Coronavirus

Coronaviruses are species in the genera of virus belonging to the subfamily Coronavirinae in the family Coronaviridae.[1][2] Coronaviruses are enveloped viruses with apositive-sense RNA genome and with a nucleocapsid of helical symmetry. The genomic size of coronaviruses ranges from approximately 26 to 32 kilobases, extraordinarily large for an RNA virus. The name "coronavirus" is derived from the Latin corona, meaning crown or halo, and refers to the characteristic appearance ofvirions under electron microscopy (E.M.) with a fringe of large, bulbous surface projections creating an image reminiscent of the solar corona. This morphology is created by the viral spike (S) peplomers, which are proteins that populate the surface of the virus and determine host tropism. Coronaviruses are grouped in the order Nidovirales, named for the Latin nidus, meaning nest, as all viruses in this order produce a 3' co-terminal nested set of subgenomic mRNA's during infection. Proteins that contribute to the overall structure of all coronaviruses are the spike (S), envelope (E), membrane (M) and nucleocapsid (N). In the specific case of the SARS coronavirus (see below), a defined receptor-binding domain on S mediates the attachment of the virus to its cellular receptor, angiotensin-converting enzyme 2 (ACE2).[3]Some coronaviruses (specifically the members of Betacoronavirus subgroup A) also have a shorter spike-like protein called hemagglutinin esterase (HE)

Diseases caused by coronaviruses

Coronaviruses primarily infect the upper respiratory and gastrointestinal tract of mammals and birds. Four to five different currently known strains of coronaviruses infect humans. The most publicized human coronavirus, SARS-CoV which causes SARS, has a unique pathogenesis because it causes both upper and lower respiratory tract infections and can also cause gastroenteritis. Coronaviruses are believed to cause a significant percentage of all common colds in human adults. Coronaviruses cause colds in humans primarily in the winter and early spring seasons. The significance and economic impact of coronaviruses as causative agents of the common cold are hard to assess because, unlikerhinoviruses (another common cold virus), human coronaviruses are difficult to grow in the laboratory. Coronaviruses can even cause pneumonia, either direct viral pneumonia or a secondary bacterial pneumonia. In chickens, the infectious bronchitis virus (IBV), a coronavirus, targets not only the respiratory tract but also the uro-genital tract. The virus can spread to different organs throughout the chicken. Coronaviruses also cause a range of diseases in farm animals and domesticated pets, some of which can be serious and are a threat to the farming industry. Economically significant coronaviruses of farm animals include porcine coronavirus (transmissible gastroenteritis coronavirus, TGE) and bovine coronavirus, which both result in diarrhea in young animals. Feline Coronavirus: two forms, Feline enteric coronavirus is a pathogen of minor clinical significance, but spontaneous mutation of this virus can result in feline infectious peritonitis (FIP), a disease associated with high mortality. There are two types ofcanine coronavirus (CCoV), one that causes mild gastrointestinal disease and one that has been found to cause respiratory disease. Mouse hepatitis virus (MHV) is a coronavirus that causes an epidemicmurine illness with high mortality, especially among colonies of laboratory mice. Prior to the discovery of SARS-CoV, MHV had been the best-studied coronavirus both in vivo and in vitro as well as at the molecular level. Some strains of MHV cause a progressive demyelinating encephalitis in mice which has been used as a murine model for multiple sclerosis. Significant research efforts have been focused on elucidating the viral pathogenesis of these animal coronaviruses, especially by virologists interested in veterinary and zoonotic diseases.

Replication
Replication of Coronavirus begins with entry to the cell which takes place in the cytoplasm in a membrane-protected microenvironment. Upon entry to the cell the virus particle is uncoated and the RNA genome is deposited into the cytoplasm. The Coronavirus genome has a 5 methylated cap and a 3polyadenylated tail. This also allows the RNA to attach to ribosomes for translation. Coronaviruses also have a protein known as a replicase encoded in its genome which allows the RNA viral genome to be transcribed into new RNA copies using the host cells machinery. The replicase is the first protein to be made as once the gene encoding the replicase is translated the translation is stopped by a stop codon. This is known as a nested transcript, where the transcript only encodes one geneit is monocistronic. The RNA genome is replicated and a long polyprotein is formed, where all of the proteins are attached. Coronaviruses have a non-structural protein called a protease which is able to

