Design of a novel multi-epitope vaccine against Marburg virus using immunoinformatics studies.

Marburg virus (MARV) is a highly contagious and virulent agent belonging to Filoviridae family. MARV causes severe hemorrhagic fever in humans and non-human primates. Owing to its highly virulent nature, preventive approaches are promising for its control. There is currently no approved drug or vaccine against MARV, and management mainly involves supportive care to treat symptoms and prevent complications. Our aim was to design a novel multi-epitope vaccine (MEV) against MARV using immunoinformatics studies. In this study, various proteins (VP35, VP40 and glycoprotein precursor) were used and potential epitopes were selected. CTL and HTL epitopes covered 79.44% and 70.55% of the global population, respectively. The designed MEV construct was stable and expressed in Escherichia coli (E. coli) host. The physicochemical properties were also acceptable. MARV MEV candidate could predict comprehensive immune responses such as those of humoral and cellular in silico. Additionally, efficient interaction to toll-like receptor 3 (TLR3) and its agonist (ß-defensin) was predicted. There is a need for validation of these results using further in vitro and in vivo studies.

Enhancement of bactericidal effects of bacteriophage and gentamicin combination regimen against Staphylococcus aureus and Pseudomonas aeruginosa strains in a mice diabetic wound model.

Diabetic patients are more susceptible to developing wound infections resulting in poor and delayed wound healing. Bacteriophages, the viruses that target-specific bacteria, can be used as an alternative to antibiotics to eliminate drug-resistant bacterial infections. Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) are among the most frequently identified pathogens in diabetic foot ulcers (DFUs). The aim of this study was assessment of bacteriophage and gentamicin combination effects on bacterial isolates from DFU infections. Specific bacteriophages were collected from sewage and animal feces samples and the phages were enriched using S. aureus and P. aeruginosa cultures. The lytic potential of phage isolates was assessed by the clarity of plaques. We isolated and characterized four lytic phages: Stp2, Psp1, Stp1, and Psp2. The phage cocktail was optimized and investigated in vitro. We also assessed the effects of topical bacteriophage cocktail gel on animal models of DFU. Results revealed that the phage cocktail significantly reduced the mortality rate in diabetic infected mice. We determined that treatment with bacteriophage cocktail effectively decreased bacterial colony counts and improved wound healing in S. aureus and P. aeruginosa infections, especially when administrated concomitantly with gentamicin. The application of complementary therapy using a phage cocktail and gentamicin, could offer an attractive approach for the treatment of wound diabetic bacterial infections.

STING pathway as a cancer immunotherapy: Progress and challenges in activating anti-tumor immunity.

The stimulator of the interferon genes (STING) signaling pathway plays a crucial role in innate immunity by detecting cytoplasmic DNA and initiating antiviral host defense mechanisms. The STING cascade is triggered when the enzyme cyclic GMP-AMP synthase (cGAS) binds cytosolic DNA and synthesizes the secondary messenger cGAMP. cGAMP activates the endoplasmic reticulum adaptor STING, leading to the activation of kinases TBK1 and IRF3 that induce interferon production. Secreted interferons establish an antiviral state in infected and adjacent cells. Beyond infections, aberrant DNA in cancer cells can also activate the STING pathway. Preclinical studies have shown that pharmacological STING agonists like cyclic dinucleotides elicit antitumor immunity when administered intratumorally by provoking innate and adaptive immunity. Combining STING agonists with immune checkpoint inhibitors may improve outcomes by overcoming tumor immunosuppression. First-generation STING agonists encountered challenges like poor pharmacokinetics, limited tumor specificity, and systemic toxicity. The development of the next-generation STING-targeted drugs to realize the full potential of engaging this pathway for cancer treatment can be a solution to overcome the current challenges, but further studies are required to determine optimal applications and combination regimens for the clinic. Notably, the controlled activation of STING is needed to preclude adverse effects. This review explores the mechanisms and effects of STING activation, its role in cancer immunotherapy, and current challenges.

