Two-point mutations in protocadherin-1 (Article Critique Sample)

Article Summary- Two-point mutations Student’s name Institution affiliation Course code and name Professor’s name Date Two-Point Mutations in Protocadherin-1 Disrupt Hantavirus Recognition And Afford Protection Against Lethal Infection Summary According to Slough et al., the FDA has not approved any countermeasures for the Sin Nombre virus (SNV) and Andes virus (ANDV), which cause severe hantavirus cardiopulmonary syndrome (HCPS) among Americans. A cadherin-superfamily protein known as protocadherin-1 (PCDH1) has formed a novel antiviral target since its identification as a vital host factor for SNV and ANDV. However, its primary role has yet to be discovered. The study applies experimental and computational methods to describe the hantavirus glycoprotein complex binding surface on the first PCDH1’s extracellular cadherin domain repeat. PCDH1 has a single amino acid residue that influences the species-specificity in the host PCDH1-SNV glycoprotein interactions and cell entry. Mutations in the single amino acid and the neighboring residue substantially protect Syrian hamsters from ANDV-caused pulmonary infection and death. The research concludes that PCDH1 is a legitimate SNV and ANDV entry receptor whose contact with hantavirus glycoprotein can be a target for developing novel mediations against HCPS. To some estimates, rodent-borne ortho hantaviruses have coevolved with rodents. The ortho hantaviruses are segmented and belong to the negative-strand RNA virus group. Zoonotic transmission of the hantaviruses can lead to hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS). The two diseases result in substantial morbidity and mortality, where the rate of cases is 40% for HCPS and 15 % for HFRS. The limited knowledge about the life cycle of the hantavirus has resulted in a challenge in developing interventions to treat either HFRS or HCPS and challenges their advancements. The "New World" clade hantavirus, like the Sin Nombre virus (SNV) and Andes virus (ANDV), are the primary etiologic HCPS agents in North and South America, respectively. Conversely, the Old World" hantaviruses, mainly found in Europe and Asia, like the Seoul virus (SEOV) and Hantavirus (HTNV), may result in HFRS in human beings. The study established that protocadherin-1 (PCDH1), belonging to the nonclustered protocadherin of the cadherin superfamily, is a clade-specific entry factor used by the New World hantaviruses. Protocadherin-1 uses a Gn/Gc tetrameric viral glycoprotein complex that influences cell entry. Upon entry, PCDH1 colocalizes with E-cadherin in the airway epithelium and on the apical cell contact sites. PCDH1 has seven extracellular cadherin repeat units and is a Type I transmembrane protein with a protocadherin unit that encloses the transmembrane and juxtamembrane sequences. PCDH1 is essential for effectively binding New World hantavirus Gn/Gc, and its loss significantly lowers ANDV infection lethality in the Syrian hamster HCPS model. The structure of PCDH1 consists of a soluble fragment with four extracellular cadherin repeat units (EC1-4) that are preserved as head-tail homodimers that form essential contacts between extracellular cadherin 1 and 4. The structure predicts how PCDH1 molecules in the adjacent cells make adhesive interactions. Reasons why understanding virus-receptor interactions in rodents is crucial for our understanding of diseases in humans Scientists have used rodents as experimental animals to test various hypotheses in humans. It is, therefore, significant to understand the virus-receptor interactions and how they affect humans. Some of the reasons include * Zoonotic Transmission Many rodents act as reservoirs of viruses, which are evolutionarily conserved over the years. Understanding virus-receptor interactions in rodents is essential in determining the possible zoonotic threats. This knowledge of various specific receptors is essential in forecasting and mediating virus transmission in humans. Since many viruses that infect rodents can infect humans, various viruses can potentially spread and cause human diseases through zoonotic transmission. According to the paper, some hantavirus's zoonotic transmission can lead to two types of humans. The two diseases are hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS). The two diseases lead to significant mortality and morbidity of about 40% for hantavirus cardiopulmonary syndrome (HCPS) and 15% for hemorrhagic fever with renal syndrome (HFRS). Although there are no current FDA-approved specific measures against the viruses that can help in the treatment of hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS), understanding their development through the study of the hantavirus life cycle will play a significant role in developing a cure for the diseases among humans. * Evolutionary Conservation of Receptors: Viruses' receptors to enter