Corrigendum to 'Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics' [Genes & Diseases 10 (2023) 1367-1401].

[This corrects the article DOI: 10.1016/j.gendis.2022.02.007.].

Corrigendum: Antimicrobial resistance in the COVID-19 landscape: is there an opportunity for anti-infective antibodies and antimicrobial peptides?

[This corrects the article DOI: 10.3389/fimmu.2022.921483.].

Cancer chemotherapy and beyond: Current status, drug candidates, associated risks and progress in targeted therapeutics.

Cancer is an abnormal state of cells where they undergo uncontrolled proliferation and produce aggressive malignancies that causes millions of deaths every year. With the new understanding of the molecular mechanism(s) of disease progression, our knowledge about the disease is snowballing, leading to the evolution of many new therapeutic regimes and their successive trials. In the past few decades, various combinations of therapies have been proposed and are presently employed in the treatment of diverse cancers. Targeted drug therapy, immunotherapy, and personalized medicines are now largely being employed, which were not common a few years back. The field of cancer discoveries and therapeutics are evolving fast as cancer type-specific biomarkers are progressively being identified and several types of cancers are nowadays undergoing systematic therapies, extending patients' disease-free survival thereafter. Although growing evidence shows that a systematic and targeted approach could be the future of cancer medicine, chemotherapy remains a largely opted therapeutic option despite its known side effects on the patient's physical and psychological health. Chemotherapeutic agents/pharmaceuticals served a great purpose over the past few decades and have remained the frontline choice for advanced-stage malignancies where surgery and/or radiation therapy cannot be prescribed due to specific reasons. The present report succinctly reviews the existing and contemporary advancements in chemotherapy and assesses the status of the enrolled drugs/pharmaceuticals; it also comprehensively discusses the emerging role of specific/targeted therapeutic strategies that are presently being employed to achieve better clinical success/survival rate in cancer patients.

Harnessing and bioprospecting botanical-based herbal medicines against potential drug targets for COVID-19: a review coupled molecular docking studies.

Since the end of February 2020, the world has come to a standstill due to the virus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). Since then, the global scientific community has explored various remedies and treatments against this virus, including natural products that have always been a choice because of their many benefits. Various known phytochemicals are well documented for their antiviral properties. Research is being carried out to discover new natural plant products or existing ones as a treatment measure for this disease. The three important targets in this regard are-papain like protease (PLpro), spike protein, and 3 chymotrypsin like proteases (3CLpro). Various docking studies are also being elucidated to identify the phytochemicals that modulate crucial proteins of the virus. The paper is simultaneously a comprehensive review that covers recent advances in the domain of the effect of various botanically derived natural products as an alternative treatment approach against Coronavirus Disease 2019 (COVID-19). Furthermore, the docking analyses revealed that rutin (inhibitor of the major protease of SARS-CoV-2), gallocatechin (e.g., interacting with 03 hydrogen bonds with a spike-like protein), lycorine (showing the best binding affinity with amino acids GLN498, THR500 and GLY446 of the spike-like protein), and quercetrin (inhabiting at its residues ASP216, PHE219, and ILE259) are promising inhibitors of SARS­CoV­2.Communicated by Ramaswamy H. Sarma.

Nano-biotechnology in tumour and cancerous disease: A perspective review.

In recent years, drug manufacturers and researchers have begun to consider the nanobiotechnology approach to improve the drug delivery system for tumour and cancer diseases. In this article, we review current strategies to improve tumour and cancer drug delivery, which mainly focuses on sustaining biocompatibility, biodistribution, and active targeting. The conventional therapy using cornerstone drugs such as fludarabine, cisplatin etoposide, and paclitaxel has its own challenges especially not being able to discriminate between tumour versus normal cells which eventually led to toxicity and side effects in the patients. In contrast to the conventional approach, nanoparticle-based drug delivery provides target-specific delivery and controlled release of the drug, which provides a better therapeutic window for treatment options by focusing on the eradication of diseased cells via active targeting and sparing normal cells via passive targeting. Additionally, treatment of tumours associated with the brain is hampered by the impermeability of the blood-brain barriers to the drugs, which eventually led to poor survival in the patients. Nanoparticle-based therapy offers superior delivery of drugs to the target by breaching the blood-brain barriers. Herein, we provide an overview of the properties of nanoparticles that are crucial for nanotechnology applications. We address the potential future applications of nanobiotechnology targeting specific or desired areas. In particular, the use of nanomaterials, biostructures, and drug delivery methods for the targeted treatment of tumours and cancer are explored.