An updated review on oral protein-based antigen vaccines efficiency and delivery approaches: a special attention to infectious diseases.

Various infectious agents affect human health via the oral entrance. The majority of pathogens lack approved vaccines. Oral vaccination is a convenient, safe and cost-effective approach with the potential of provoking mucosal and systemic immunity and maintaining individual satisfaction. However, vaccines should overcome the intricate environment of the gastrointestinal tract (GIT). Oral protein-based antigen vaccines (OPAVs) are easier to administer than injectable vaccines and do not require trained healthcare professionals. Additionally, the risk of needle-related injuries, pain, and discomfort is eliminated. However, OPAVs stability at environmental and GIT conditions should be considered to enhance their stability and facilitate their transport and storage. These vaccines elicit the local immunity, protecting GIT, genital tract and respiratory epithelial surfaces, where numerous pathogens penetrate the body. OPAVs can also be manipulated (such as using specific incorporated ligand and receptors) to elicit targeted immune response. However, low bioavailability of OPAVs necessitates development of proper protein carriers and formulations to enhance their stability and efficacy. There are several strategies to improve their efficacy or protective effects, such as incorporation of adjuvants, enzyme inhibitors, mucoadhesive or penetrating devices and permeation enhancers. Hence, efficient delivery of OPAVs into GIT require proper delivery systems mainly including smart target systems, probiotics, muco-adhesive carriers, lipid- and plant-based delivery systems and nano- and microparticles.

Nucleic acid-based vaccine platforms against the coronavirus disease 19 (COVID-19).

The coronavirus disease 2019 (COVID-19) pandemic has infected 673,010,496 patients and caused the death of 6,854,959 cases globally until today. Enormous efforts have been made to develop fundamentally different COVID-19 vaccine platforms. Nucleic acid-based vaccines consisting of mRNA and DNA vaccines (third-generation vaccines) have been promising in terms of rapid and convenient production and efficient provocation of immune responses against the COVID-19. Several DNA-based (ZyCoV-D, INO-4800, AG0302-COVID19, and GX-19N) and mRNA-based (BNT162b2, mRNA-1273, and ARCoV) approved vaccine platforms have been utilized for the COVID-19 prevention. mRNA vaccines are at the forefront of all platforms for COVID-19 prevention. However, these vaccines have lower stability, while DNA vaccines are needed with higher doses to stimulate the immune responses. Intracellular delivery of nucleic acid-based vaccines and their adverse events needs further research. Considering re-emergence of the COVID-19 variants of concern, vaccine reassessment and the development of polyvalent vaccines, or pan-coronavirus strategies, is essential for effective infection prevention.

Protective role of flavonoids quercetin and silymarin in the viral-associated inflammatory bowel disease: an updated review.

Inflammatory bowel disease (IBD) is a chronic recurrent inflammation of the gastrointestinal tract (GIT). IBD patients are susceptible to various infections such as viral infections due to the long-term consumption of immunosuppressive drugs and biologics. The antiviral and IBD protective traits of flavonoids have not been entirely investigated. This study objective included an overview of the protective role of flavonoids quercetin and silymarin in viral-associated IBD. Several viral agents such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV) and enteric viruses can be reactivated and thus develop or exacerbate the IBD conditions or eventually facilitate the disease remission. Flavonoids such as quercetin and silymarin are non-toxic and safe bioactive compounds with remarkable anti-oxidant, anti-inflammatory and anti-viral effects. Mechanisms of anti-inflammatory and antiviral effects of silymarin and quercetin mainly include immune modulation and inhibition of caspase enzymes, viral binding and replication, RNA synthesis, viral proteases and viral assembly. In the nutraceutical sector, natural flavonoids low bioavailability and solubility necessitate the application of delivery systems to enhance their efficacy. This review study provided an updated understanding of the protective role of quercetin and silymarin against viral-associated IBD.

Antibacterial effects of single phage and phage cocktail against multidrug-resistant Klebsiella pneumoniae isolated from diabetic foot ulcer.