host cells are often evolutionarily conserved across species. Studying virus-receptor interactions in rodents helps identify analogous receptors in humans. Understanding the receptor conservation between humans and rodents offers a basis for potential discoveries in human health. This knowledge is valuable for predicting the potential susceptibility of humans to certain viruses based on their interactions with rodent receptors. * Disease Dynamics and Prevention As earlier mentioned, rodents have acted as natural reservoirs of viruses that can cause illness in humans; thus, understanding the molecular interactions between the viruses and host receptors is essential in understanding the transmission in humans and also helpful in developing appropriate prevention and curative measures. According to the paper, protocadherin-1 is the primary hantavirus receptor in rodents. Protocadhrein-1 identified by the study belongs to nonclustered protocadherins whose entry into the host cells is as specific as other New World hantaviruses. Protocadherin-1 (PCDH1) directly uses the viral Gn/Gc tetrameric glycoprotein complex in mediating its entry into the host cells. Upon entry into the host cell, protocadherin-1 expresses itself in the epithelium of the air pathway, where it cohabits with E-cadherin on the apical intercell contact sites. It is also expressed in the vascular endothelial cells that remain the primary hantavirus infection target. Protocadherin-1 is a susceptibility gene for asthma and air pathway hyperresponsiveness. The gene products have been shown to regulate the epithelial barrier function by mechanisms yet to be discovered. Understanding the interaction between the rodent receptors and the virus can help develop preventive measures—for instance, many viruses spread through contact with rodent products such as urine and fecal matter. Preventing contact with these products is essential in reducing the spread of the viruses through the human population. Besides, understanding how viruses interact with rodent receptors may benefit the development of antiviral vaccines or drugs. Since many viruses are host-specific, understanding the hantavirus's life cycles in rodents helps develop either drugs or vaccines that target a specific life cycle stage, thus developing a cure. This knowledge about the virus-receptor interactions can also help understand transmission across species. Hantaviruses, whose main transmitters are rodents, cause hantavirus cardiopulmonary syndrome, one of the most severe human diseases. This study on how two-point mutations in protocadherin-1 disrupt hantavirus recognition and their protection provision against lethal infections has provided insights into molecular transmission mechanisms across species. This knowledge is essential in protecting hantaviruses. The discovery of particular receptors involved in hantavirus recognition in rodents provides room for targeted treatments. Understanding the molecular particulars of virus-receptor interactions may lead to identifying novel therapeutic targets that can disrupt viral entry and lower illness severity. Reasons why laboratory mice are resistant to ANDV infection and ways through which laboratory mice might be made susceptible to ANDV * Receptor Specificity Based on the paper's findings, laboratory mice resist ADNV since the hantaviruses are postulated host-specific. Since the hantaviruses are host-specific, various molecular hindrances exist to cross-species viral infection. ANDV, like many hantaviruses, depends on specific cell entry receptors. According to the study, protocadherin-1 is the ANDV receptor in Syrian golden hamsters. ADNVs have long-tailed pygmy rice rats as their primary hosts. Laboratory mice may lack the necessary receptor or have a variant that does not allow efficient ANDV entry, rendering them resistant to infection. The study discovered that when engineered, laboratory mice do not possess the functional type 1 interferon response that has shown high susceptibility to SEOV and HTNV infection. This lack of functional type 1 interferon response has not been reported to support SNV or ANDV infections; therefore, the study proposed that some murine barriers at cellular levels could prevent the infection of ANDV or SNV. The hypothesis was tested by infecting primary lung microvascular endothelial cells (MLMECs) and primary human pulmonary microvascular endothelial cells (HPMECs) with recombinant vesicular stomatitis viruses rVSVs) which are replication competent and express ANDV (rVSV-ANDV-Gn/Gc) or SNV (rVSV-SNV-Gn/Gc) Gn/Gc. The study indicated that mouse cells had a significant reduction of -100 times susceptibility to rVSV-SNV-Gn/Gc and a slight reduction of -2 times susceptibility to rVSV-ANDV-Gn/Gc relative to the human cells. * Other factors Apart from receptor specificity, other host characteristics, including immunological responses, genetic variations, and antiviral syst...