Specific Receptors Research Articles

Antimicrobial Neuropeptides and Their Receptors: Immunoregulator and Therapeutic Targets for Immune Disorders

The interaction between the neuroendocrine system and the immune system plays a key role in the onset and progression of various diseases. Neuropeptides, recognized as common biochemical mediators of communication between these systems, are receiving increasing attention because of their potential therapeutic applications in immune-related disorders. Additionally, many neuropeptides share significant similarities with antimicrobial peptides (AMPs), and evidence shows that these antimicrobial neuropeptides are directly involved in innate immunity. This review examines 10 antimicrobial neuropeptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), α-melanocyte stimulating hormone (α-MSH), ghrelin, adrenomedullin (AM), neuropeptide Y (NPY), urocortin II (UCN II), calcitonin gene-related peptide (CGRP), substance P (SP), and catestatin (CST). Their expression characteristics and the immunomodulatory mechanisms mediated by their specific receptors are summarized, along with potential drugs targeting these receptors. Future studies should focus on further investigating antimicrobial neuropeptides and advancing the development of related drugs in preclinical and/or clinical studies to improve the treatment of immune-related diseases.

Sphingosine-1-Phosphate Metabolic Pathway in Cancer: Implications for Therapeutic Targets

Cancer biology revolves around understanding how cells undergo uncontrolled proliferation leading to the formation of malignant tumors. Key aspects include self-sufficiency in growth signals, the lack of response to signals of growth inhibition, the evasion of apoptosis, sustained angiogenesis, the evasion of immune response, the capacity to invade and metastasize, and alterations in cellular metabolism. A vast amount of research, which is exponentially growing, over the past few decades highlights the role of sphingolipids in cancer. They act not only as structural membrane components but also as bioactive molecules that regulate cell fate in different physio-pathological conditions. In cancer, sphingolipid metabolism is dysregulated, contributing to tumor progression, metastasis, and drug resistance. In this review, we outline the impact of sphingosine-1-phosphate (S1P) as a key bioactive sphingolipid in cancer. We give an overview of its metabolism summarizing the role of S1P as an intracellular and extracellular mediator through specific plasma membrane receptors in different cancers. We also describe previous findings on how the disruption in the balance between S1P and ceramide (Cer) is common in cancer cells and can contribute to tumorigenesis and resistance to chemotherapy. We finally consider the potential of targeting the metabolic pathways of S1P as well as its receptors and transporters as a promising therapeutic approach in cancer treatments.

Gintonin Binds to Reduced LPA4 Receptor Subtype in Human Cortical Neurons in Alzheimer’s Disease Brains

Ginseng, a traditional herbal medicine with a long history of use, is known to support human health, particularly by influencing brain function. Recent studies have identified gintonin, a lysophosphatidic acid (LPA) receptor ligand derived from ginseng, as a key bioactive. However, the specific LPA receptor subtypes targeted by gintonin in the human brain to exert its anti-Alzheimer’s (AD) effects remain unclear. This study aimed to elucidate the LPA receptor subtype targeted by gintonin in the human cortex. Using a fluorescent gintonin conjugate, we investigated receptor binding in cortical samples from healthy individuals (n = 4) and AD patients (n = 4). Our results demonstrated that fluorescent gintonin selectively binds to human cortical neurons rather than glial cells and that gintonin-binding sites are co-localized with the LPA4 receptor subtype. Furthermore, the expression of LPA4 receptors was significantly reduced in the cortical neurons of AD patients. These results suggest that the LPA4 receptor may serve as a novel histopathological marker for AD and represent a promising therapeutic target for gintonin-based prevention and treatment strategies.

Therapeutics of bitter plants from Northeast region of India and their pharmacological and phytochemical perspectives.

Natural resources have been used for food and medicine since the beginning of human civilization, and they have always been a low-cost, easily accessible source for individuals. Northeast region of India (NER) represents a significant portion of India's flora and fauna. Marginality, fragility, inaccessibility, ethnicity, and cultural diversity thrived in the region, resulting in the richest reservoir of genetic variation of bioresources. Several bitter plants are used by the locals as both food and medicine to treat a variety of diseases. These medicinal plants are an excellent source of chemically diverse biologically active phytometabolites. There have been few efforts to raise awareness about health benefits of bitter plant resources abound in this region that may provides opportunities for their sustainable utilization. Understanding the structural features of plant derived bitterants in relationship with specific bitter receptor will provide research prospects to identify biomolecules with health benefits. In this context the present review is intended to deliver phyto-pharmacological aspects of bitter plant resources of NER together with detailed understanding of possible association between plant derived phytometabolites as bitter agonists with extraoral bitter receptors.