Therapeutic properties and pharmacological activities of asiaticoside and madecassoside: A review.

Centella asiatica is an ethnomedicinal herbaceous species that grows abundantly in tropical and sub-tropical regions of China, India, South-Eastern Asia and Africa. It is a popular nutraceutical that is employed in various forms of clinical and cosmetic treatments. C. asiatica extracts are reported widely in Ayurvedic and Chinese traditional medicine to boost memory, prevent cognitive deficits and improve brain functions. The major bioactive constituents of C. asiatica are the pentacyclic triterpenoid glycosides, asiaticoside and madecassoside, and their corresponding aglycones, asiatic acid and madecassic acid. Asiaticoside and madecassoside have been identified as the marker compounds of C. asiatica in the Chinese Pharmacopoeia and these triterpene compounds offer a wide range of pharmacological properties, including neuroprotective, cardioprotective, hepatoprotective, wound healing, anti-inflammatory, anti-oxidant, anti-allergic, anti-depressant, anxiolytic, antifibrotic, antibacterial, anti-arthritic, anti-tumour and immunomodulatory activities. Asiaticoside and madecassoside are also used extensively in treating skin abnormalities, burn injuries, ischaemia, ulcers, asthma, lupus, psoriasis and scleroderma. Besides medicinal applications, these phytocompounds are considered cosmetically beneficial for their role in anti-ageing, skin hydration, collagen synthesis, UV protection and curing scars. Existing reports and experimental studies on these compounds between 2005 and 2022 have been selectively reviewed in this article to provide a comprehensive overview of the numerous therapeutic advantages of asiaticoside and madecassoside and their potential roles in the medical future.

Translational aspect in peptide drug discovery and development: An emerging therapeutic candidate.

In the last two decades, protein-protein interactions (PPIs) have been used as the main target for drug development. However, with larger or superficial binding sites, it has been extremely difficult to disrupt PPIs with small molecules. On the other hand, intracellular PPIs cannot be targeted by antibodies that cannot penetrate the cell membrane. Peptides that have a combination of conformational rigidity and flexibility can be used to target difficult binding interfaces with appropriate binding affinity and specificity. Since the introduction of insulin nearly a century ago, more than 80 peptide drugs have been approved to treat a variety of diseases. These include deadly diseases such as cancer and human immunodeficiency virus infection. It is also useful against diabetes, chronic pain, and osteoporosis. Today, more research is being done on these drugs as lessons learned from earlier approaches, which are still valid today, complement newer approaches such as peptide display libraries. At the same time, integrated genomics and peptide display libraries are new strategies that open new avenues for peptide drug discovery. The purpose of this review is to examine the problems in elucidating the peptide-protein recognition mechanism. This is important to develop peptide-based interventions that interfere with endogenous protein interactions. New approaches are being developed to improve the binding affinity and specificity of existing approaches and to develop peptide agents as potentially useful drugs. We also highlight the key challenges that must be overcome in peptide drug development to realize their potential and provide an overview of recent trends in peptide drug development. In addition, we take an in-depth look at early efforts in human hormone discovery, smart medicinal chemistry and design, natural peptide drugs, and breakthrough advances in molecular biology and peptide chemistry.

Traditional uses, phytochemistry, pharmacology and toxicology of garlic (Allium sativum), a storehouse of diverse phytochemicals: A review of research from the last decade focusing on health and nutritional implications.

Allium sativum L. (Garlic) is a fragrant herb and tuber-derived spice that is one of the most sought-after botanicals, used as a culinary and ethnomedicine for a variety of diseases around the world. An array of pharmacological attributes such as antioxidant, hypoglycemic, anti-inflammatory, antihyperlipidemic, anticancer, antimicrobial, and hepatoprotective activities of this species have been established by previous studies. A. sativum houses many sulfur-containing phytochemical compounds such as allicin, diallyl disulfide (DADS), vinyldithiins, ajoenes (E-ajoene, Z-ajoene), diallyl trisulfide (DATS), micronutrient selenium (Se) etc. Organosulfur compounds are correlated with modulations in its antioxidant properties. The garlic compounds have also been recorded as promising immune-boosters or act as potent immunostimulants. A. sativum helps to treat cardiovascular ailments, neoplastic growth, rheumatism, diabetes, intestinal worms, flatulence, colic, dysentery, liver diseases, facial paralysis, tuberculosis, bronchitis, high blood pressure, and several other diseases. The present review aims to comprehensively enumerate the ethnobotanical and pharmacological aspects of A. sativum with notes on its phytochemistry, ethnopharmacology, toxicological aspects, and clinical studies from the retrieved literature from the last decade with notes on recent breakthroughs and bottlenecks. Future directions related to garlic research is also discussed.

