Mechanistic insights into the interplays between neutrophils and other immune cells in cancer development and progression.

Cancer is considered a major public health concern worldwide and is characterized by an uncontrolled division of abnormal cells. The human immune system recognizes cancerous cells and induces innate immunity to destroy those cells. However, sustained tumors may protect themselves by developing immune escape mechanisms through multiple soluble and cellular mediators. Neutrophils are the most plenteous leukocytes in the human blood and are crucial for immune defense in infection and inflammation. Besides, neutrophils emancipate the antimicrobial contents, secrete different cytokines or chemokines, and interact with other immune cells to combat and successfully kill cancerous cells. Conversely, many clinical and experimental studies signpost that being a polarized and heterogeneous population with plasticity, neutrophils, particularly their subpopulations, act as a modulator of cancer development by promoting tumor metastasis, angiogenesis, and immunosuppression. Studies also suggest that tumor infiltrating macrophages, neutrophils, and other innate immune cells support tumor growth and survival. Additionally, neutrophils promote tumor cell invasion, migration and intravasation, epithelial to mesenchymal transition, survival of cancer cells in the circulation, seeding, and extravasation of tumor cells, and advanced growth and development of cancer cells to form metastases. In this manuscript, we describe and review recent studies on the mechanisms for neutrophil recruitment, activation, and their interplay with different immune cells to promote their pro-tumorigenic functions. Understanding the detailed mechanisms of neutrophil-tumor cell interactions and the concomitant roles of other immune cells will substantially improve the clinical utility of neutrophils in cancer and eventually may aid in the identification of biomarkers for cancer prognosis and the development of novel therapeutic approaches for cancer treatment.

Multidrug Resistance Profiles and Resistance Mechanisms to ß-Lactams and Fluoroquinolones in Bacterial Isolates from Hospital Wastewater in Bangladesh.

Multidrug resistance (MDR) is one of the deadliest public health concerns of the 21st century, rendering many powerful antibiotics ineffective. The current study provides important insights into the prevalence and mechanisms of antibiotic resistance in hospital wastewater isolates. In this study, we determined the MDR profile of 68 bacterial isolates collected from five different hospitals in Dhaka, Bangladesh. Of them, 48 bacterial isolates were identified as Enterobacteriaceae. Additionally, we investigated the prevalence and distribution of five beta-lactam resistance genes, as well as quinolone resistance mechanisms among the isolates. The results of this study showed that 87% of the wastewater isolates were resistant to at least three different antibiotic classes, as revealed using the disc diffusion method. Resistance to ß-lactams was the most common, with 88.24% of the isolates being resistant, closely followed by macrolides (80.88% resistant). Polymyxin was found to be the most effective against wastewater isolates, with 29.41% resistant isolates. The most common ß-lactam resistance genes found in wastewater isolates were blaTEM (76.09%), blaCTX-M1 (71.74%), and blaNDM (67.39%). Two missense mutations in the quinolone resistance-determining region (QRDR) of gyrA (S83L and D87N) and one in both parC (S80I) and parE (S458A) were identified in all isolates, and one in parE (I529L), which had not previously been identified in Bangladesh. These findings suggest that hospital wastewater acts as an important reservoir of antibiotic-resistant bacteria wherein resistance mechanisms to ß-lactams and fluoroquinolones are obvious. Our data also emphasize the need for establishing a nationwide surveillance system for antibiotic resistance monitoring to ensure that hospitals sanitize their wastewater before disposal, and regulation to ensure hospital wastewater is kept away from community settings.

Microbial co-infections in COVID-19: Associated microbiota and underlying mechanisms of pathogenesis.