Receptor-ligand interactions for optimized endocytosis in targeted therapies.

Receptor-mediated endocytosis plays a crucial role in the success of numerous therapies and remains central to advancing drug development. This process begins with ligand binding to specific receptors, triggering the internalization and intracellular trafficking of receptor-ligand complexes. These complexes are subsequently directed into distinct routes, either toward lysosomal degradation or recycling to the cell surface, with implications for therapeutic outcomes. This review examines receptor-ligand interactions as key modulators of endocytosis, emphasizing their role in shaping therapeutic design and efficacy. Advances in selecting receptor-ligand pairs and engineering ligands with optimized properties have enabled precise control over internalization, endosomal sorting, and trafficking, providing tailored solutions for diverse therapeutic applications. Leveraging these insights, strategies such as RNA-based therapies, antibody-drug conjugates (ADCs), and targeted protein degradation (TPD) platforms have been refined to selectively avoid or promote lysosomal degradation, thereby enhancing therapeutic efficacy. By bridging fundamental mechanisms of receptor-mediated endocytosis with innovative therapeutic approaches, this review offers a framework for advancing precision medicine.

Regulation of tick attachment and rapid engorgement via dopamine receptors in the Asian longhorned tick Haemaphysalis longicornis.

Dopamine plays multifaceted roles in the physiology of insects and ticks, acting as a key neurotransmitter and modulator of various biological processes. In ticks, it plays a particularly important role in regulating salivary gland function, which is essential for successful tick feeding on hosts. Salivary secretion in ticks is orchestrated by the collection of saliva in the acinar lumen mediated by the dopamine receptor (D1) and the expulsion of collected saliva into the salivary duct mediated by the invertebrate specific D1-like dopamine receptor (InvD1L). However, the function of dopamine receptors in different feeding stages and other tissues remains unclear. In this study, D1 and InvD1L of Haemaphysalis longicornis (Haelo-D1 and Haelo-InvD1L, respectively) were found to be involved in tick attachment and the rapid phase of blood feeding. Both receptors were identified and profiled in the synganglion, salivary glands, and midgut of H. longicornis females across different feeding stages. Functional analyses revealed that both receptors were activated by dopamine in a concentration-dependent manner with distinct sensitivities. RNA interference (RNAi) targeting these receptors significantly reduced dopamine-mediated salivation and delayed tick attachment and blood feeding. Furthermore, RNAi prolonged rapid engorgement phases and reduced the final body weight of replete ticks. These results highlight the crucial roles of D1 and InvD1L in regulating salivary secretion in ixodid ticks and facilitating their attachment and rapid engorgement, thereby offering potential targets for novel tick control strategies aimed at disrupting feeding and reducing pathogen transmission.

Navigating liver cancer: Precision targeting for enhanced treatment outcomes.

Cancer treatments such as surgery and chemotherapy have several limitations, including ineffectiveness against large or persistent tumors, high relapse rates, drug toxicity, and non-specificity of therapy. Researchers are exploring advanced strategies for treating this life-threatening disease to address these challenges. One promising approach is targeted drug delivery using prodrugs or surface modification with receptor-specific moieties for active or passive targeting. While various drug delivery systems have shown potential for reaching hepatic cells, nano-carriers offer significant size, distribution, and targetability advantages. Engineered nanocarriers can be customized to achieve effective and safe targeting of tumors by manipulating physical characteristics such as particle size or attaching receptor-specific ligands. This method is particularly advantageous in treating liver cancer by targeting specific hepatocyte receptors and enzymatic pathways for both passive and active therapeutic strategies. It highlights the epidemiology of liver cancer and provides an in-depth analysis of the various targeting approaches, including prodrugs, liposomes, magneto-liposomes, micelles, glycol-dendrimers, magnetic nanoparticles, chylomicron-based emulsion, and quantum dots surface modification with receptor-specific moieties. The insights from this review can be immensely significant for preclinical and clinical researchers working towards developing effective treatments for liver cancer. By utilizing these novel strategies, we can overcome the limitations of conventional therapies and offer better outcomes for liver cancer patients.

