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Direct damage to the host is a general mechanism utilized by pathogenic organisms to ensure infection and destruction of the host cell.
- Describe the different processes used by pathogens to damage the host and ensure infection
- Pathogenic organisms must have mechanisms in place to evade attack by the immune system.
- Pathogens can produce enzymes that disrupt normal tissue and allow for further invasion into the tissues.
- Pathogens can produce toxins that interfere with protein function deemed necessary by the host cell for proper maintenance.
- diphtheria: A disease of the upper respiratory tract caused by a toxin secreted by Corynebacterium diphtheriae.
- phagocytosis: the process by which a cell incorporates foreign particles intracellularly.
Direct damage to the host is a general mechanism utilized by pathogenic organisms to ensure infection and destruction of the host cell. The pathogenic organism typically causes damage due to its own growth process. The promotion of disease is characterized by the ability of a pathogenic organism to enter a host and inflict damage and destruction onto the host cell. The pathogenic organism must exhibit specific characteristics that promote its growth into a host cell including, but not limited to, the ability to invade, colonize, and attach to host cells.
The ability of a pathogen to gain entrance to a host cell is fundamental in the ability of the pathogen to promote and cause disease. The ability to manipulate the process of phagocytosis is a mechanism often utilized by bacteria to ensure they effectively invade a host. Phagocytosis is a process utilized by phagocytes (white blood cells) as a defense mechanism to protect from foreign bodies. The phagocytes engulf invaders and present them to additional factors within the immune system that result in their destruction. However, a successful and destructive pathogen often exhibits the ability to evade phagocytosis.
The mechanism(s) utilized by pathogens to avoid phagocytosis include avoiding both contact and engulfment. Pathogens that exhibit the ability to avoid contact utilize various processes to accomplish this, including: the ability to grow in regions of the body where phagocytes are incapable of reaching; the ability to inhibit the activation of an immune response; inhibiting and interfering with chemotaxis which drives the phagocytes to site of infection; and ‘tricking’ the immune system to identify the bacteria as ‘self. ‘ Additional mechanism(s) by which bacteria can avoid destruction is by avoiding engulfment. This is accomplished by the ability of the bacteria to exhibit produce molecules that interfere with the phagocytes ability to internalize the bacteria. Molecules that interfere with this process include certain types of proteins and sugars that block engulfment.
Once the pathogen has successfully evaded engulfment and destruction by the immune system, it is detrimental because the bacteria then multiply. Often times, bacteria will directly attach themselves to host cells and utilize nutrients from the host cell for their own cellular processes. Upon the use of host nutrients for its own cellular processes, the bacteria may also produce toxins or enzymes that will infiltrate and destroy the host cell. The production of these destructive products results in the direct damage of the host cell. The waste products of the microbes will also damage to the cell. Examples of bacteria that will damage tissue by producing toxins, include, Corynebacterium diphtheriae and Streptococcus pyogenes. Specifically, Corynebacterium diphtheriae causes diphtheria, which isa disease of the upper respiratory tract. It produces a toxin, diphtheria toxin, which alters host protein function. The toxin can then result in damage to additional tissues including the heart, liver, and nerves. Streptococcus pyogenes is associated with strep throat and “flesh-eating disease. ” The bacteria produce enzymes which function in disrupting fibrin clots. Fibrin clots will form at sites of injury, in this case, at the site of foreign invasion. The enzymes, capable of digesting fibrin, will open an area within the epithelial cells and promote invasion of the bacteria into the tissues.
Direct coupling of the cell cycle and cell death machinery by E2F
Unrestrained E2F activity forces S phase entry and promotes apoptosis through p53-dependent and -independent mechanisms. Here, we show that deregulation of E2F by adenovirus E1A, loss of Rb or enforced E2F-1 expression results in the accumulation of caspase proenzymes through a direct transcriptional mechanism. Increased caspase levels seem to potentiate cell death in the presence of p53-generated signals that trigger caspase activation. Our results demonstrate that mitogenic oncogenes engage a tumour suppressor network that functions at multiple levels to efficiently induce cell death. The data also underscore how cell cycle progression can be coupled to the apoptotic machinery.
