Post Translational Modifications (PTMs) can alter many fundamental properties of a protein. One or combinations of them have been known to regulate the dynamics of many cellular pathways and consequently regulate all vital processes. Understandably, pathogens have evolved sophisticated strategies to subvert these mechanisms to achieve instantaneous control over host functions. Here, we present the first report of modulation by intestinal pathogen Salmonella enterica serovar Typhimurium (ST) of host SUMOylation, a PTM pathway central to all fundamental cellular processes. Both in cell culture and in mouse model, we observed ST infection led to a dynamic SUMO-conjugateted proteome alteration. The intracellular survival of ST was dependent on SUMO status as revealed by reduced infection and Salmonella induced filaments (SIFs) in SUMO-upregulated cells. ST dependent SUMO modulation was seen as a result of depletion of crucial SUMO-pathway enzymes Ubc-9 and PIAS1, both at the protein and transcript levels. Mechanistically, depletion of Ubc-9 relied on upregulation of small non-coding RNA miR30c and miR30e during ST infection. This was necessary and sufficient for both down-modulation of Ubc-9 and a successful infection. Thus, we demonstrate a novel strategy of pathogen mediated perturbation of host SUMOylation, an integral mechanism underlying ST infection and intracellular survival.

With a death toll of over one million worldwide, the COVID-19 pandemic caused by SARS-CoV-2 has become the most devastating humanitarian catastrophe in recent decades. The fear of acquiring infection and spreading to vulnerable people has severely impacted society’s socio-economic status. To put an end to this growing number of infections and deaths as well as to switch from restricted to everyday living, an effective vaccine is desperately needed. As a result, enormous efforts have been made globally to develop numerous vaccine candidates in a matter of months. Currently, over 30 vaccine candidates are under assessment in clinical trials, with several undergoing preclinical studies. Here, we reviewed the major vaccine candidates based on the specific vaccine platform utilized to develop them. We also discussed the immune responses generated by these candidates in humans and preclinical models to determine vaccine safety, immunogenicity, and efficacy. Finally, immune responses induced in recovered COVID-19 patients and their possible vaccine development implications were also briefly reviewed.

Dengue virus and Zika virus are mosquito-borne, single-stranded, positive-sense RNA viruses that belong to the Flaviviridae family. Both the viruses are closely related and have similarities with other flaviviruses. Dengue virus (DENV) causes a severe febrile illness with fever, joint pain, and rash leading to a life-threatening condition in severe cases. While Zika virus (ZIKV) primarily causes mild fever, it can be passed from a pregnant mother to her fetus, resulting in severe birth defect microcephaly and even causing a rare autoimmune disease—Guillain–Barre syndrome. To date, there are no approved DENV and ZIKA vaccines available, except a Dengue vaccine (Dengvaxia, Sanofi Pasteur Inc., Lyon, France) recently approved to be used only for 9–16 years of age groups living in endemic areas and having a previous record of confirmed dengue infection. There are several potential vaccine candidates in the clinical trials based on multiple vaccine platforms, such as live attenuated, subunit, nucleic acid, and viral vector-based vaccines. In the current review, we have focused exclusively on the nucleic acid vaccine platform and discussed the progress of all the DNA/RNA vaccine candidates under preclinical and clinical studies for DENV and ZIKA viruses. Additionally, we have described a brief history of the emergence of these flaviviruses, major structural similarities between them, prominent vaccine targets, and the mechanism of virus entry and infection.

In the original version of our article

Purpose: Recurrent and metastatic human papillomavirus (HPV)–associated head and neck squamous cell carcinoma (R/M HPV+ HNSCC) remains largely incurable, with genetic drivers incompletely defined. We profiled the genetic landscape of R/M HPV+ HNSCC and functionally characterized genetic alterations strongly enriched in this cancer type. Experimental Design: We identified genetic alterations uniquely enriched in 159 R/M HPV+ tumors. High-priority alterations were functionally modeled, examining proliferation, clonogenicity, migration/invasion, apoptosis, therapy response, in vivo growth, metastasis, and immune contexture. Results: Compared with HPV+ primary tumors, R/M HPV+ tumors were enriched for TP53 mutations (prespecified FDR threshold met; OR, 6.23; P = 0.02) and were associated with poorer survival. Within R/M disease, cylindromatosis lysine 63 deubiquitinase (CYLD) alterations were specific to HPV+ tumors (21% vs. 0% in HPV−). TP53 mutations were predominantly clonal and associated with whole-genome duplication. Expression of TP53 gain-of-function (GOF) mutants (R175H, G245C, R273C) in HPV+ HNSCC cells increased clonogenic survival, migration/invasion, lung metastatic burden in vivo, and cisplatin IC50, without altering radiation sensitivity. CYLD knockdown accelerated cellular growth yet increased radiosensitivity. Transcriptomic analyses linked CYLD loss to NF-κB/TNFα pathway activation, a T cell–inflamed microenvironment, and checkpoint upregulation. Conclusions: R/M HPV+ HNSCC is genomically and functionally shaped by two axes with therapeutic implications: TP53 GOF mutations promote metastatic phenotypes and cisplatin resistance, whereas CYLD loss defines an HPV-specific subset with enhanced radiation sensitivity and immune activation. These data support using TP53 and CYLD as predictive biomarkers to guide investigation into precision strategies for systemic therapy choices, p53-targeted/Wee1 strategies, and radiotherapy–immunotherapy combinations in high-risk or R/M HPV+ HNSCC.