Monkeypox Virus Infection

Monkeypox is a smallpox-like rare infectious disease that is mainly spread by wild animals such as rodents and squirrels. Monkeypox virus belongs to the Orthopoxvirus genus in the Poxviridae family. The disease is mainly spread in West and Central Africa, but was discovered during the pox-like disease outbreak of the virus in Denmark in 1958.

 

How Do You Get Infected by Monkeypox Virus?

Monkeypox virus infection is transmitted to human through the handling of infected animals or by direct contact with an infected animal’s body fluid. It can also be transmitted from one person to another through contact with large infective respiratory droplets or direct contact with infected person.

 

What Is The Incubation Period Of Monkeypox Virus?

The incubation period of Monkeypox may vary from person to person depending on the person’s immune defense system. However, the incubation period for the virus is between 7 to 21 days.

 

What Are The Symptoms Of Monkeypox?

The symptoms of Monkeypox include:

  • High fever
  • Sore throat
  • Headache
  • Malaise
  • Cough
  • Swollen lumph nodes

Rashes appear on the patient’s body within 1 to 3 days after the appearance of fever. The rashes often begins from the face and spread throughout the body.

Before falling off, the lesions progress through the following stages:

  • Macules
  • Papules
  • Vesicles
  • Pustules
  • Scabs

 

How Long Can Monkey Infection Last?

The illness usually lasts for four weeks or less in some cases. The death rate of Monkeypox is as many as 1 in 10 persons who contact the disease.

 

How Can You Prevent Monkeypox Infection?

To prevent yourself from contacting Monkeypox virus, do the following:

  • Avoid contact with animals that are carriers of the virus such as rodents and squirrels.
  • Infected persons should be isolated and quarantined.
  • Avoid contact with materials used by infected persons.
  • Always maintain good hygiene and wash hands after contact with infected patients.
  • Use personal protective equipment when attending to patients.

 

Treatment Of Monkeypox

There is currently no treatment for Monkeypox virus infection. However, smallpox vaccines, antiviral medicines, and vaccinia immune globulin (VIG) can be used in preventing the outbreak of the disease.

 

 

 

 

Matrix Metalloproteinases (MMPs)

Matrix metalloproteinases (MMPs) are a family of Zinc-dependent endopeptidase that degrade various proteins of the extracellular matrix (ECM). As members of the metzincin group of proteases, they share the conserved zinc-binding motif in their catalytic active site. Initially, MMPs were thought to function mainly in degrading ECM, but recent studies has shown that they also function significantly as regulators of extracellular tissue signaling networks.

MMPs are defined by the presence of two conserved zinc-binding motifs. One motif is a cysteine-containing pro-domain, whose function is partly to restrain catalytic; whereas the other motif is a histidine-rich catalytic domain, responsible for the endopeptidase activity.

MMPs Are Involved in Various Physiological and Pathological Processes.

MMPs are involved in numerous physiological and pathological processes. In physiological process, MMPs are involved in embryonic development, wound repair, ovulation, bone remodeling, macrophage function and in neutrophil function. They are also involved in pathological processes such as inflammation, tumor metastasis, rheumatoid arthritis, gastric ulcer, among others.

 Matrix Metalloproteinases and EMT in Tumor Metastasis

Epithelia-mesenchymal transition (EMT) plays its central role in normal embryonic development. But recent studies have shown its roles in pathological processes, such as cancer progression, fibrosis, and chronic inflammation.

MMPs associate with EMT in cancer progression through three mechanisms:

  • Elevated levels of MMPs in the tumor microenvironment induce EMT in epithelia cells.
  • EMT in cancer then produces more MMPs, thereby facilitating cell invasion and metastasis.
  • EMT can generate activated stromal-like cells that drive cancer progression through further MMPs production.

Role of MMPs in Tumor Metastasis

The role of MMPs in tumor metastasis was initially believed to be limited to the degradation of ECM and basement membrane collagen. But now, we know that MMPs paly critical roles at every step of tumor progression. MMPs influence several biological functions, such as modification of signaling pathways, regulation of cytokines involved in immune responses, and tumor growth by stimulating angiogenesis, which leads to the spread of cancer.