Diabetic foot ulcer (DFU) is associated with long-term hospitalization and amputation. Antibiotic resistance has made the infection eradication more difficult. Hence, seeking alternative therapies such as phage therapy seems necessary. Bacteriophages are viruses targeting specific bacterial species. Klebsiella pneumoniae (K. pneumoniae) is among causative agents of the DFU. In this study, the therapeutic effects of single phage and phage cocktail were investigated against multidrug-resistant (MDR) K. pneumonia isolated from DFU. Bacteriophages were isolated from animal feces and sewage samples, and were enriched and propagated using K. pneumoniae as the host. Thirty K. pneumoniae clinical isolates were collected from hospitalized patients with DFU. The antibiotic susceptibility pattern was determined using agar disk diffusion test. The phages' morphological traits were determined using transmission electron microscopy (TEM). The killing effect of isolated phages was assessed using plaque assay. Four phage types were isolated and recognized including KP1, KP2, KP3, and KP4. The bacterial rapid regrowth was observed following each single phage-host interaction, but not phage cocktail due to the evolution of mutant strains. Phage cocktail demonstrated significantly higher antibacterial activity than each single phage (p < 0.05) without any bacterial regrowth. The employment of phage cocktail was promising for the eradication of MDR-K. pneumoniae isolates. The development of phage therapy in particular, phage cocktail is promising as an efficient approach to eradicate MDR-K. pneumoniae isolated from DFU. The application of a specific phage cocktail can be investigated to try and achieve the eradication of various infections.

Occurrence of virulence factors and carbapenemase genes in Salmonella enterica serovar Enteritidis isolated from chicken meat and egg samples in Iraq.

BACKGROUND: Food-borne infections mainly due to Salmonella enterica serovar Enteritidis (S. Enteritidis) are major concerns worldwide. S. Enteritidis isolates may serve as reservoirs for spreading antimicrobial drug resistance genes including carbapenemases. This study aimed to screen the occurrence of virulence factors, carbapenemases, and antibiotic resistance genes in S. Enteritidis isolated from chicken meat and eggs in Iraq. RESULTS: In total, 1000 non-duplicated chicken meat and 1000 egg samples were collected during 2019-2020. Presumptive S. Enteritidis isolates were initially identified by standard bacteriology tests and then were confirmed using polymerase chain reaction (PCR). Carbapenem resistance was detected using the disk diffusion method. Virulence and carbapenemase genes were screened using the PCR method. In total, 100 (5.0%) S. Enteritidis isolates were identified from 2000 samples collected using phenotypic and molecular methods. These isolates were identified from 4.9% chicken meat (n = 49/1000) and 5.1% egg (n = 51/1000) samples, respectively. The most and the least susceptibility was found to gentamicin and ceftazidime antibiotics, respectively. The prevalence of different virulence factors were as follows: phoP/Q (40.0%), traT (30.0%), stn (22.0%), slyA (11.0%), and sopB (9.0%). Among 20 carbapenem-resistant S. Enteritidis isolates, the most predominant carbapenemase gene was blaIMP (35.0%, n = 7), followed by blaOXA-48-like (25.0%, n = 5), and blaNDM (10.0%, n = 2), while the blaKPC and blaVIM genes were not detected. The coexistence of blaIMP, blaOXA-48-like, and blaNDM genes was determined in two isolates. The prevalence of different antibiotic resistance genes were as follows: tetA (87.1%), tetB (87.1%), dfrA1 (77.6%), and sul1 (83.6%). CONCLUSION: Considering the existence of carbapenem-resistant S. Enteritidis harboring different virulence and antibiotic resistance genes in chicken meat and egg samples, adherence to proper hygienic conditions should be considered.

Individual genetic variability mainly of Proinflammatory cytokines, cytokine receptors, and toll-like receptors dictates pathophysiology of COVID-19 disease.