Folate metabolism in myelofibrosis: a missing key?

Folates serve as key enzyme cofactors in several biological processes. Folic acid supplementation is a cornerstone practice but may have a "dark side". Indeed, the accumulation of circulating unmetabolized folic acid (UMFA) has been associated with various chronic inflammatory conditions, including cancer. Additionally, by engaging specific folate receptors, folates can directly stimulate cancer cells and modulate the expression of genes coding for pro-inflammatory and pro-fibrotic cytokines.This evidence could be extremely relevant for myelofibrosis (MF), a chronic myeloproliferative neoplasm typified by the unique combination of clonal proliferation, chronic inflammation, and progressive bone marrow fibrosis. Folate supplementation is frequently associated with conventional or investigational drugs in the treatment of MF-related anemia to tackle ineffective erythropoiesis. In this review, we cover the different aspects of folate metabolism entailed in the behavior and function of normal and malignant hematopoietic cells and discuss the potential implications on the biology of myelofibrosis.

CX3CL1 Regulation of Gliosis in Neuroinflammatory and Neuroprotective Processes

Among the different chemokines, C-X3-C motif chemokine ligand 1 or CX3CL1, also named fractalkine, is one of the most interesting due to its characteristics, including its unique structure, not shared by any other chemokine, and its ability to function both in a membrane-bound form and in a soluble form, among others. However, undoubtedly, its most relevant characteristic from the neuroscientific point of view is its role as a messenger used by neurons to communicate with microglia. The study of the interaction between both cell types and the key role that CX3CL1 seems to play has facilitated the identification of CX3CL1 as a crucial modulator of microglial activation and a promising target in the fight against neuroinflammation. As a result, numerous studies have contributed to elucidate the involvement of CX3CL1 and its specific receptor CCX3CR1 in the progression of different neuroinflammatory and neurodegenerative processes, with Alzheimer’s and Parkinson’s diseases being the most studied ones. However, the different animal and cellular models used to reproduce the pathological conditions to be analyzed, as well as the difficulties inherent to studies performed on human samples, have hindered the collection of compatible results in many cases. In this review, we summarize some of the most relevant data describing the alterations found for the CX3CL1/CX3CR1 signaling axis in different neurodegenerative conditions in which neuroinflammation is known to play a relevant role.

DOP023 Bifidobacterium-candida warfare in the gut of patients with ulcerative colitis

Abstract Background C. albicans is identified more frequently in the gut of patients with active ulcerative colitis (UC), and may drive inflammation through activation of specific fungal receptors in the intestine. Pathogenic expansion of C. albicans in UC may occur due to loss of specific protective bacterial strains. Prior work has suggested that Bifidobacterium species may antagonize Candida species. However, relationships of Bifidobacterium species with Candida species in patients with UC are not known, and whether Bifidobacterium may mechanistically suppress C. albicans growth is unclear. Methods We utilized data from the Study of a Prospective Adult Research Cohort with IBD to interrogate relationships between fungal and bacterial species during varying inflammatory phases of UC. Relative abundances of fungal and bacterial taxa was obtained from 18 internal transcribed spacer sequences and shotgun sequences. Spearman’s correlations between fungal and bacterial relative abundance were performed. To further assess observed bacterial-fungal correlations in vitro, cell-free supernatants from lab-derived and patient-derived strains were utilized to assess their suppressive ability in competitive assays. Results We found that C. albicans is increased in active UC vs during remission (q-val <0.05). Across all patients, 15 unique Bifidobacterium species were identified, including B. adolescentis, B. longum, and B. bifidum [Fig 1A]. The relative abundance of fecal B. adolescentis was negatively associated with C. albicans abundance in UC (p<0.05) [1B]. Multiple strains of B. adolescentis were detected [1C], although these strains did not demonstrate significant genetic variability when compared to a reference marker [1D]. We further observed that cell-free supernatants from lab-derived strains of both Bifidobacterium adolescentis (ATCC 15703) and Bifidobacterium bifidum (ATCC 29521) were able to inhibit C. albicans (ATCC 18804) growth [2CD], while cell-free supernatants from control species Blautia producta (ATCC 27340) only showed partial inhibition of C. albicans [2B]. Using donated fecal samples from 7 patients with active UC, we were able to isolate in culture 11 separate isolates of Bifidobacterium strains (confirmed by MALDI-TOF), and 1 isolate of Candida species, with inhibitory assays between patient derived strains ongoing. Conclusion Bifidobacterium adolescentis is negatively associated with C. albicans in fecal samples from UC patients. Both B. adolescentis and B. bifidum strains completely suppress C. albicans growth in vitro. Bifidobacterium species may provide colonization resistance against C. albicans in the UC gut. Loss of Bifidobacterium strains may allow for C. albicans expansion which may contribute to inflammation and relapse.