MMP-11 Plays Dual Roles in Tumors

Unlike many members of MMPs, MMP-8 and MMP-12 were reported to exert antitumor effects, thereby suppressing tumor growth. MMP-11 on the other hand plays a dual role in cancer progression. In one hand, MMP-11 promotes cancer development by inhibiting apoptosis and enhancing the invasion of cancer cells; on the other hand, however, MMP-11 plays a negative role against cancer development through the suppression of metastasis.

MMPs play Major Roles In Rheumatoid Arthritis

Rheumatoid arthritis (RA) is characterized by progressive joint destruction with loss of bone and cartilage as well as the aggressive activation of synovian fibroblasts (SFs) bearing a tumor-like appearance.

During joint destruction, RASFs secrete various proteases, including MMPs that degrade ECM
components, mainly proteoglycans and collagens, of articular cartilage in the affected joints.

However, among the various MMPs involved in articular degradation, MMP-1 and MMP-13 cleave collagens, whereas MMP-3 and MMP-9 target proteoglycans which are comprised of aggrecan.

This way, the degradation of proteoglycans at the surface and the subsequent degradation of collagen fibrils in the deep zone together result in the destruction of articular cartilage.

MMPs Play Major Roles In Infectious Diseases

In a normal immune responses, when the host immune system is challenged by an invading
organism, it must first recruit leucocytes to the site of infection, eradicate the pathogen and then dampen the response to allow the resolution of inflammation.

Matrix metalloproteinases play an important role in this process both by degrading components of the extracellular matrix and by modulating cytokine and chemokine activity.

 

REFERENCES

Hook D, Keller R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech Dev. 2003;120(11):1351–83.

Cheng S, Lovett DH. Gelatinase A (MMP-2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation. Am J Pathol. 2003;162(6):1937–49.

Lopez-Otin C., Matrisian L.M. Emerging roles of proteases in tumour suppression. Nat. Rev. Cancer. 2007;7:800–808.

Zhang X., Huang S., Guo J., Zhou L., You L., Zhang T., Zhao Y. Insights into the distinct roles of MMP-11 in tumor biology and future therapeutics (Review) Int. J. Oncol. 2016;48:1783–1793.

Araki, Y., & Mimura, T. (2017). Matrix Metalloproteinase Gene Activation Resulting from Disordred Epigenetic Mechanisms in Rheumatoid Arthritis. International journal of molecular sciences, 18(5), 905. https://doi.org/10.3390/ijms18050905

Elkington, P. T., O’Kane, C. M., & Friedland, J. S. (2005). The paradox of matrix metalloproteinases in infectious disease. Clinical and experimental immunology142(1), 12–20. https://doi.org/10.1111/j.1365-2249.2005.02840.x

Molecular Mechanism of Malaria Parasite Infection

Malaria is a life-threatening disease that is caused by Plasmodium parasites. It is transmitted to individuals through the bite of an infected female anopheles mosquito. Malaria is a tropical disease that is prevalent in Sub-Saharan African populations.

There are five species of plasmodium parasites, which affect humans. They are:

  • Plasmodium falciparum
  • Plasmodium vivax
  • Plasmodium malariae
  • Plasmodium ovale

Among the five species of plasmodium parasite, Plasmodium falciparum causes the most severe and life-threatening malaria, while Plasmodium vivax is the most widely distributed, representing 53% of malaria incidences.

 

Symptoms of Malaria

The signs and symptoms if malaria may include:

  • Fever
  • Headache
  • Chills
  • Vomiting and diarrhea
  • Nausea
  • Tiredness
  • Muscular pain

 

How Is Malaria Parasite Transmitted?

Malaria parasite can only be transmitted when an infective female anopheles mosquito bites and feeds on the blood of and person. At first, the female anopheles mosquito bites and feeds on the blood of an infective person, thereby taking along the blood plasmodium sporozoites. When the mosquito bites another individual, it injects the plasmodium sporozoites into the blood circulation, from it they move to the liver of the newly infected person.