Cellular landscaping of cisplatin resistance in cervical cancer.

Cervical cancer (CC) caused by human papillomavirus (HPV) is one of the largest causes of malignancies in women worldwide. Cisplatin is one of the widely used drugs for the treatment of CC is rendered ineffective owing to drug resistance. This review highlights the cause of resistance and the mechanism of cisplatin resistance cells in CC to develop therapeutic ventures and strategies that could be utilized to overcome the aforementioned issue. These strategies would include the application of nanocarries, miRNA, CRIPSR/Cas system, and chemotherapeutics in synergy with cisplatin to not only overcome the issues of drug resistance but also enhance its anti-cancer efficiency. Moreover, we have also discussed the signaling network of cisplatin resistance cells in CC that would provide insights to develop therapeutic target sites and inhibitors. Furthermore, we have discussed the role of CC metabolism on cisplatin resistance cells and the physical and biological factors affecting the tumor microenvironments.

Antimicrobial Resistance in the COVID-19 Landscape: Is There an Opportunity for Anti-Infective Antibodies and Antimicrobial Peptides?

Although COVID-19 has captured most of the public health attention, antimicrobial resistance (AMR) has not disappeared. To prevent the escape of resistant microorganisms in animals or environmental reservoirs a "one health approach" is desirable. In this context of COVID-19, AMR has probably been affected by the inappropriate or over-use of antibiotics. The increased use of antimicrobials and biocides for disinfection may have enhanced the prevalence of AMR. Antibiotics have been used empirically in patients with COVID-19 to avoid or prevent bacterial coinfection or superinfections. On the other hand, the measures to prevent the transmission of COVID-19 could have reduced the risk of the emergence of multidrug-resistant microorganisms. Since we do not currently have a sterilizing vaccine against SARS-CoV-2, the virus may still multiply in the organism and new mutations may occur. As a consequence, there is a risk of the appearance of new variants. Nature-derived anti-infective agents, such as antibodies and antimicrobial peptides (AMPs), are very promising in the fight against infectious diseases, because they are less likely to develop resistance, even though further investigation is still required.

Potential Therapeutic Targets and Vaccine Development for SARS-CoV-2/COVID-19 Pandemic Management: A Review on the Recent Update.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly pathogenic novel virus that has caused a massive pandemic called coronavirus disease 2019 (COVID-19) worldwide. Wuhan, a city in China became the epicenter of the outbreak of COVID-19 in December 2019. The disease was declared a pandemic globally by the World Health Organization (WHO) on 11 March 2020. SARS-CoV-2 is a beta CoV of the Coronaviridae family which usually causes respiratory symptoms that resemble common cold. Multiple countries have experienced multiple waves of the disease and scientific experts are consistently working to find answers to several unresolved questions, with the aim to find the most suitable ways to contain the virus. Furthermore, potential therapeutic strategies and vaccine development for COVID-19 management are also considered. Currently, substantial efforts have been made to develop successful and safe treatments and SARS-CoV-2 vaccines. Some vaccines, such as inactivated vaccines, nucleic acid-based, and vector-based vaccines, have entered phase 3 clinical trials. Additionally, diverse small molecule drugs, peptides and antibodies are being developed to treat COVID-19. We present here an overview of the virus interaction with the host and environment and anti-CoV therapeutic strategies; including vaccines and other methodologies, designed for prophylaxis and treatment of SARS-CoV-2 infection with the hope that this integrative analysis could help develop novel therapeutic approaches against COVID-19.

Can Immunization of Hens Provide Oral-Based Therapeutics against COVID-19?