separate the proteins in the chain. This is a form of genetic economy for the virus allowing it to encode the greatest number of genes in a small number of nucleotides. Coronavirus transcription involves a discontinuous RNA synthesis (template switch) during the extension of a negative copy of the subgenomic mRNAs. Basepairing during transcription is a requirement. Coronavirus N protein is required for coronavirus RNA synthesis, and has RNA chaperone activity that may be involved in template switch. Both viral and cellular proteins are required for replication and transcription. Coronaviruses initiate translation by cap-dependent and cap-independent mechanisms. Cell macromolecular synthesis may be controlled after Coronavirus infection by locating some virus proteins in the host cell nucleus. Infection by different coronaviruses cause in the host alteration in the transcription and translation patterns, in the cell cycle, thecytoskeleton, apoptosis and coagulation pathways, inflammation, and immune and stress responses.

Severe acute respiratory syndrome

In 2003, following the outbreak of Severe acute respiratory syndrome (SARS) which had begun the prior year in Asia, and secondary cases elsewhere in the world, the World Health Organization issued a press release stating that a novel coronavirus identified by a number of laboratories was the causative agent for SARS. The virus was officially named the SARS coronavirus (SARS-CoV). The epidemic resulted in over 8,000 infections, about 10% of which resulted in death. [3] X-ray crystallography studies performed at the Advanced Light Source of Lawrence Berkeley National Laboratory have begun to give hope of a vaccine against the disease "since [the spike protein] appears to be recognized by the immune system of the host.

Recent discoveries of novel human coronaviruses

Following the high-profile publicity of SARS outbreaks, there has been a renewed interest in coronaviruses among virologists. For many years, scientists knew about only two human coronaviruses (HCoV-229E and HCoV-OC43). The discovery of SARS-CoV added a third human coronavirus. By the end of 2004, three independent research labs reported the discovery of a fourth human coronavirus. It has been named NL63, NL, and the New Haven coronavirus by different research groups.[6] The three labs are still arguing over which one discovered the virus first and has the right to name it. Early in 2005, a research team at the University of Hong Kong reported finding a fifth human coronavirus in two patients with pneumonia. They named it Human coronavirus HKU1. In September 2012, what is believed to be a sixth new type of coronavirus, tentatively referred to as Novel Coronavirus 2012,[7] being like SARS (but still distinct from it and from the common-cold coronavirus) was discovered in Qatar and Saudi Arabia.[8] The World Health Organisation has accordingly issued a global alert[9] and an interim case definition to help countries to strengthen health protection measures against it.[10] The WHO update on 28 September 2012 said that the virus did not seem to pass easily from person to person.[11] However, on May 12, 2013, a case of contamination from human to human in France was confirmed by the French Ministry of Social Affairs and Health.[12] In addition, cases of person-to-person transmission have been reported by the Ministry of Health in Tunisia. Two confirmed cases seem to have caught the disease from their late father, who became ill after a visit to Qatar and Saudi Arabia. So far there have been twenty-two cases and ten deaths in eastern Saudi Arabia.[13] After the DutchErasmus Medical Centre sequenced the virus, the virus was given a new name, Human Corona Virus-Erasmus Medical Centre (HCoV-EMC). The final name for the virus is: Middle East respiratory syndrome coronavirus (MERS-CoV).

Host tropism
Host tropism is the name given to a process of tropism that determines which cells can become infected by a given pathogen. Various factors determine the ability of a pathogen to infect a particular cell. Viruses, for example, must bind to specific cell surface receptors to enter a cell. If a cell does not express these receptors then the virus cannot normally infect it. Viral tropism is determined by a combination of susceptibility and permissiveness: a host cell must be both permissive (allow viral entry) and susceptible (possess the receptor complement needed for viral entry) for a virus to establish infection.

An example of this is the human immunodeficiency virus, which exhibits tropism for CD4 related immune cells (e.g. T helper cells, macrophages or dendritic cells). These cells express a CD4 receptor, to which HIVcan bind, through the gp120 and gp41 proteins on its surface. Another example is the EpsteinBarr virus (EBV).

Hemagglutinin esterase
Hemagglutininesterase is a protein of the envelope of some viruses. Its function is related with the pathogenicity of the virus and with its interaction with the host. It may help the virus bind and enter the mucuslayer of the intestinal way.

Viral pneumonia
Viral pneumonia is a pneumonia caused by a virus.[1] Viruses are one of the two major causes of pneumonia, the other being bacteria; less common causes are fungi and parasites. Viruses are the most common cause of pneumonia in children, while in adults bacteria are a more common cause

Signs and symptoms

Symptoms of viral pneumonia include fever, non-productive cough, runny nose, and systemic symptoms (e.g. myalgia, headache). Different viruses cause different symptoms.