When the sporozoites get to the liver cells they rapidly bind and invade the liver cells and undergo rapid multiplication. This leads to the release of infective merozoites which invade red blood cells and destroy them.

 

Life Cycle of Plasmodium Falciparum

The life cycle of malaria parasites involves two hosts which are the female anopheles mosquito and human hosts. In humans, the parasite grows and multiply in the liver cells and then in the red blood cells, where successive broods of parasites grow and destroy the cells, releasing the merozoites, which continue to the cycle by invading other red blood cells.

 

Stages of Life Cycle of Plasmodium Falciparum

As seen above, malaria parasite passes through several stages in its life cycle. We shall look at the major stages which are the human stages and the mosquito stages of the life cycle of plasmodium falciparum.

 

The human stage (Exo-erythrocytic schizogony)

In the liver, the sporozoites infect the liver cells and mature into Schizonts, which rupture and release the Merozoites. In plasmodium vivax, and plasmodium ovale a dormant stage called hypnozoites can persist in the liver, if untreated, and cause relapses by invading the bloodstream weeks or months later.

 

Human Blood Stage (Erythrocytic Schizogony)

In this stage, the merozoites released infect red blood cells and form a ring-stage, trophozoites. The trophozoites differentiate into sexual erythrocytic stage called gametocytes.

The blood stage parasites are responsible for the clinical manifestations of the disease.

 

Mosquito stage (Sporogonic cycle)

During blood meal, the female anopheles mosquito ingests the male and female gametocytes. The male gametocyte is called microgametocyte while the female gametocyte is called macrogametocyte.

In the mosquito’s stomach, the microgametes penetrate the macrogametes to form the zygotes. The zygotes then become motile and elongated, and are called Ookinetes. The ookinetes invade the mid gut of wall of the mosquito, where they develop into Oocysts. The Oocysts grow, rupture and release sporozoites. These then make their way to the mosquito’s salivary glands.

When the mosquito bites and feeds on another person’s blood, the sporozoites are inoculated, thereby repeating the life cycle of malaria.

 

Molecular Mechanism of Plasmodium Falciparum Erythrocyte Invasion

The entry of parasite into the erythrocytes is the key to establishing blood stage infection and thus, central to both acute and severe malaria. When the merozoites invades the red blood cells, it changes its orientation until its apical end containing specialized secretory organelles called micronemes, rhoptries and base granules is pointed at the erythrocyte.

The binding and invasion of erythrocytes are carried out by two proteins of the apical secretory organelles. These proteins are the reticulocyte-binding protein homologous (RHs) and erythrocyte-binding-like proteins (EBLs).

In EBLs, a dufy-binding-like (DBL) domain mediates specific binding to different host cell receptors, including glycophorins A, B, and C as well as duffy blood antigen. But in RHs, complement receptor 1 (CR1) and basigin are the receptors for PfRH4 and PfRH5 respectively.

Whereas RHs have early role in host sensing, EBLs play a direct role in junction formation. This suggests that RH sensing and subsequent interaction with a suitable host erythrocyte sends a signal to the merozoite that triggers the subsequent steps of invasion.

 

PfRH1 interaction with its receptor on erythrocyte surface initiates invasion of parasite.

The complex invasion process of merozoite erythrocyte invasion begins with the interaction of a relatively small amount of PfRH1 with its receptor on the erythrocyte surface. This interaction leads to a signaling cascade that leads to the release of intracellular Ca2+ stores, followed by triggering of microneme and rhoptry discharge and junction formation.

PfRH1 is located at the Rhoptry duct. Whereas its role in parasite invasion is known, its receptor on erythrocyte is unknown. PfRH1 is sialic acid-dependent and binds to its receptor in a protease sensitive manner.