Serotonin receptor 5-HT7 modulates inflammatory-associated functions of macrophages

The hormone and neurotransmitter serotonin regulates numerous physiological functions within the central nervous system and in the periphery upon binding to specific receptors. In the periphery, the serotonin receptor 7 (5-HT7R) is expressed on different immune cells including monocytes and macrophages. To investigate the impact of 5-HT7R-mediated signaling on macrophage properties, we used human THP-1 cells and differentiated them into pro-inflammatory M1- and anti-inflammatory M2-like macrophages. Pharmacological 5-HT7R activation with the specific agonist LP-211 especially modulates morphology of M1-like macrophages by increasing the number of rounded cells. Furthermore, 5-HT7R stimulation results in significantly reduced phagocytic and migratory ability of M1-like macrophages. Noteworthy, LP-211 treatment leads to changes in secretory properties of all macrophage types with the highest effects obtained for M0- and M2c-like macrophages. Finally, the importance of 5-HT7R for regulation of phagocytosis was confirmed in human primary CD14+ cells. These results indicate that 5-HT7R activation selectively impairs basic functions of macrophages and might thus be a new access point for the modulation of macrophage responses in the future treatment of inflammatory diseases.

Exploring Genetic and Receptor-Based Dopaminergic Strategies for Antidepressant Drug Development.

The dopamine (DA) system is central to mood regulation, motivation, and reward processing, making it a critical focus for understanding Major Depressive Disorder (MDD). While the dopaminergic system's role in MDD pathophysiology has been acknowledged, gaps remain in linking specific receptor subtypes and genetic factors to depression-like phenotypes. This study explores the interplay between dopamine receptor subtypes (D1-D5) and associated genetic variations, particularly focusing on receptor heterodimers and polymorphisms influencing dopamine biosynthesis, signalling, and metabolism. A comprehensive review of molecular mechanisms highlights key findings: alterations in D1-D2 heterodimers contribute to mood dysregulation; D3 receptor downregulation correlates with depressive behaviour; and genetic polymorphisms, including those in tyrosine hydroxylase and dopamine transporter (DAT) genes, influence dopamine levels and receptor functions. Emerging data from neuroimaging and animal models confirm the pivotal role of dopamine receptor subtypes in MDD, offering insights into their therapeutic targeting. Here, we show that dopaminergic dysfunction underpins MDD's pathophysiology, with receptor-specific mechanisms presenting novel drug targets. Understanding these pathways facilitates precision medicine approaches, bridging the gap between genetic predisposition and receptor pharmacology, and paving the way for tailored antidepressant strategies with improved efficacy and reduced side effects.

Comprehensive review of plant small signaling peptides: From stress adaptation mechanisms to practical solutions for crop resilience.

Small signaling peptides (SSPs), short proteins of fewer than 100 amino acids, serve as pivotal signaling molecules with diverse structural features, post-translational modifications, and functional roles. They regulate various aspects of plant growth and development by modulating specific cellular signaling pathways. Research has shown that many SSPs are essential for mediating responses to environmental stresses. This review presents the structure, characteristics, and classification of plant SSPs and elucidates their roles in resistance signaling pathways through interactions with their specific receptors. We then summarize recent findings on the biological functions and regulatory mechanisms of SSPs in response to both biotic and abiotic stresses. Finally, we discuss the potential applications and future prospects of these peptides in plant protection. This review offers valuable insights for enhancing plant resilience to environmental stress and advancing sustainable agricultural practices, while also providing key references and perspectives to accelerate research on SSPs in plants.