The novel coronavirus infectious disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has traumatized the whole world with the ongoing devastating pandemic. A plethora of microbial domains including viruses (other than SARS-CoV-2), bacteria, archaea and fungi have evolved together, and interact in complex molecular pathogenesis along with SARS-CoV-2. However, the involvement of other microbial co-pathogens and underlying molecular mechanisms leading to extortionate ailment in critically ill COVID-19 patients has yet not been extensively reviewed. Although, the incidence of co-infections could be up to 94.2% in laboratory-confirmed COVID-19 cases, the fate of co-infections among SARS-CoV-2 infected hosts often depends on the balance between the host's protective immunity and immunopathology. Predominantly identified co-pathogens of SARS-CoV-2 are bacteria such as Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, Acinetobacter baumannii, Legionella pneumophila and Clamydia pneumoniae followed by viruses including influenza, coronavirus, rhinovirus/enterovirus, parainfluenza, metapneumovirus, influenza B virus, and human immunodeficiency virus. The cross-talk between co-pathogens (especially lung microbiomes), SARS-CoV-2 and host is an important factor that ultimately increases the difficulty of diagnosis, treatment, and prognosis of COVID-19. Simultaneously, co-infecting microbiotas may use new strategies to escape host defense mechanisms by altering both innate and adaptive immune responses to further aggravate SARS-CoV-2 pathogenesis. Better understanding of co-infections in COVID-19 is critical for the effective patient management, treatment and containment of SARS-CoV-2. This review therefore necessitates the comprehensive investigation of commonly reported microbial co-pathogens amid COVID-19, their transmission pattern along with the possible mechanism of co-infections and outcomes. Thus, identifying the possible co-pathogens and their underlying molecular mechanisms during SARS-CoV-2 pathogenesis may shed light in developing diagnostics, appropriate curative and preventive interventions for suspected SARS-CoV-2 respiratory infections in the current pandemic.

Mutational insights into the envelope protein of SARS-CoV-2.

The ongoing mutations in the structural proteins of SARS-CoV-2 are the major impediment for prevention and control of the COVID-19 disease. Presently we focused on evolution of the envelope (E) protein, one of the most enigmatic and less studied protein among the four structural proteins (S, E, M and N) associated with multitude of immunopathological functions of SARS-CoV-2. In the present study, we comprehensively analyzed 81,818 high quality E protein sequences of SARS-CoV-2 globally available in the GISAID database as of 20 August 2020. Compared to Wuhan reference strain, our mutational analysis explored only 1.2 % (982/81818) mutant strains undergoing a total of 115 unique amino acid (aa) substitutions in the E protein, highlighting the fact that most (98.8 %) of the E protein of SARS-CoV-2 strains are highly conserved. Moreover, we found 58.77 % (134 of 228) nucleotides (nt) positions of SARS-CoV-2 E gene encountering a total of 176 unique nt-level mutations globally, which may affect the efficacy of real time RT-PCR-based molecular detection of COVID-19. Importantly, higher aa variations observed in the C-terminal domain (CTD) of the E protein, particularly at Ser55-Phe56, Arg69 and the C-terminal end (DLLV: 72-75) may alter the binding of SARS-CoV-2 Envelope protein to tight junction-associated PALS1 and thus could play a key role in COVID-19 pathogenesis. Furthermore, this study revealed the V25A mutation in the transmembrane domain which is a key factor for the homopentameric conformation of E protein. Our analysis also observed a triple cysteine motif harboring mutation (L39M, A41S, A41V, C43F, C43R, C43S, C44Y, N45R) which may hinder the binding of E protein with spike glycoprotein. These results therefore suggest the continuous monitoring of the structural proteins including the envelope protein of SARS-CoV-2 since the number of genome sequences from across the world are continuously increasing.

In silico Evolutionary Divergence Analysis Suggests the Potentiality of Capsid Protein VP2 in Serotype-Independent Foot-and-Mouth Disease Virus Detection.

Foot-and-mouth disease (FMD) is an economically devastating disease of the livestock worldwide and caused by the FMD virus (FMDV), which has seven immunologically distinct serotypes (O, A, Asia1, C, and SAT1-SAT3). Studies suggest that VP2 is relatively conserved among three surface-exposed capsid proteins (VP1-VP3) of FMDV, but the level of conservation has not yet been reported. Here we analyzed the comparative evolutionary divergence of VP2 and VP1 to determine the level of conservation in VP2 at different hierarchical levels of three FMDV serotypes (O, A, and Asia1) currently circulating in Asia through an in-depth computational analysis of 14 compiled datasets and designed a consensus VP2 protein that can be used for the development of a serotype-independent FMDV detection tool. The phylogenetic analysis clearly represented a significant level of conservation in VP2 over VP1 at each subgroup level. The protein variability analysis and mutational study showed the presence of 67.4% invariant amino acids in VP2, with the N-terminal end being highly conserved. Nine inter-serotypically conserved fragments located on VP2 have been identified, among which four sites showed promising antigenicity value and surface exposure. The designed 130 amino acid long consensus VP2 protein possessed six surface-exposed B cell epitopes, which suggests the possible potentiality of the protein for the development of a serotype-independent FMDV detection tool in Asia. Conclusively, this is the first study to report the comparative evolutionary divergence between VP2 and VP1, along with proposing the possible potentiality of a designed protein candidate in serotype-independent FMDV detection.