The main task of MMR is to remove base mismatches and small insertion/deletion loops (IDLs) introduced during replication. In Escherichia coli, the main players in MMR are MutS, MutL and MutH. MutH nicks the non-methylated strand and thereby enables discrimination between the newly synthesized strand and the template. MMR is bidirectional, i.e. nicking and degradation can occur from either the 5′ or 3′ side of the mismatch. In eukaryotes, several MutS and MutL homologues are involved in MMR MutH homologues appear to be absent. Inactivation of human MMR causes hereditary nonpolyposis colorectal cancer (HNPCC) and some types of sporadic tumor. In the course of human MMR, base mismatches are bound by the MutS-homologous heterodimer MSH2-MSH6, while small IDLs can be bound by MSH2-MSH6 and MSH2-MSH3. Subsequently, the MutL-homologous heterodimer MLH1-PMS2 is recruited. In some eukaryotes additional MutL homologues exist. These form heterodimers with MLH1 and may play a minor role in MMR. It is not yet understood how eukaryotes distinguish between the new and the old strand. Strand discrimination may be either mediated by the replication accessory factor PCNA or could be simply achieved by recognition of nicks, gaps or free 3′ ends that are present in the nascent strand during replication. In a downstream step, the newly synthesized strand is degraded, which removes the mismatch. MMR patches are ∼100 to >1000 nucleotides in length. EXO1 is involved in 5′ to 3′ excision. It is not yet clear which factors participate in 3′ to 5′ excision, but DNA Pol δ and ϵ and EXO1 may be involved. MMR is completed after DNA synthesis by the replication machinery and ligation of the remaining nick.
2 CYTOKINE RESPONSE ASSOCIATED WITH NEUTROPHIL RECRUITMENT
COVID-19 patients often develop a cytokine release syndrome (CRS) that is responsible for the respiratory distress syndrome and the multi-organs injuries as result of secondary haemophagocytic-lymphohoistocytosis. The CRS observed in COVID-19 patients resembles the immune dysregulation caused by other highly pathogenic respiratory viruses such as SARS-CoV and MERS-CoV. 11 In order to understand the potential triggers of CRS, we evaluated the general response of lung epithelial cells as a result of SAR-CoV-2 infection. We analyzed RNAseq data from primary human lung epithelial that were mock treated or infected with SARS-CoV-2 (USA-WA1/2020) at an multiplicity of infection (MOI) of 2. This data set is available in GEO as the GSE147507 data set. Using iPathwayGuide (www.advaitabio.com) we determined what cytokines and chemokines were differentially expressed in these groups. All statistical applications were performed by the iPathwayGuide software, which includes GO analysis, network analysis, pathway analysis, and differentially expressed genes. 12-15
In the cytokine-cytokine receptor and chemokine signaling pathways, we found several proinflammatory cytokines/chemokines that were differentially expressed (Fig. 1A,B and Supporting Information Fig. S1). Two chemokines with the highest fold change were GM-CSF2 (logFC = 2.981 and P = 1.000e-6) and GM-CSF3 (logFC = 4.852 and P = 1.000e-6) (Fig. 1A, B and Supporting Information Fig. S1).