Innate and acquired immunity responses are crucial for viral infection elimination. However, genetic variations in coding genes may exacerbate the inflammation or initiate devastating cytokine storms which poses severe respiratory conditions in coronavirus disease-19 (COVID-19). Host genetic variations in particular those related to the immune responses determine the patients' susceptibility and COVID-19 severity and pathophysiology. Gene polymorphisms such as single nucleotide polymorphisms (SNPs) of interferons, TNF, IL1, IL4, IL6, IL7, IL10, and IL17 predispose patients to the severe form of COVID-19 or severe acute respiratory syndrome coronavirus-2 (SARS-COV-2). These variations mainly alter the gene expression and cause a severe response by B cells, T cells, monocytes, neutrophils, and natural killer cells participating in a cytokine storm. Moreover, cytokines and chemokines SNPs are associated with the severity of COVID-19 and clinical outcomes depending on the corresponding effect. Additionally, genetic variations in genes encoding toll-like receptors (TLRs) mainly TLR3, TLR7, and TLR9 have been related to the COVID-19 severe respiratory symptoms. The specific relation of these mutations with the novel variants of concern (VOCs) infection remains to be elucidated. Genetic variations mainly within genes encoding proinflammatory cytokines, cytokine receptors, and TLRs predispose patients to COVID-19 disease severity. Understanding host immune gene variations associated with the SARS-COV-2 infection opens insights to control the pathophysiology of emerging viral infections.

Virulence traits and plasmid-mediated quinolone resistance among Aggregatibacter actinomycetemcomitans from Iraq: Low rate of highly virulent JP2 genotype.

Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) is an important causative agent of periodontitis acting by employment of a series of virulence factors. Our aim was to evaluate the virulence traits and plasmid-mediated quinolone resistance of A. actinomycetemcomitans isolates in Iraq. A total of 1580 samples were collected from dental caries (n = 1190) and periodontitis (n = 390) among which 200 samples were positive. The antibiotic susceptibility pattern and biofilm formation were performed. The antibiotic resistance and virulence determinants were screened using polymerase chain reaction (PCR) technique. The ltx3 and ltx4 primers were used for identification of highly virulent JP2 type. A. actinomycetemcomitans was identified among dental caries (n = 114) and periodontitis (n = 86) samples. The JP2 type was identified in six periodontitis samples. Sixty (30% of) isolates were multidrug-resistant (MDR). Eighty-four (42% of) A. actinomycetemcomitans isolates formed strong biofilms and 44% of them had moderate-level biofilms. The detected virulence genes included ltxA (96%), cdtB (64%), qseB (62%), qseC (58%) and rcpA (58%). There was a significant relation between the existence of ltxA (42%, p = 0.041) and rcpA (64%, p = 0.022) genes and the biofilm formation. The JP2 genotype was identified in six adolescents with periodontitis. The rate of qnrA, qnrB, qnrC, qnrD, qnrS and aac(6')-Ib-cr plasmid-mediated quinolone resistance genes included 22%, 18%, 16%, 16%, 14% and 0%, respectively. The qnrA (66.7%) and qnrB (53.4%) genes were significantly detected higher in MDR strains. Herein, A. actinomycetemcomitans from dental caries and periodontitis had relatively high rate of resistance to ß-lactams but low resistance levels to quinolones. Moreover, most of the resistant isolates carried the qnrA-S genes. A majority of them had ltxA gene, half of them contained all the virulence genes and JP2 genotype was found in six isolates from periodontitis. Furthermore, half of the isolates produced biofilms which was significantly related to the ltxA and rcpA genes. Screening of virulence genes and antibiotic resistance pattern determination contribute to the control, diagnosis and eradication of these isolates.

Anticancer traits of chimeric antigen receptors (CARs)-Natural Killer (NK) cells as novel approaches for melanoma treatment.