Cause
Common causes of viral pneumonia are: Influenza virus A and B[3] Respiratory syncytial virus (RSV)[3] Human parainfluenza viruses (in children)[3]

Rarer viruses that commonly result in pneumonia include: Adenoviruses (in military recruits)[3] Metapneumovirus[4] Severe acute respiratory syndrome virus (SARS coronavirus) [5]

Viruses that primarily cause other diseases, but sometimes cause pneumonia include: Herpes simplex virus (HSV), mainly in newborns Varicella-zoster virus (VZV) Measles virus Rubella virus Cytomegalovirus (CMV), mainly in people with immune system problems

The most commonly identified agents in children are respiratory syncytial virus, rhinovirus, human metapneumovirus, human bocavirus, and parainfluenza viruses.

Pathophysiology
Viruses must invade cells in order to reproduce. Typically, a virus will reach the lungs by traveling in droplets through the mouth and nose with inhalation. There, the virus invades the cells lining the airways and the alveoli. This invasion often leads to cell death either through direct killing by the virus or by self-destruction through apoptosis. Further damage to the lungs occurs when the immune system responds to the infection. White blood cells, in particular lymphocytes, are responsible for activating a variety of chemicals (cytokines) which cause leaking of fluid into the alveoli. The combination of cellular destruction and fluid-filled alveoli interrupts the transportation of oxygen into the bloodstream. In addition to the effects on the lungs, many viruses affect other organs and can lead to illness affecting many different bodily functions. Viruses also make the body more susceptible to bacterial infection; for this reason, bacterial pneumonia often complicates viral pneumonia.

Prevention
The best prevention against viral pneumonia is vaccination against influenza, adenovirus, chickenpox, herpes zoster, measles, and rubella.

Treatment
In cases of viral pneumonia where influenza A or B are thought to be causative agents, patients who are seen within 48 hours of symptom onset may benefit from treatment with oseltamivir or zanamivir.Respiratory syncytial virus (RSV) may be treated with ribavirin. Herpes simplex virus and varicella-zoster virus infections are usually treated with aciclovir, whilst ganciclovir is used to treat cytomegalovirus. There is no known efficacious treatment for pneumonia caused by SARS coronavirus, adenovirus, hantavirus, parainfluenza or H1N1 virus[citation needed]; treatment is largely supportive

Bacterial pneumonia
Bacterial pneumonia is a type of pneumonia caused by bacterial infection.

Sign and symptoms

Fever Rigors Cough Runny nose Dyspnea - shortness of breath Chest pain[2] Pneumococcal pneumonia can cause coughing up of blood , or Hemoptysis,Characteristically associated with "rusty" sputum

Types
Gram-positive
Streptococcus pneumoniae (J13) is the most common bacterial cause of pneumonia in all age groups except newborn infants. Streptococcus pneumoniae is a Gram-positive bacterium that often lives in the throat of people who do not have pneumonia. Other important Gram-positive causes of pneumonia are Staphylococcus aureus (J15.2) and Bacillus anthracis.

Gram-negative
Gram-negative bacteria are seen less frequently: Haemophilus influenzae (J14), Klebsiella pneumoniae (J15.0), Escherichia coli (J15.5), Pseudomonas aeruginosa (J15.1), Bordetella pertussis, andMoraxella catarrhalis are the most common. These bacteria often live in the gut and enter the lungs when contents of the gut (such as vomit or faeces) are inhaled.

Atypical
"Atypical" bacteria are Coxiella burnetii, Chlamydophila pneumoniae (J16.0), Mycoplasma pneumoniae (J15.7), and Legionella pneumophila. Many people falsely believe they are called "atypical" because they are uncommon and/or do not respond to common antibiotics and/or cause atypical symptoms. In reality, they are "atypical" because they do not gram stain as well as gram-negative and gram-positive organisms. Pneumonia caused by Yersinia pestis is usually called pneumonic plague.