EBA-175 binding and parasite invasion of red blood cells

EBA-175 is located on the microneme and is responsible for the binding and invasion of merozoites to erythrocytes. Unlike PfRH1, EBA-175 receptor is known; it binds to the glycophorin A (GpA). GpA is the major glycoprotein found on human erythrocytes and is heavily sialylated. It is a 131 amino acid transmembrane dimer. Each monomer spans the membrane once exposing its N terminus extracellularly. The EBA-175/GpA is the dorminant chymotrypsin-resistant invasion pathway.

 

 

REFERENCES

 

Templeton, T. J., and Kaslow, D. C. (1997) Mol. Biochem. Parasitol. 84, 13–24

Collins, W. E., Miller, L. H., Glew, R. H., Contacos, P. G., Howard, W. A., and Wyler, D. J. (1973) J. Parasitol. 59, 855–858

Schmidt, L. H. (1978) Am. J. Trop. Med. Hyg. 27, 671–702

Collins, W. E., Galland, G. G., Sullivan, J. S., and Morris, C. L. (1994) Am. J. Trop. Med. Hyg. 51, 224–232

Pei X, Guo X, Coppel R, Mohandas N, An X. Plasmodium falciparum erythrocyte membrane protein 3 (PfEMP3) destabilizes erythrocyte membrane skeleton. J Biol Chem. 2007; 282:26754– 26758. [PubMed: 17626011]

Safeukui I, Correas JM, Brousse V, Hirt D, Deplaine G, Mule S, Lesurtel M, Goasguen N, Sauvanet A, Couvelard A, Kerneis S, Khun H, Vigan-Womas I, Ottone C, Molina TJ, Treluyer JM, Mercereau-Puijalon O, Milon G, David PH, Buffet PA. Retention of Plasmodium falciparum ring-infected erythrocytes in the slow, open microcirculation of the human spleen. Blood. 2008; 112:2520–2528. [PubMed: 18579796]

Camus, D. Hadley, T.J. A Plasmodium falciparum antigen that binds to host erythrocytes and merozoites. Science. 1985; 230: 553-556

Triglia, T., M. T. Duraisingh, R. T. Good, and A. F. Cowman. 2005. Reticulocyte-binding protein homologue 1 is required for sialic acid-dependent invasion into human erythrocytes by Plasmodium falciparumMol. Microbiol. 55:162-174.

Triglia, T., W. H. Tham, A. Hodder, and A. F. Cowman. 2009. Reticulocyte binding protein homologues are key adhesins during erythrocyte invasion by Plasmodium falciparumCell. Microbiol. 11:1671-1687.

 

 

 

 

 

 

How zinc supplementation prevents Viral replication in covid-19 patients

Covid-19 is a systemic disease that affects the lungs and multiple organs and tissues. It is transmitted, rapidly from one person to another in close proximity, through contact with virus laden aerosols discharged in coughs and sneezes. Most affected patients die as a result of acute respiratory distress syndrome.

There are several variants of Covid-19, but the Alpha, Delta, and Omicron variants are most widely spread with severe health breakdown.

 

Symptoms Of Covid-19

The symptoms of covid-19 are similar to those of normal cold and flu. They are:

  • High temperature or chills
  • Continuous cough
  • Change in the sense of smell and taste
  • Short breath
  • Feeling of tiredness
  • Headache and body pains

 

Viral Life Cycle And Cell Invasion Of Covid-19

Once the virus gained entrance into the host body, it binds to host receptors and enters the host cells through endocytosis or membrane fusion. The virus is made up of for structural proteins, which are the,

  • Spike (S) protein
  • Membrane (M) protein
  • Envelope (E) protein
  • Nucleocapsid (N) protein

The S protein protrudes from the viral surface and is the most important viral protein for host attachment and penetration. It is composed of two functional subunits (S1 and S2). The S1 is responsible for viral binding to the host cell receptor, angiotensin-converting enzyme 2 (ACE-2) and the S2 subunit plays a role in the fusion of viral and host cellular membranes.