Owing to non-responsiveness of a high number of patients to the common melanoma therapies, seeking novel approaches seem as an unmet requirement. Chimeric antigen receptor (CAR) T cells were initially employed against recurrent or refractory B cell malignancies. However, advanced stages or pretreated patients have insufficient T cells (lymphopenia) amount for collection and clinical application. Additionally, this process is time-consuming and logistically cumbersome. Another limitation of this approach is toxicity and cytokine release syndrome (CRS) progress and neurotoxicity syndrome (NS). Natural killer (NK) cells are a versatile component of the innate immunity and have several advantages over T cells in the application for therapies such as availability, unique biological features, safety profile, cost effectiveness and higher tissue residence. Additionally, CAR NK cells do not develop Graft-versus-host disease (GvHD) and are independent of host HLA genotype. Notably, the NK cells number and activity is affected in the tumor microenvironment (TME), paving the way for developing novel approaches by enhancing their maturation and functionality. The CAR NK cells short lifespan is a double edge sword declining toxicity and reducing their persistence. Bispecific and Trispecific Killer Cell Engagers (BiKE and Trike, respectively) are emerging and promising immunotherapies for efficient antibody dependent cell cytotoxicity (ADCC). CAR NK cells have some limitations in terms of expanding and transducing NK cells from donors to achieve clinical response. Clinical trials are in scarcity regarding the CAR NK cell-based cancer therapies. The CAR NK cells short life span following irradiation before infusion limits their efficiency inhibiting their in vivo expansion. The CAR NK cells efficacy enhancement in terms of lifespan TME preparation and stability is a goal for melanoma treatment. Combination therapies using CAR NK cells and chemotherapy can also overcome therapy limitations.

The efficacy of AuNP-probe conjugate nanobiosensor in non-amplification and amplification forms for the diagnosis of leishmaniasis.

Nanobiosensor platforms have emerged as convenient and promising approaches with remarkable efficacy for the diagnosis of infectious diseases. Gold nanoparticles (AuNPs) have been widely used due to numerous advantageous properties such as optical, electrical, physicochemical and great biomolecules binding capabilities. This study aimed to apply AuNP-Probe Conjugate for the detection of Leishmania spp., using colorimetric and amplification methods targeting parasitic ITS2 fragment. The first method was carried out by hybridization of 10µL of DNA with 4 µL of probe and addition of 5 µL of 0.2 N HCl (non-amplification method). Second method was followed by polymerase chain reaction (PCR) amplification using thiolated primer, 5 µL of AuNP and 5 µL of 0.2 N HCl. The appearance of red and purple colors indicated positive and negative results, respectively. The minimum of detection for non-amplification and amplification methods for three strains of Leishmania namely L. major, L. tropica and L. infantum were determined to be 32 fg/µL and 16 fg/µL, respectively. Sensitivity for detection of visceral leishmaniasis (VL) for non-amplification and amplification methods included 96% and 100%, respectively and for cutaneous leishmaniasis (CL) included 98% and 100%, respectively. The results of this investigation revealed that sensitivity of amplification method was the same as RT-qPCR, while that of non-amplification method was lower. However, this method was promising because of no need for any equipment, high specificity, enough sensitivity, low cost and rapidity (less than 30 min) to complete after genomic DNA extraction.

Opportunities and obstacles for the melanoma immunotherapy using T cell and chimeric antigen receptor T (CAR-T) applications: a literature review.

Chimeric antigen receptor T (CAR-T) cell therapy procedure includes taking personal T cells and processing or genetic engineering using specific antigens and in vitro expanding and eventually infusing into the patient's body to unleash immune responses. Adoptive cell therapy (ACT) includes lymphocytes taking, in vitro selection and expansion and processing for stimulation or activation and infusion into the patient's body. Immune checkpoint inhibitors (ICIs), ACT and CAR-T cell therapies have demonstrated acceptable results. However, rare CAR-T cells tissue infiltration, off-target toxicity and resistance development include main disadvantages of CAR-T cell based therapy. Selection of suitable target antigens and novel engineered immune cells are warranted in future studies using "surfaceome" analysis. Employment of cytokines (IL-2, IL-7) for T cells activation has been also associated with specific anti-melanoma function which overcome telomeres shortening and further T cells differentiation. In resistant cases, rapidly accelerated fibrosarcoma B-type and mitogen-activated extracellular signal-regulated kinase inhibitors have been mostly applied. The aim of this study was evaluation of CAR-T cell and adoptive cell therapies efficiency for the treatment of melanoma.