In the current worldwide pandemic situation caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the newest coronavirus disease (COVID-19), therapeutics and prophylactics are urgently needed for a large population. Some of the prophylaxis strategies are based on the development of antibodies targeting viral proteins. IgY antibodies are a type of immunoglobulin present in birds, amphibians, and reptiles. They are usually obtained from egg yolk of hyper-immunized hens and represent a relatively inexpensive source of antibodies. Specific IgY can be produced by immunizing chickens with the target antigen and then purifying from the egg yolk. Chicken IgY has been widely explored as a clinical anti-infective material for prophylaxis, preventive medicine, and therapy of infectious diseases. Administered non-systemically, IgY antibodies are safe and effective drugs. Moreover, passive immunization with avian antibodies could become an effective alternative therapy, as these can be obtained relatively simply, cost-efficiently, and produced on a large scale. Here, we highlight the potential use of polyclonal avian IgY antibodies as an oral prophylactic treatment for respiratory viral diseases, such as COVID-19, for which no vaccine is yet available.

Bacterial membranes enhance the immunogenicity and protective capacity of the surface exposed tick Subolesin-Anaplasma marginale MSP1a chimeric antigen.

Ticks are vectors of diseases that affect humans and animals worldwide. Tick vaccines have been proposed as a cost-effective and environmentally sound alternative for tick control. Recently, the Rhipicephalus microplus Subolesin (SUB)-Anaplasma marginale MSP1a chimeric antigen was produced in Escherichia coli as membrane-bound and exposed protein and used to protect vaccinated cattle against tick infestations. In this research, lipidomics and proteomics characterization of the E. coli membrane-bound SUB-MSP1a antigen showed the presence of components with potential adjuvant effect. Furthermore, vaccination with membrane-free SUB-MSP1a and bacterial membranes containing SUB-MSP1a showed that bacterial membranes enhance the immunogenicity of the SUB-MSP1a antigen in animal models. R. microplus female ticks were capillary-fed with sera from pigs orally immunized with membrane-free SUB, membrane bound SUB-MSP1a and saline control. Ticks ingested antibodies added to the blood meal and the effect of these antibodies on reduction of tick weight was shown for membrane bound SUB-MSP1a but not SUB when compared to control. Using the simple and cost-effective process developed for the purification of membrane-bound SUB-MSP1a, endotoxin levels were within limits accepted for recombinant vaccines. These results provide further support for the development of tick vaccines using E. coli membranes exposing chimeric antigens such as SUB-MSP1a.

Prospects for vaccination against the ticks of pets and the potential impact on pathogen transmission.

Diseases transmitted by arthropod vectors such as ticks greatly impact human and animal health. In particular, many diseases of dogs and cats are potentially transmissible to people by arthropod vectors and therefore their control is important for the eradication of vector-borne diseases (VBD). Vaccination is an environmentally friendly alternative for vector control that allows control of several VBD by targeting their common vector. Recent results have shown that it is possible to use vector protective antigens for the control of arthropod vector infestations and pathogen infection. However, as reviewed in this paper, very little progress has been made for the control of ectoparasite infestations and VBD in pets using vaccination with vector protective antigens. The growing interaction between pets and people underlines the importance of developing new interventions for the monitoring and control of VBD.

Tonsils of the soft palate do not mediate the response of pigs to oral vaccination with heat-inactivated Mycobacterium bovis.

Mycobacterium bovis causes animal tuberculosis (TB) in cattle, humans, and other mammalian species, including pigs. The goal of this study was to experimentally assess the responses of pigs with and without a history of tonsillectomy to oral vaccination with heat-inactivated M. bovis and challenge with a virulent M. bovis field strain, to compare pig and wild boar responses using the same vaccination model as previously used in the Eurasian wild boar (Sus scrofa), to evaluate the use of several enzyme-linked immunosorbent assays (ELISAs) and lateral flow tests for in vivo TB diagnosis in pigs, and to verify if these tests are influenced by oral vaccination with inactivated M. bovis. At necropsy, the lesion and culture scores were 20% to 43% higher in the controls than those in the vaccinated pigs. Massive M. bovis growth from thoracic tissue samples was observed in 4 out of 9 controls but in none of the 10 vaccinated pigs. No effect of the presence or absence of tonsils was observed on these scores, suggesting that tonsils are not involved in the protective response to this vaccine in pigs. The serum antibody levels increased significantly only after challenge. At necropsy, the estimated sensitivities of the ELISAs and dual path platform (DPP) assays ranged from 89% to 94%. In the oral mucosa, no differences in gene expression were observed in the control group between the pigs with and without tonsils. In the vaccinated group, the mRNA levels for chemokine (C-C motif) receptor 7 (CCR7), interferon beta (IFN-ß), and methylmalonyl coenzyme A mutase (MUT) were higher in pigs with tonsils. Complement component 3 mRNA levels in peripheral blood mononuclear cells (PBMC) increased with vaccination and decreased after M. bovis challenge. This information is relevant for pig production in regions that are endemic for M. bovis and for TB vaccine research.