T cells in cardiac health and disease.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, with inflammation playing a pivotal role in its pathogenesis. T lymphocytes are crucial components of the adaptive immune system that have emerged as key mediators in both cardiac health and the development and progression of CVD. This Review explores the diverse roles of T cell subsets, including Th1, Th17, γδ T cells, and Tregs, in myocardial inflammatory processes such as autoimmune myocarditis and myocardial infarction. We discuss the contribution of T cells to myocardial injury and remodeling, with emphasis on specific immune receptors, e.g., CD69, that have a critical role in regulating immune tolerance and maintaining the balance between T cell subsets in the heart. Additionally, we offer a perspective on recent advances in T cell-targeted therapies and their potential to modulate immune responses and improve clinical outcomes in patients with CVD and in heart transplant recipients. Understanding the intricate interplay between T cells and cardiovascular pathology is essential for developing novel immunotherapeutic strategies against CVD.

The experience of using an opioid peptide (tyrosyl-D-arginyl-phenylalanyl-glycine amide) in oncological practice

BACKGROUND: The use of tyrosyl-D-arginyl-phenylalanine-glycine amide, a highly specific μ1-opioid receptor agonist, is one of the most promising new approaches for the treatment of acute postoperative pain. AIMS: To investigate the efficacy and safety of tyrosyl-D-arginyl-phenylalanine-glycine amide in cancer patients depending on the type of anesthesia used in various types of surgical interventions. MATERIALS AND METHODS: The study included 80 patients aged 29 to 86 years (mean age 66 years (Q1;Q3 – 59;71 years)), 46 (57.5%) men and 34 (42.5%) women, with a physical status of I–III according to the American Society of Anesthesiologists (ASA) classification, scheduled for surgical treatment of cancer. Patients received a specific type of anesthesia: multimodal combined general anesthesia with mechanical ventilation in the control group (Group K, n=40) or combined anesthesia (general + epidural/intercostal block in thoracic surgeries) in the comparison group (Group C, n=40). All patients followed a general protocol of systemic postoperative pain management based on tyrosyl-D-arginyl-phenylalanine-glycine amide, administered at a dose of 4 mg, 3 times daily. The first dose was given when the pain intensity on the Numeric Rating Scale for pain (NRS) exceeded 3 points at rest and 4 points during movement. Pain intensity on the NRS (in points) at rest and during movement was assessed at specific time points – 15, 30, 45, 60, 120, and 240 minutes after the first dose. RESULTS: In Group K, the initial pain intensity (on NRS, points) at rest was higher than in Group C (Me 6, Q1;Q3 – 5;7 vs. Me 5, Q1;Q3 – 5;6, respectively, p = 0.038). While the median values of initial pain intensity during movement were similar between the groups (7 points), the interquartile range was higher in Group K (Q1;Q3 – 6;8 in Group K vs. Q1;Q3 – 6;7 in Group C, p = 0.045). Lower pain values were recorded in Group C at rest at 45 and 60 minutes (p = 0.005 and p = 0.008, respectively) and during movement at 30 minutes (p = 0.036). CONCLUSIONS: The combination of tyrosyl-D-arginyl-phenylalanyl-glycine amide with regional perioperative blockades is the optimal method for managing acute pain in the early postoperative period in patients who have undergone complex and traumatic oncological surgical interventions.

A Susceptible Cell-Selective Delivery (SCSD) of mRNA-Encoded Cas13d Against Influenza Infection.

To bolster the capacity for managing potential infectious diseases in the future, it is critical to develop specific antiviral drugs that can be rapidly designed and delivered precisely. Herein, a CRISPR/Cas13d system for broad-spectrum targeting of influenza A virus (IAV) from human, avian, and swine sources is designed, incorporating Cas13d mRNA and a tandem CRISPR RNA (crRNA) specific for the highly conserved regions of viral polymerase acidic (PA), nucleoprotein (NP), and matrix (M) gene segments, respectively. Given that the virus targets cells with specific receptors but is not limited to a single organ, a Susceptible Cell Selective Delivery (SCSD) system is developed by modifying a lipid nanoparticle with a peptide mimicking the function of the hemagglutinin of influenza virus to target sialic acid receptors. The SCSD system can precisely deliver an all-RNA-based CRISPR/Cas13d system into potentially infected cells. This drug is shown to reduce the viral load in the lungs by 2.37 log10 TCID50mL-1 and protect 100% of mice from lethal influenza infection. The SCSD-based CRISPR/Cas13d system shows promise for the flexible and efficient therapy of infections caused by rapidly evolving and novel viruses.

Discovering Cell-Targeting Ligands and Cell-Surface Receptors by Selection of DNA-Encoded Chemical Libraries against Cancer Cells without Predefined Targets.