Current information on the association of Helicobacter pylori with autophagy and gastric cancer.

Helicobacter pylori (H. pylori) is a Gram-negative bacterium and causative agent of gastric cancer. H. pylori induce defective autophagy or inhibit it by means of CagA and vacuolating cytotoxin A (VacA) toxins leading to the gastric cancer induction. Impaired or defective autophagy leads to the accumulation of cytotoxic materials, such as ROS and P62 that lead to increased mutations in the DNA, genome instability, and risk of cancer formation. H. pylori CagA may inhibit autophagy through the c-Met-PI3k/Akt-mTOR signaling pathway. However, VacA induces autophagy by some signaling pathways. In the gastric epithelial cells, VacA is a necessary and sufficient factor for the creation of autophagy. While CagA is a negative regulator of this phenomenon, the elimination of this gene from H. pylori has increased autophagy and the production of inflammatory cytokines is reduced. In gastrointestinal cancers, some of the microRNAs (miRNAs) act as tumor suppressors and some other are oncogenes by regulating various genes expression. H. pylori can also modify autophagy through a mechanism that includes the function of miRNAs. In autophagy, oncogenic miRNAs inhibit activation of some tumor suppressor signaling pathways (e.g., ULK1 complex, Beclin-1 function, and Atg4 messaging), whereas tumor suppressor miRNAs can block the activation of oncogenic signaling pathways. For instance, Beclin-1 is negatively regulated by miRNA-376b (oncogenic miRNA) and miRNA-30a (tumor suppressor miRNA). Similarly, Atg4 by miRNA-376b (oncogenic miRNA) and miRNA-101 (tumor suppressor miRNA). So, this apparent paradox can be explained as that both Beclin-1 and Atg4 play different roles in a particular cell or tissue.

Potential antigen candidates for subunit vaccine development against Helicobacter pylori infection.

Helicobacter pylori (H. pylori) is a resident bacterium in the stomach that accounts for 75% cases of gastric cancer. In this review, we comprehensively studied published papers on H. pylori vaccines using Google Scholar and NCBI databases to gather information about vaccines against H. pylori. Considering the pivotal roles of the enzyme urease (in production of NH3 and neutralization of the acidic medium of the stomach), cytotoxin-associated gene A, and vacuolating cytotoxin A proteins in H. pylori infection, they could be the best candidates for the construction of recombinant vaccines. The outer membrane porins (Hop), blood group antigen-binding adhesin (BabA), sialic acid-binding adhesin (SabA), and outer inflammatory protein A, play significant roles in binding of bacterium to human gastric tissues, and because binding is the first step in bacterial fixation and colonization, these antigens also can be considered as suitable candidates for designing vaccines. Likely, other significant bacterial antigens, such as NapA (chemotactic factor for recruitment of human neutrophils and monocytes to the site of infection), duodenal ulcer promoting protein A (to promote duodenal ulcer), and Hsp60 (as a molecular chaperon for activation of urease enzyme), can be used in the construction of subunit vaccines. New vaccines in use currently, such as DNA vaccines and subunit vaccines, can efficiently replace the dead and attenuated vaccines. Nonetheless, the results show that urease enzyme is most used compared with bacterial components in the designing and construction of recombinant vaccines. The BabA and SabA antigens belong to the outer membrane porins family in H. pylori and are required for binding and fixation of the bacterium to the human gastric tissues.

Probiotics importance and their immunomodulatory properties.