CSF3 is mainly an inducer of neutrophil colony formation and it is associated with the regulation of neutrophil proliferation and maturation. 16-19 CSF2 is involved in the regulation of multiple immune cell types, especially macrophages but, in addition to stimulation of macrophage colonization, CSF2 also promotes the generation of neutrophils. 18-21 Furthermore, CSF2 plays a role in the generation of immature dendritic cells. 22 All of these processes of differentiation are mediated through the direct action of CSF2 and CSF3 on the bone marrow where it promotes the generation and release of mature colonies of myeloid cells. 20 Additionally, both colony-stimulating chemokines are capable of inducing the expression of proinflammatory cytokines, which in turn enhance the inflammatory response. 23 CSF3 expression has been linked to pulmonary neutrophilia that is seen in acute respiratory distress syndrome. 23 Furthermore, both of these factors are able to act locally on these cell subtypes to induce various aspects involved in an immune response, such as enhanced immune cell survival and increased production of inflammatory cytokines. 24, 25 The up-regulation of CSF2 and CSF3 found in this analysis suggests that these SARS-CoV-2-infected epithelial cells are sending signals to the bone marrow to produce more macrophages, eosinophils, and neutrophils to eliminate the threat. 23
A second set of related cytokines that were up-regulated during SARS-CoV-2 infection were CXCL1, CXCL2, CXCL3, CXCL6, CXCL5, and CXCL8 (or IL-8) (Fig. 1 and Supporting Information Fig. S1). All six of these cytokines are part of the CXC chemokine family. This specific set of CXC chemokines bind to the CXCR2 receptor. 26, 27 One of the primary roles of this set of cytokines is to act as a chemoattractant for neutrophils as well as to promote adherence to endothelial cells. 28-34 CXCL1 (logFC = 1.419 and R = 1.000e-6) and CXCL2 (logFC = 1.393 and R = 1.000e-6) have been shown to be critical for neutrophil recruitment to the lungs. 35, 36 CXC chemokines are produced by different cell types in response to proinflammatory signals such as IL-1β (logFC = 1.065 and R = 1.000e-6), IL-1α(logFC = 1.074 and R = 1.000e-6), and TNF-α (logFC = 1.809 and R = 2.865e-4), all of which were up-regulated in SARS-CoV-2-infected epithelial cells. 37 In addition to their roles in neutrophil recruitment to sites of infection, this set of CXC chemokines are also involved in the recruitment of various other cell types. CXCL8 (logFC = 2.335 and R = 1.000e-6) is a chemoattractant for basophils, eosinophils, and peripheral blood T lymphocytes. 38-40 More importantly, CXCL8 is also the primary neutrophil chemoattractant in the lungs. 41 CXCL1-3 are closely related and are important for the recruitment and activation of basophils, eosinophils, monocytes, and lymphocytes, in addition to neutrophil recruitment. 42 CXCL5 (logFC = 3.487 and R = 1.000e-6) has been found to be involved in different types of inflammatory diseases and has been shown to be expressed by alveolar type II epithelial cells in response to LPS. 43-46
Interestingly, we observed that CXCL14 (logFC = −1.446 and R = 7.498e-6) was down-regulated in these data sets (Fig. 1 and Supporting Information Fig. S1). CXCL14 is a potent inhibitor of epithelial cell chemotaxis and function as a negative feedback to decrease immune cells recruitment. 47 Inhibition of CXCL14 allows a sustained and enhanced immune cell recruitment. Therefore, the finding of down-regulation of CXCL14 in SARS-CoV-2-infected epithelial cells suggest a removal of the regulator of immune cell recruitment leading to a persistent and enhanced enrollment of immune cells to the lungs, the site of the infection. This enhanced recruitment might lead to a disproportionate inflammatory response, a characteristic of CRS observed in patients infected with SARS-CoV-2.
When we analyzed the potential cell type targeted by these chemokines, we observed that the up-regulated CXCL1, CXCL2, CXLC3, CXCL5, and CXCL8 have a predominant function related to the recruitment of neutrophils to the lungs. Additionally, the down-regulation of CXCL14 fosters the capacity of epithelial cells to release chemokines, which will lead to further neutrophil recruitment. These data suggest that lung epithelial cells respond to SARS-CoV-2 infection by secreting a group of proinflammatory cytokines and chemokines that promote neutrophil recruitment into the infected tissues.