 

Corona Virus Undergoes Two-step Protease Cleavage After Activation

After binding to the ACE-2, the S protein undergoes activation through a two-step protease cleavage. The first cleavage is for priming at the S1/S2 cleavage site. The second cleavage activation occurs at a position adjacent to a fusion peptide within S2 subunit. Thus, the initial cleavage is for stabilization of S2 subunit while the second cleavage is activates the S protein and causes a conformational change that leads to viral and host cell membrane fusion.

Once the virus has gained entrance into the host cell, it undergoes viral replication and formation of a negative strand RNA by the pre-existing single-stranded positive RNA through RNA polymerase activity. The negative stranded RNA newly formed starts to produce new strands of positive RNAs, which then synthesize new proteins in the cytoplasm.

The viral N protein now binds the new genomic RNA and the M protein facilitates its integration to the cellular endoplasmic reticulum (ER). The newly formed nucleocapsids are then enclosed in the ER membrane and transported to the lumen. From the lumen, it is transported through Golgi vesicles to the cell membrane and then, through exocytosis to the extracellular space. The new viral particles are now ready to infect the next epithelia cell.

 

How Does Zinc Protect The Body From Entering Of The Virus?

When an individual is infected with coronavirus, the virus first targets the epithelium and ciliary dyskinesia for damage, thereby impairing mucocilia clearance. But zinc supplementation increases ciliary beat frequencies and thereby improves ciliary clearance of viral particles. The improved ciliary clearance also reduces bacterial infection.

 

How Does Zinc Directly Inhibit Viral Replication?

At first, zinc prevents viral fusion with the host membrane, decreases the viral polymerase functions, impairs the protein translation and processing and blocks viral particle release. It also destabilizes the viral envelope. When supplemented with a small concentration of the zinc ionophores pyrithione or hinokitol, zinc decreases viral RNA synthesis by directly inhibiting the RNA-dependent RNA polymerase of the virus.

 

REFERENCES

Wessels I, Maywald M, Rink L. Zinc as a gatekeeper of immune function. Nutrients. (2017) 9:1286. doi: 10.3390/nu9121286

Gammoh NZ, Rink L. Zinc in infection and inflammation. Nutrients. (2017) 9:624. doi: 10.20944/preprints201705.0176.v1

Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; in press.

Peptic ulcer

Peptic ulcer occurs when there is an open sore in the gastro-intestinal tract. That is, when there is an open sore in the patient’s stomach and/or upper part of the small intestine.

Peptic ulcer can be gastric or duodenal:

Gastric ulcer occurs when the open sore is on the inside of the stomach.

Duodenal ulcer occurs on the inside of the upper part of the small intestine.

 

Symptoms of Peptic ulcer

There are several symptoms of peptic ulcer. The most common among them are:

  • Heart burn
  • Nausea
  • Bloating
  • Burning stomach pain
  • Frequent stool

Burning stomach pain remains the most common among the symptoms. Burning stomach pain results from imbalance in the stomach pH homeostasis. When the stomach pH value becomes acidic, the mucosa lining decreases and thereby exposes the stomach and intestinal walls to acid burn.

The burning stomach pain can be managed by eating foods that are rather alkaline or by taking medications that buffers the stomach or intestinal acidic pH value.

 

Causes of peptic ulcer

The digestive tract is coated with mucosa layer that normally protects the wall from acid burn. When the pH value in the digestive tract shifts from alkaline to acidic value, the mucosa layer is damaged, thereby compromising its ability to secrete bicarbonate, a buffer solution. With the mucosa layer being damaged, the stomach wall is exposed to acid burn.

  • The common causes of peptic ulcer include

  • Helicobacter pyroli (H.pylori) bacteria. Helicobacter pylori bacteria live in the gastro-intestinal wall mucosa. Often, H.pylori do not cause any harm to the host stomach cell wall, however, it can cause inflammation. It also impairs the secretion of bicarbonate, thereby promoting gastric acidity.
  • H.pylori infection can be transmitted from person to person in close contact and through food and water.
  • Regular use of pain relievers. Pain relievers such as aspirin, ibuprofen, corticosteroids, and NSAIDs can irritate the lining of the stomach and small intestine.
  • Regular intake of acidified beverages. Regular intakes of certain beverages have been reported among some patients to induce irritation on the lining of the stomach and small intestine. This report is particularly popular among Nigerian population of patients.
  • Coffee and spicy foods. Whereas it is not certain that coffee and spicy foods can cause peptic ulcer, several patients in Nigeria report of irritation on the stomach and intestine each time they took coffee or spicy foods. Some of them experience immediate heart burn.