Oral vaccination with heat inactivated Mycobacterium bovis activates the complement system to protect against tuberculosis.

Tuberculosis (TB) remains a pandemic affecting billions of people worldwide, thus stressing the need for new vaccines. Defining the correlates of vaccine protection is essential to achieve this goal. In this study, we used the wild boar model for mycobacterial infection and TB to characterize the protective mechanisms elicited by a new heat inactivated Mycobacterium bovis vaccine (IV). Oral vaccination with the IV resulted in significantly lower culture and lesion scores, particularly in the thorax, suggesting that the IV might provide a novel vaccine for TB control with special impact on the prevention of pulmonary disease, which is one of the limitations of current vaccines. Oral vaccination with the IV induced an adaptive antibody response and activation of the innate immune response including the complement component C3 and inflammasome. Mycobacterial DNA/RNA was not involved in inflammasome activation but increased C3 production by a still unknown mechanism. The results also suggested a protective mechanism mediated by the activation of IFN-γ producing CD8+ T cells by MHC I antigen presenting dendritic cells (DCs) in response to vaccination with the IV, without a clear role for Th1 CD4+ T cells. These results support a role for DCs in triggering the immune response to the IV through a mechanism similar to the phagocyte response to PAMPs with a central role for C3 in protection against mycobacterial infection. Higher C3 levels may allow increased opsonophagocytosis and effective bacterial clearance, while interfering with CR3-mediated opsonic and nonopsonic phagocytosis of mycobacteria, a process that could be enhanced by specific antibodies against mycobacterial proteins induced by vaccination with the IV. These results suggest that the IV acts through novel mechanisms to protect against TB in wild boar.

Tick capillary feeding for the study of proteins involved in tick-pathogen interactions as potential antigens for the control of tick infestation and pathogen infection.

BACKGROUND: Ticks represent a significant health risk to animals and humans due to the variety of pathogens they can transmit during feeding. The traditional use of chemicals to control ticks has serious drawbacks, including the selection of acaricide-resistant ticks and environmental contamination with chemical residues. Vaccination with the tick midgut antigen BM86 was shown to be a good alternative for cattle tick control. However, results vary considerably between tick species and geographic location. Therefore, new antigens are required for the development of vaccines controlling both tick infestations and pathogen infection/transmission. Tick proteins involved in tick-pathogen interactions may provide good candidate protective antigens for these vaccines, but appropriate screening procedures are needed to select the best candidates. METHODS: In this study, we selected proteins involved in tick-Anaplasma (Subolesin and SILK) and tick-Babesia (TROSPA) interactions and used in vitro capillary feeding to characterize their potential as antigens for the control of cattle tick infestations and infection with Anaplasma marginale and Babesia bigemina. Purified rabbit polyclonal antibodies were generated against recombinant SUB, SILK and TROSPA and added to uninfected or infected bovine blood to capillary-feed female Rhipicephalus (Boophilus) microplus ticks. Tick weight, oviposition and pathogen DNA levels were determined in treated and control ticks. RESULTS: The specificity of purified rabbit polyclonal antibodies against tick recombinant proteins was confirmed by Western blot and against native proteins in tick cell lines and tick tissues using immunofluorescence. Capillary-fed ticks ingested antibodies added to the blood meal and the effect of these antibodies on tick weight and oviposition was shown. However, no effect was observed on pathogen DNA levels. CONCLUSIONS: These results highlighted the advantages and some of the disadvantages of in vitro tick capillary feeding for the characterization of candidate tick protective antigens. While an effect on tick weight and oviposition was observed, the effect on pathogen levels was not evident probably due to high tick-to-tick variations among other factors. Nevertheless, these results together with previous results of RNA interference functional studies suggest that these proteins are good candidate vaccine antigens for the control of R. microplus infestations and infection with A. marginale and B. bigemina.

Vaccination with proteins involved in tick-pathogen interactions reduces vector infestations and pathogen infection.