Small molecules that can bind to specific cells have broad applications in cancer diagnosis and treatment. Screening large chemical libraries against live cells is an effective strategy for discovering cell-targeting ligands. The DNA-encoded chemical library (DEL or DECL) technology has emerged as a robust tool in drug discovery and has been successfully utilized in identifying ligands for biological targets. However, nearly all DEL selections have predefined targets, while target-agnostic DEL selections interrogating the entire cell surface remain underexplored. Herein, we systematically optimized a cell-based DEL selection method against cancer cells without predefined targets. A 104.96-million-member DEL was selected against MDA-MB-231 and MCF-7 breast cancer cells, representing high and low metastatic properties, respectively, which led to the identification of cell-specific small molecules. We further demonstrated cell-targeting applications of these ligands in cancer photodynamic therapy and targeted drug delivery. Finally, leveraging the DNA tag of DEL compounds, we identified α-enolase (ENO1) as the cell surface receptor of one of the ligands targeting the more aggressive MDA-MB-231 cells. Overall, this work offers an efficient approach for discovering cell-targeting small molecule ligands by using DELs and demonstrates that DELs can be a useful tool to identify specific surface receptors on cancer cells.

The Q226L mutation can convert a highly pathogenic H5 2.3.4.4e virus to bind human-type receptors.

H5Nx viruses continue to wreak havoc in avian and mammalian species worldwide. The virus distinguishes itself by the ability to replicate to high titers and transmit efficiently in a wide variety of hosts in diverse climatic environments. Fortunately, transmission to and between humans is scarce. Yet, if such an event were to occur, it could spark a pandemic as humans are immunologically naïve to H5 viruses. A significant determinant of transmission to and between humans is the ability of the influenza A virus hemagglutinin (HA) protein to shift from an avian-type to a human-type receptor specificity. Here, we demonstrate that a 2016 2.3.4.4e virus HA can convert to human-type receptor binding via a single Q226L mutation, in contrast to a cleavage-modified 2016 2.3.4.4b virus HA. Using glycan arrays, x-ray structural analyses, tissue- and direct glycan binding, we show that L133aΔ and 227Q are vital for this phenotype. Thus, whereas the 2.3.4.4e virus HA only needs a single amino acid mutation, the modified 2.3.4.4b HA was not easily converted to human-type receptor specificity.

Small-molecule-induced ERBB4 activation to treat heart failure

Heart failure is a common and deadly disease requiring new treatments. The neuregulin-1/ERBB4 pathway offers cardioprotective benefits, but using recombinant neuregulin-1 as therapy has limitations due to the need for intravenous delivery and lack of receptor specificity. We hypothesize that small-molecule activation of ERBB4 could protect against heart damage and fibrosis. To test this, we conduct a screening of 10,240 compounds and identify eight structurally similar ones (EF-1 to EF-8) that induce ERBB4 dimerization, with EF-1 being the most effective. EF-1 reduces cell death and hypertrophy in cardiomyocytes and decreases collagen production in cardiac fibroblasts in an ERBB4-dependent manner. In wild-type mice, EF-1 inhibits angiotensin-II-induced fibrosis in males and females and reduces heart damage caused by doxorubicin and myocardial infarction in females, but not in Erbb4-null mice. This study shows that small-molecule ERBB4 activation is feasible and may lead to a novel class of drugs for treating heart failure.

How prevalent are lactoferrin receptors in Gram-negative bacteria?

Surface receptors in Gram-negative bacteria that bind and extract iron from the host glycoproteins transferrin (Tf) or lactoferrin (Lf) was discovered 35 years ago in pathogenic Neisseria species and subsequently was discovered in other pathogens of humans and food production animals. These bacterial species reside exclusively on the mucosal surfaces of the respiratory or genitourinary tract of their mammalian host and rely on their host specific Tf and Lf receptors to acquire iron for survival. Since the specificity of the bacterial Tf receptors was shown to be due to selective pressures on the host Tf, their presence in bacteria that reside in both mammals and birds indicates that they arose over 320 million years ago. Once Lf arose in mammals due to a gene duplication event, Lf receptors subsequently arose from Tf receptors. The focus on pathogens for discovery of these receptors has led to a limited understanding of how prevalent the Tf and Lf receptors are in commensal species and raises the question whether they are present in additional bacterial lineages. Since the Lf receptor provides a secondary iron acquisition system plus can provide protection from cationic peptides its presence varies in bacterial lineages.