High-fat diet impairs ferroptosis and promotes cancer invasiveness via downregulating tumor suppressor ACSL4 in lung adenocarcinoma
Authors: Yixiang Zhang, Songyu Li, Fengzhou Li, Changsheng Lv and Qing-kai Yang
Common pathways and functional profiles reveal underlying patterns in Breast, Kidney and Lung cancers
Authors: Sergio Romera-Giner, Zoraida Andreu Martínez, Francisco García-García and Marta R. Hidalgo
Polymorphism on human aromatase affects protein dynamics and substrate binding: spectroscopic evidence
Authors: Giovanna Di Nardo, Almerinda Di Venere, Chao Zhang, Eleonora Nicolai, Silvia Castrignanò, Luisa Di Paola, Gianfranco Gilardi and Giampiero Mei
A novel gene selection method for gene expression data for the task of cancer type classification
Authors: N. Özlem ÖZCAN ŞİMŞEK, Arzucan ÖZGÜR and Fikret GÜRGEN
Prediction and mechanistic analysis of drug-induced liver injury (DILI) based on chemical structure
Authors: Anika Liu, Moritz Walter, Peter Wright, Aleksandra Bartosik, Daniela Dolciami, Abdurrahman Elbasir, Hongbin Yang and Andreas Bender
The ancient Virus World and evolution of cells
Authors: Eugene V Koonin, Tatiana G Senkevich and Valerian V Dolja
A putative RNA-interference-based immune system in prokaryotes: computational analysis of the predicted enzymatic machinery, functional analogies with eukaryotic RNAi, and hypothetical mechanisms of action
Authors: Kira S Makarova, Nick V Grishin, Svetlana A Shabalina, Yuri I Wolf and Eugene V Koonin
Rooting the tree of life by transition analyses
Authors: Thomas Cavalier-Smith
A novel virus genome discovered in an extreme environment suggests recombination between unrelated groups of RNA and DNA viruses
Authors: Geoffrey S Diemer and Kenneth M Stedman
On the origin of life in the Zinc world: 1. Photosynthesizing, porous edifices built of hydrothermally precipitated zinc sulfide as cradles of life on Earth
Authors: Armen Y Mulkidjanian
Collection published: 10 April 2020
Collection published: 13 April 2020
Collection published: 20 April 2020
Collection published: 21 April 2020
Collection published: 23 April 2020
14.4B: Direct Damage - Biology
What is a Pest?
We know that certain insects can feed on the blood of people or other vertebrate animals, and can transmit diseases that are very serious health concerns. These are pests. Nearly every kind of plant in nature is food to one insect or another. When insects feed on plants that we as humans dont want them to, they become pests. Agricultural crops and horticultural plants are consumed by a number of different insects and are at risk from the time the seed is planted until the crop is harvested, stored, or consumed. When insects compete for the same foods as humans, we consider them pests. If insects sting, bite, annoy, contaminate, or make life less pleasurable in any way, people consider them pests. Insect pests may damage homes, clothing, or other products that we make, store, or use. Insects that harm us or our animals, destroy our foods, or damage our buildings, structures, or the materials we producein short, compete with humans in any wayare called pests.
Chromosomes in the Cell
Sometimes a piece of chromosome breaks off, resulting in a deletion of genetic material. The effects of the loss of a portion of a chromosome depend on the particular genes lost. One of the earliest deletions noted with staining techniques was the loss of a portion of the short arm of chromosome 5. Affected infants have a rounded, moonlike face and utter feeble, plaintive cries described as similar to the mewing of a cat, and the disorder is named cri du chat (French, “cat cry”) syndrome. The cry disappears with time as the larynx improves and is rarely heard after the first year of life. The facial features also change with age, and the moon-shaped face becomes long and thin. Most patients survive beyond childhood, but they rank among the most profoundly retarded (IQ usually <20). Examples of deletion syndromes are shown in Table 2-2 .