Management and treatment

Peptic ulcer can be managed by taking antacids. However, antacids only offer temporary relief; they don’t cure peptic ulcer. Treatment of peptic ulcer can be done by taking the following medications:

Proton pump inhibitor (PPI). PPI drugs reduce acid level in the stomach and intestinal lining, thereby allowing the open sores to heal.

Histamine receptor blockers also function like proton pump inhibitors.

Antibiotics which kill H.pylori bacteria.

 

LIPOPROTEIN SYNTHESIS IN MYCOBACTERIUM TUBERCULOSIS INFECTION

 

Tuberculosis (TB) is caused by a bacterium called mycobacterium tuberculosis. The bacterium usually attack the lungs, however, TB bacteria can attack any part of the body such as the kidney, spine and brain. In some cases, people infected with TB bacteria do not show any symptom. In such cases, the health condition is called latent TB infection (LTBI).

Childhood TB contributes to approximately 15 -40% of all TB cases and is usually acquired from contact with infectious adult. The high rate of TB transmission among children can be attributed to population density and prolonged diagnostic delay in endemic areas. Majority of the childhood TB cases and deaths occur in low income nations.

Spread of mycobacterium tuberculosis infection

TB bacteria are airborne and are spread from person to person. People living in clustered areas with limited ventilation are at high risk of contracting TB infection. Once a person is infected with TB bacteria, the bacteria settle in the lungs where they grow before moving into the blood stream.

Mechanism of action of mycobacterium tuberculosis infection

In the course of infection, mycobacterium tuberculosis is phagocytized by macrophages and other innate system cells upon entry into the lungs. The receptors involved in uptake M.Tuberculosis can vary and the bacterium has adapted phagocytosis through, for example, the mannose receptor or the CR3 receptor to prevent macrophage activation.  Mycobacterium tuberculosis, while residing in the phagosomes, delays phagosome maturation and fusion with lysosomes. It therefore replicates inside macrophages as their niche within the immune system.

A delayed adaptive immune response can contain the pathogen in granulomas during later stages. One of the immune evasion strategies of Mycobacterium tuberculosis is the deregulation of lipid metabolism, leading to the formation of foamy macrophages, a hallmark of granulation in tuberculosis lesions.

Mycobacterium tuberculosis lipoprotein biosynthesis

Mycobacterium tuberculosis Lipoproteins are a group of selected bacteria proteins characterized by a lipidated N-terminus.

Lipoproteins play major roles in M.Tuberculosis infection. The common features of lipoprotein are the presence of a conserved consensus sequence called Cysteine at position +1. Lipobox directs the processing of the proplipoprotein to form the mature acylated protein. This process is mediated by the consecutive activity of prolipoprotein diacylglyceryl ransferace (Lgt) and lipoprotein signal peptidase (LspA).

In Gram-negative bacteria, the prolipoproteins are translocated across the cytoplasmic membrane via a secA-dependent pathway. After translocation of the preprolipoprotein, the p of the preprolipoprotein, the phosphatidylglycerol:prolipoprotein diacylglyceryl transferase (lgt) transfers a diacylglyceryl moiety from phosphaatylglycerol to the sulph diacylglyceryl transferase (lgt) transfers a diacylglyceryl moiety from phosphaatylglycerol to the sulphydryl group of the prolipoprotein.

Diacylglyceryl modification is a prerequisite for the cleavage of the signal peptide bythe lipoprotein-specific sgnal peptidase (LspA). Lipoproteins are anchored to the cell membrane by the lipidated N-terminus. LspA is essential for growth and viability of Gram-negative bacteria.