Mammalian intestine contains a large diversity of commensal microbiota, which is far more than the number of host cells. Probiotics play an insecure and protective role against the colonization of intestinal pathogenic microbes and increase mucosal integrity by stimulating epithelial cells. Probiotics have innate capabilities in many ways, including receptor antagonism, receptor expression, binding and expression of adapter proteins, expression of negative regulatory signal molecules, induction of microRNAs, endotoxin tolerance, and ultimately secretion of immunomodulatory proteins, lipids, and metabolites to modulate the immune system. Probiotic bacteria can affect homeostasis, inflammation, and immunopathology through direct or indirect effects on signaling pathways as immunosuppressant or activators. Probiotics suppress inflammation by inhibiting various signaling pathways such as the nuclear factor-κB (NF-κß) pathway, possibly related to alterations in mitogen-activated protein kinases and pattern recognition receptors pathways. Probiotics can also inhibit the binding of lipopolysaccharides to the CD14 receptor, thereby reducing the overall activation of NF-κß and producing proinflammatory cytokines. Some effects of modulation by probiotics include cytokine production by epithelial cells, increased mucin secretion, increased activity of phagocytosis, and activation of T and natural killer T cells, stimulation of immunoglobulin A production and decreased T cell proliferation. Intestinal microbiota has a major impact on the systemic immune system. Specific microbiota controls the differentiation of cells in lamina propria, in which Th17 cells secrete interleukin 17. The presence of Th17 and Treg cells in the small intestine is associated with intestinal microbiota, with the preferential Treg differentiation and the absence of Th17 cells, possibly reflecting alterations in the lamina propria cytokines and the intestinal gut microbiota.

Memory and CAR-NK cell-based novel approaches for HIV vaccination and eradication.

Human immunodeficiency virus (HIV) is one of the critical infectious agents with thousands of newly infected people worldwide. High mutational capability and rapid diversification, inhibition of humoral and cellular immune responses, and thus inability for recognition of an immunogenic region in the viral envelope by the immune system are major challenges. Natural killer (NK) cells are multifunctional, playing a key role in the identification and elimination of HIV-infected cells. These cells identify and eliminate virus-infected cells in a multilateral manner, such as ligand stress, antibody-dependent cell cytotoxicity (ADCC), T follicular helper (Tfh), and the activation of most of the stimulatory receptors. Moreover, these cells release cytokines leading to the activation of cytotoxic lymphocytes (CTLs) and dendritic cells (DCs), contributing to efficient viral elimination. Some subsets of NK cells exhibit putatively enhanced effector functions against viruses following vaccination easily expanded and identified by NK cell lines culture. Furthermore, NK cells promote the elimination of HIV-infected cells which reduce the expression of major histocompatibility complex (MHC) molecules. Memory NK cells have higher functionality and renewable potential. A pioneering strategy to establish an efficacious HIV vaccine would include stimulation of the accumulation and long-term maintenance of these HIV-reactive NK cells. CAR-NK (chimeric antigen receptor-natural killer) cells-based antiviral therapies have emerged as novel approaches with the ability of antigen recognition and more advantages than CAR-T (chimeric antigen receptor-T) cells. Recent development of induced pluripotent stem cell (iPSC)-derived NK cells with enhanced activity and efficiency conferred a promising insight into CAR-NK cell-based therapies. Therefore, memory and CAR-NK cells-based approaches can emerge as novel strategies providing implications for HIV vaccine design and therapy.

Mycobacterium avium paratuberculosis and Mycobacterium avium complex and related subspecies as causative agents of zoonotic and occupational diseases.

Mycobacterium avium complex (MAC) and Mycobacterium avium paratuberculosis (MAP) cause zoonotic infections transmitted by birds and livestock herds. These pathogens have remained as serious economic and health threats in most areas of the world. As zoonotic diseases, the risk of development of occupational disease and even death outcome necessitate implementation of control strategies to prevent its spread. Zoonotic MAP infections include Crohn's disease, inflammatory bowel disease, ulcerative colitis, sarcoidosis, diabetes mellitus, and immune-related diseases (such as Hashimoto's thyroiditis). Paratuberculosis has classified as type B epidemic zoonotic disease according to world health organization which is transmitted to human through consumption of dairy and meat products. In addition, MAC causes pulmonary manifestations and lymphadenitis in normal hosts and human immunodeficiency virus (HIV) progression (by serotypes 1, 4, and 8). Furthermore, other subspecies have caused respiratory abscesses, neck lymph nodes, and disseminated osteomyelitis in children and ulcers. However, the data over the occupational relatedness of these subspecies is rare. These agents can cause occupational infections in susceptible herd breeders. Several molecular methods have been recognized as proper strategies for tracking the infection. In this study, some zoonotic aspects, worldwide prevalence and control strategies regarding infections due to MAP and MAC and related subspecies has been reviewed.