Deletions of varied types, notably interstitial and terminal, played a role in delineating the segment of chromosome 21 responsible for Down syndrome. Deletions of different segments of one of the long arms of chromosome 21 in trisomy 21 individuals (resulting in partial trisomy) have made it possible to identify the chromosome region responsible for the phenotypic features of Down syndrome. The “Down syndrome critical region” has been identified as a 5- to 10-Mb region of the chromosome and encompasses bands 21q22.2 to 21q22.3.
Is ionizing radiation always harmful?
No, ionizing radiation is only harmful to an organism as a whole when its amount gets too high. We are constantly bombarded with very small amounts of ionizing radiation that occur naturally, and we get along just fine with our lives without being seriously harmed by this radiation. There are trace amounts of naturally-occurring radioactive atoms in the air, in the rocks, in our food, and inside our bodies. When these atoms radioactively decay, they emit ionizing radiation. By its nature of being ionizing, such radiation can damage individual molecules, even at low intensity. But if the amount of ionizing radiation exposure is very low, our bodies can handle a few damaged molecules without any problem, so that there is no net harm done to our bodies.
Ionizing radiation is radiation that has enough energy per particle to rip electrons off of atoms and therefore break chemical bonds. In contrast, radiation types such as microwaves, radio waves, and visible light are non-ionizing, meaning that they do not have enough energy to permanently damage molecules beyond simple heating effects. Ionizing radiation includes X-rays, gamma rays, neutron radiation, proton radiation, and high-speed electrons. Natural sources of ionizing radiation include the radioactive decay of unstable atoms that exist everywhere and cosmic rays from space. Man-made sources include medical scans such as X-ray images as well as nuclear power plants, nuclear weapons testing, and any industrial or scientific process that involves nuclear reactions or high energies. Advocating that humans cease all nuclear activity in order that our exposure to ionizing radiation will be reduced to zero makes no sense since we will always be exposed to some amount of ionizing radiation from natural sources. The more logical approach is to allow nuclear research and technology to proceed, but put strong regulations and safety procedures in place so that humans are never exposed to ionizing radiation amounts that are above the safety threshold.
The amount of total harm that ionizing radiation can cause a human depends on the total amount of radiation received, which is a function of the intensity of the radiation and the length of time that the person is exposed to the radiation. The total amount of ionizing radiation received by a body is termed the "dose". Since different tissues react differently to ionizing radiation, of more importance is the "effective dose", which is the total amount of ionizing radiation received that is able to do biological damage. A person that is exposed to higher-than-normal levels of radiation, but only for limited amounts of time, will not receive a significantly higher effective dose and thus may still be in the safe zone. For instance, employees can safely work in nuclear reactor facilities as long as they monitor their radiation exposure and limit their time in the facilities so that their dose does not exceed safe levels.
It is hard to set one standard threshold above which radiation exposure becomes seriously harmful since the definition of "seriously harmful" is subjective. Medium-low doses of ionizing radiation can still cause nausea and may still cause a miniscule increase in the chance of getting cancer, although this increase may be too small to be considered significant. Despite the complexity of this field, general safety thresholds can still be set. Experimentally, cancer risk has only been found to increase for doses above 100 mSv per year according to the World Nuclear Association. A good safety threshold should therefore be set at a value that is well below 100 mSv per year. The U.S. Nuclear Regulatory Commission sets the occupational safety limit for ionizing radiation exposure to be 50 mSv per year. For comparison, natural background radiation provides a dose of 3 mSv per year, a single typical banana provides 0.0001 mSv, a single set of dental X-rays provides about 0.005 mSv, a single set of barium X-rays provides about 5 mSv, and a single full-body CT scan provides about 20 mSv. As you can see, a single medical scan is too weak to cause harm even though it may involve ionizing radiation. On the other hand, undergoing several full-body CT scans in a short period of time can make the radiation add up to a total dose that is at a harmful level. For this reason, medical doctors are trained to avoid ordering too many radiation-intensive scans for a single patient in a short amount of time (unless the benefits outweigh the risks, e.g. if the scan helps save a patient from imminent death, it is worth the increased cancer risk).
