear impact assessment underlie the tension. The power of indigenous measures for sensitization and mobilization can be harnessed in the COVID-19 fight by strengthening appropriate behavioral outputs consistent with the pandemic control.

Deteriorating human microbiome – An emerging global health challenge

The study of human microbiome and its relationship with health and disease is one of the most exciting areas of research in health all over the world, especially after the failure of human genome project to deliver its expected results. Our body is composed of 30 trillion human cells. But it is host to close to 100 trillion bacterial and fungal cells. 70 – 90% of all cells in our body are non human. They reside on every inch of our skin, in our nose, mouth, ears, in our oesophagus, stomach and most abundantly in our gut. They are not a random phenomenon but have co-evolved with us humans over millions of years. Collectively these bacteria weigh about 3 pounds. The more we read about research on microbiome or microbiota, the name given to all these friendly symbiotic partners, the more we get interested in their role in health and disease. According to Martin J. Blaser, director of the Human Microbiome Program, who has also served as the president of Infectious Disease Society of America, in his best seller ‘Missing Microbes' (1), “It is our microbiome that keeps us healthy and parts of it are disappearing. The reason for this disaster is all around us – overuse of antibiotics in humans and animals, caesarean sections and widespread use of sanitizers and antiseptics, to name just a few.”

A Saudi Arabian Public Health Perspective of Tuberculosis

Tuberculosis is a global health challenge due to its spreading potential. The Kingdom of Saudi Arabia (KSA) faces a challenge in the spread of tuberculosis from migrant workers, but the foremost threat is the huge number of pilgrims who travel to visit sacred sites of the Islamic world located in the holy cities of Makkah and Al Madina. Pilgrims visit throughout the year but especially in the months of Ramadan and Zul-Hijah. The rise of resistance in Mycobacterium tuberculosis is an established global phenomenon that makes such large congregations likely hotspots in the dissemination and spread of disease at a global level. Although very stringent and effective measures exist, the threat remains due to the ever-changing dynamics of this highly pathogenic disease. This overview primarily highlights the current public health challenges posed by this disease to the Saudi health system, which needs to be highlighted not only to the concerned authorities of KSA, but also to the concerned global quarters since the pilgrims and migrants come from all parts of the world with a majority coming from high tuberculosis-burdened countries.

Current Status of HIV-1 Vaccines

HIV-1 infection and its progression to AIDS remains a significant global health challenge, particularly for low-income countries. Developing a vaccine to prevent HIV-1 infections has proven to be immensely challenging with complex biological acquisition and infection, unforeseen clinical trial disappointments, and funding issues. This paper discusses important landmarks of progress in HIV-1 vaccine development, various vaccine strategies, and clinical trials.

BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment

Hepatocellular carcinoma (HCC) represents a global health challenge with limited therapeutic options. Anti-angiogenic immune checkpoint inhibitor-based combination therapy has been introduced for progressed HCC, but improves survival only in a subset of HCC patients. Tyrosine-kinase inhibitors (TKI) such as sorafenib represent an alternative treatment option but have only modest efficacy. Using different HCC cell lines and HCC tissues from various patients reflecting HCC heterogeneity, we investigated whether the sorafenib response could be enhanced by combination with pro-apoptotic agents, such as TNF-related apoptosis-inducing ligand (TRAIL) or the BH3-mimetic ABT-737, which target the death receptor and mitochondrial pathway of apoptosis, respectively. We found that both agents could enhance sorafenib-induced cell death which was, however, dependent on specific BH3-only proteins. TRAIL augmented sorafenib-induced cell death only in NOXA-expressing HCC cells, whereas ABT-737 enhanced the sorafenib response also in NOXA-deficient cells. ABT-737, however, failed to augment sorafenib cytotoxicity in the absence of BIM, even when NOXA was strongly expressed. In the presence of NOXA, BIM-deficient HCC cells could be in turn strongly sensitized for cell death induction by the combination of sorafenib with TRAIL. Accordingly, HCC tissues sensitive to apoptosis induction by sorafenib and TRAIL revealed enhanced NOXA expression compared to HCC tissues resistant to this treatment combination. Thus, our results suggest that BH3-only protein expression determines the treatment response of HCC to different sorafenib-based drug combinations. Individual profiling of BH3-only protein expression might therefore assist patient stratification to certain TKI-based HCC therapies.

Dairy-Derived and Egg White Proteins in Enhancing Immune System Against COVID-19

Coronavirus disease (COVID-19) is a global health challenge, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) triggers a plethora of respiratory disturbances and even multiple organs failure that can be fatal. Nutritional intervention is one of the key components toward to a proper management of COVID-19 patients, especially in those requiring medication, and should thus be considered the first-line treatment. Immuno-modulation and -stimulation are currently being explored in COVID-19 management and are gaining interest by food and pharmaceutical industries. Various dietary combinations, bioactive components, nutrients and fortified foods have been reported to modulate inflammation during disease progression. Dietary combinations of dairy-derived products and eggs are gaining an increasing attention given the huge immunomodulatory and anti-inflammatory properties attributed to some of their chemical constituents. Eggs are complex dietary components containing many essential nutrients and bioactive compounds as well as a high-quality proteins. Similarly, yogurts can replenish beneficial bacteria and contains macronutrients capable of stimulating immunity by enhancing cell immunity, reducing oxidative stress, neutralizing inflammation and regulating the intestinal barriers and gut microbiome. Thus, this review highlights the impact of nutritional intervention on COVID-19 management, focusing on the immunomodulatory and inflammatory effects of immune-enhancing nutrients.