Herbal medicine as an auspicious therapeutic approach for the eradication of Helicobacter pylori infection: A concise review.

Helicobacter pylori (H. pylori) causes gastric mucosa inflammation and gastric cancer mostly via several virulence factors. Induction of proinflammatory pathways plays a crucial role in chronic inflammation, gastric carcinoma, and H. pylori pathogenesis. Herbal medicines (HMs) are nontoxic, inexpensive, and mostly anti-inflammatory reminding meticulous emphasis on the elimination of H. pylori and gastric cancer. Several HM has exerted paramount anti-H. pylori traits. In addition, they exert anti-inflammatory effects through several cellular circuits such as inhibition of 5'-adenosine monophosphate-activated protein kinase, nuclear factor-κB, and activator protein-1 pathway activation leading to the inhibition of proinflammatory cytokines (interleukin 1α [IL-1α], IL-1ß, IL-6, IL-8, IL-12, interferon γ, and tumor necrosis factor-α) expression. Furthermore, they inhibit nitrous oxide release and COX-2 and iNOS activity. The apoptosis induction in Th1 and Th17-polarized lymphocytes and M2-macrophagic polarization and STAT6 activation has also been exhibited. Thus, their exact consumable amount has not been revealed, and clinical trials are needed to achieve optimal concentration and their pharmacokinetics. In the aspect of bioavailability, solubility, absorption, and metabolism of herbal compounds, nanocarriers such as poly lactideco-glycolide-based loading and related formulations are helpful. Noticeably, combined therapies accompanied by probiotics can also be examined for better clearance of gastric mucosa. In addition, downregulation of inflammatory microRNAs (miRNAs) by HMs and upregulation of those anti-inflammatory miRNAs is proposed to protect the gastric mucosa. Thus there is anticipation that in near future HM-based formulations and proper delivery systems are possibly applicable against gastric cancer or other ailments because of H. pylori.

Bacterial l-asparaginases for cancer therapy: Current knowledge and future perspectives.

l-Asparaginases hydrolyzing plasma l-asparagine and l-glutamine has attracted tremendous attention in recent years owing to remarkable anticancer properties. This enzyme is efficiently used for acute lymphoblastic leukemia (ALL) and lymphosarcoma and emerged against ALL in children, neoplasia, and some other malignancies. Cancer cells reduce the expression of l-asparaginase leading to their elimination. The l-asparaginase anticancerous application approach has made incredible breakthrough in the field of modern oncology through depletion of plasma l-asparagine to inhibit the cancer cells growth; particularly among children. High level of l-asparaginase enzyme production by Escherichia coli, Erwinia species, Streptomyces, and Bacillus subtilis species is highly desirable as bacterial alternative enzyme sources for anticancer therapy. Thermal or harsh conditions stability of those from the two latter bacterial species is considerable. Some enzymes from marine bacteria have conferred stability in adverse conditions being more advantageous in cancer therapy. Several side effects exerted by l-asparaginases such as hypersensitivity should be hindered or decreased through alternative therapies or use of immune-suppressor drugs. The l-asparaginase from Erwinia species has displayed remarkable traits in children with this regard. Noticeably, Erwinia chrysanthemi l-asparaginase exhibited negligible glutaminase activity representing a promising efficiency mitigating related side effects. Application of software such as RSM would optimize conditions for higher levels of enzyme production. Additionally, genetic recombination of the encoding gene would indisputably help improving enzyme traits. Furthermore, the possibility of anticancer combination therapy using two or more l-asparaginases from various sources is plausible in future studies to achieve better therapeutic outcomes with lower side effects.