When the dose is high enough, ionizing radiation causes two types of harm to humans: direct tissue damage and cancer. Direct tissue damage happens when enough molecules are broken apart that the cells simply can no longer function. This can lead to radiation burns, radiation sickness, organ failure, and even death. In contrast, cancer results when the cells receive a small enough amount of damage that they can still live and function, but damage to the genes causes the cells to pursue aggressive and uncontrolled growth.
Computer evaluation of direct and indirect damage induced by free and DNA𠄋ound Iodine in the chromatin fibre
Purpose: When Iodine‐125 decays within chromatin, several in vivo experiments have shown that the radiobiological effects are caused mainly by indirect mechanisms and that more than one DNA double strand break (DSB) is produced per decay. We present calculations to evaluate the contribution of direct and indirect effects of radiation tracks to produce DNA damage induced by bound and free I‐125 in a model of chromatin DNA.
Materials and methods: A solenoid model of chromatin with 18 nucleosomal elements placed in bulk water (more than 600,000 atoms) is used where the initial I‐125 decay takes place. All physical and chemical events initiated by Auger and X‐rays were taken into account. The yields of single strand breaks (SSB) and DSB were derived using direct effects on DNA and indirect reactions of all radical species generated in the radiolysis of the bulk water.
Results: The distribution of damage complexity for free and DNA–bound I‐125 is presented. We obtained more than 1.3 DSB per decay, with nearly equal contributions from direct and indirect effects. However, for the most complex type of damage, located at the decay site, the direct effect is about 70% of the total number. To show the protective effect of histones, simulations were carried out with and without the presence of histones.
Motor Neuron Disease
Motor neuron disease describes a collection of neurodegenerative diseases that specifically affect the motor neurons, causing the death of the cells. There are various different types of motor neuron diseases, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), bulbar onset MND or progressive bulbar palsy (PBP), and progressive muscular atrophy (PMA).
Because the motor neurons are no longer effectively signaling the muscles, motor neuron disease causes muscle weakening, stiffening, and wasting. This causes a diverse range of symptoms that are dependent upon the specific disease and the individual.
The onset of motor neuron disease can be subtle, and the initial signs and symptoms include muscle weakness with potential cognitive and behavioral changes. The disease can impact a sufferers’ ability to eat and drink, talk, walk, and breathe. Eventually, most affected individuals will lose the ability to carry out these tasks entirely.
ALS, also called Lou Gehrig’s disease, is the most common type of motor neuron disease. Two notably individuals that died as a result of complications of the condition are Stephen Hawking and Christopher Reeve. In 2014, the viral video fad termed the “Ice Bucket Challenge” increased awareness of, and research funding for, the condition.
The causes of motor neuron disease are largely unknown. The disease is thought to be the result of both genetic and environmental factors, and sometimes there can be a familial link. Studies have identified mutations around the gene C21orf2 which are thought to be linked with some cases of ALS.
Upper Motor Neuron Lesion
An upper motor neuron lesion, also called pyramidal insufficiency, refers to damage to the motor neurons of the brain or brain stem that travel to the spinal cord. Such damage can occur as a result of a variety of disorders, including multiple sclerosis (MS), stroke, brain injury, or cerebral palsy.
The resulting effects are referred to as upper motor neuron disease (UMND). The symptoms include muscle weakness, poor motor control, poor posture, and exaggerated reflex responses.
Lower Motor Neuron Lesion
Lower motor neuron lesions are damage to the lower motor neurons that travel from the spinal cord to the effector muscles. The symptoms include muscle paralysis and weakness, and the lesions are usually caused by a systemic infection, such as Lyme disease, HIV, or the Herpes virus (which can cause Bell palsy).