Tick-borne pathogens cause diseases that greatly impact animal health and production worldwide. The ultimate goal of tick vaccines is to protect against tick-borne diseases through the control of vector infestations and reducing pathogen infection and transmission. Tick genetic traits are involved in vector-pathogen interactions and some of these molecules such as Subolesin (SUB) have been shown to protect against vector infestations and pathogen infection. Based on these premises, herein we characterized the efficacy of cattle vaccination with tick proteins involved in vector-pathogen interactions, TROSPA, SILK, and Q38 for the control of cattle tick, Rhipicephalus (Boophilus) microplus infestations and infection with Anaplasma marginale and Babesia bigemina. SUB and adjuvant/saline placebo were used as positive and negative controls, respectively. The results showed that vaccination with Q38, SILK and SUB reduced tick infestations and oviposition with vaccine efficacies of 75% (Q38), 62% (SILK) and 60% (SUB) with respect to ticks fed on placebo control cattle. Vaccination with TROSPA did not have a significant effect on any of the tick parameters analyzed. The results also showed that vaccination with Q38, TROSPA and SUB reduced B. bigemina DNA levels in ticks while vaccination with SILK and SUB resulted in lower A. marginale DNA levels when compared to ticks fed on placebo control cattle. The positive correlation between antigen-specific antibody titers and reduction of tick infestations and pathogen infection strongly suggested that the effect of the vaccine was the result of the antibody response in vaccinated cattle. Vaccination and co-infection with A. marginale and B. bigemina also affected the expression of genes encoding for vaccine antigens in ticks fed on cattle. These results showed that vaccines using tick proteins involved in vector-pathogen interactions could be used for the dual control of tick infestations and pathogen infection.

Tick vaccines and the control of tick-borne pathogens.

Ticks are obligate hematophagous ectoparasites that transmit a wide variety of pathogens to humans and animals. The incidence of tick-borne diseases has increased worldwide in both humans and domestic animals over the past years resulting in greater interest in the study of tick-host-pathogen interactions. Advances in vector and pathogen genomics and proteomics have moved forward our knowledge of the vector-pathogen interactions that take place during the colonization and transmission of arthropod-borne microbes. Tick-borne pathogens adapt from the vector to the mammalian host by differential gene expression thus modulating host processes. In recent years, studies have shown that targeting tick proteins by vaccination can not only reduce tick feeding and reproduction, but also the infection and transmission of pathogens from the tick to the vertebrate host. In this article, we review the tick-protective antigens that have been identified for the formulation of tick vaccines and the effect of these vaccines on the control of tick-borne pathogens.

Reciprocal regulation of NF-kB (Relish) and Subolesin in the tick vector, Ixodes scapularis.

BACKGROUND: Tick Subolesin and its ortholog in insects and vertebrates, Akirin, have been suggested to play a role in the immune response through regulation of nuclear factor-kappa B (NF-kB)-dependent and independent gene expression via interaction with intermediate proteins that interact with NF-kB and other regulatory proteins, bind DNA or remodel chromatin to regulate gene expression. The objective of this study was to characterize the structure and regulation of subolesin in Ixodes scapularis. I. scapularis is a vector of emerging pathogens such as Borrelia burgdorferi, Anaplasma phagocytophilum and Babesia microti that cause in humans Lyme disease, anaplasmosis and babesiosis, respectively. The genome of I. scapularis was recently sequenced, and this tick serves as a model organism for the study of vector-host-pathogen interactions. However, basic biological questions such as gene organization and regulation are largely unknown in ticks and other arthropod vectors. PRINCIPAL FINDINGS: The results presented here provide evidence that subolesin/akirin are evolutionarily conserved at several levels (primary sequence, gene organization and function), thus supporting their crucial biological function in metazoans. These results showed that NF-kB (Relish) is involved in the regulation of subolesin expression in ticks, suggesting that as in other organisms, different NF-kB integral subunits and/or unknown interacting proteins regulate the specificity of the NF-kB-mediated gene expression. These results suggested a regulatory network involving cross-regulation between NF-kB (Relish) and Subolesin and Subolesin auto-regulation with possible implications in tick immune response to bacterial infection. SIGNIFICANCE: These results advance our understanding of gene organization and regulation in I. scapularis and have important implications for arthropod vectors genetics and immunology highlighting the possible role of NF-kB and Subolesin/Akirin in vector-pathogen interactions and for designing new strategies for the control of vector infestations and pathogen transmission.