Pathophysiology
Bacteria typically enter the lung with inhalation, though they can reach the lung through the bloodstream if other parts of the body are infected. Often, bacteria live in parts of the upper respiratory tract and are continuously being inhaled into the alveoli. Once inside the alveoli, bacteria travel into the spaces between the cells and also between adjacent alveoli through connecting pores. This invasion triggers theimmune system to respond by sending white blood cells responsible for attacking microorganisms (neutrophils) to the lungs. The neutrophils engulf and kill the offending organisms but also release cytokines that result in a general activation of the immune system. This results in the fever, chills, and fatigue common in bacterial and fungal pneumonia. The neutrophils, bacteria, and fluid leaked from surrounding blood vessels fill the alveoli and result in impaired oxygen transportation.

Bacteria often travel from the lung into the blood stream and can result in serious illness such as septic shock, in which there is low blood pressure leading to damage in multiple parts of the body including thebrain, kidney, and heart. They can also travel to the area between the lungs and the chest wall, called the pleural cavity.

Gram-positive organisms

Streptococcus pneumoniae amoxicillin (or erythromycin in patients allergic to penicillin); cefuroxime and erythromycin in severe cases. Staphylococcus aureus flucloxacillin (to counteract the organism's -lactamase).

Gram-negative organisms
Haemophilus influenzae doxycycline Klebsiella pneumoniae Escherichia coli Pseudomonas aeruginosa ciprofloxacin Moraxella catarrhalis

Atypical organisms
Chlamydophila pneumoniae doxycycline Chlamydophila psittaci erythromycin Mycoplasma pneumoniae erythromycin Coxiella burnetti erythromycin Legionella pneumophila erythromycin, with rifampicin sometimes added.

People who have difficulty breathing due to pneumonia may require extra oxygen. An extremely sick individual may require artificial ventilation and intensive care as life-saving measures while his or her immune system fights off the infectious cause with the help of antibiotics and other drugs.

Hemagglutinin
Hemagglutinin or haemagglutinin (British English) refers to a substance that causes red blood cells to agglutinate. This process is called hemagglutinationor haemagglutination. Antibodies[1] and lectins[2] are commonly known hemagglutinins.

Types
Examples include: Influenza hemagglutinin Measles hemagglutinin Parainfluenza hemagglutinin-neuraminidase Mumps hemagglutinin-neuraminidase The PH-E form of phytohaemagglutinin

Uses in serology
Hemagglutination can be used to identify RBC surface antigens (with known antibodies) or to screen for antibodies (with RBCs with known surface antigens). Using anti-A and anti-B antibodies that bind specifically to either the A or to the B blood group surface antigens on RBCs it is possible to test a small sample of blood and determine the ABO blood group (or blood type) of an individual. The bedside card method of blood grouping relies on visual agglutination to determine an individual's blood group. The card has dried blood group antibody reagents fixed onto its surface and a drop of the individual's blood is placed on each area on the card. The presence or absence of visual agglutination enables a quick and convenient method of determining the ABO and Rhesus status of the individual. Agglutination of red blood cells is used in the Coombs test.

Atypical pneumonia
Atypical pneumonia, also known as walking pneumonia, is an atypical pneumonia not caused by one of the more traditional pathogens. Its clinical presentation contrasts to that of "typical"

pneumonia. A variety of microorganisms can cause it. When it develops independently from another disease it is called primary atypical pneumonia (PAP). The term was introduced in the 1930s[1][2] and was contrasted with the bacterial pneumonia caused by Streptococcus pneumoniae, at that time the best known and most commonly occurring form of pneumonia. The distinction was historically considered important as it differentiated those more likely to present with "typical" respiratory symptoms and lobar pneumonia from those more likely to present with "atypical" generalized symptoms (such as fever, headache, and myalgia) andbronchopneumonia.[3] Distinction between atypical and typical pneumonia, however, is medically insufficient. For the treatment of pneumonia it is important to know the exact causal organism. Moreover, S. pneumoniae has become a relatively less important cause.

Terminology
"Primary atypical pneumonia" is called primary because it develops independently of other diseases. "Atypical pneumonia" is atypical in that it is caused by atypical organisms (other than Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis).[4] These atypical organisms include specialbacteria, viruses, fungi, and protozoa. In addition, this form of pneumonia is atypical in presentation with only moderate amounts of sputum, no consolidation, only small increases in white cell counts, and no alveolar exudate.[5][6] At the time that atypical pneumonia was described first, organisms like Mycoplasma, Chlamydophila, and Legionella still were not recognized as bacteria and instead considered as viruses. Hence "atypical pneumonia" was also called "non-bacterial".[7] In literature the term atypical pneumonia (contrasted with bacterial pneumonia) is still in use, though incorrect. Meanwhile, many of such organisms are identified as bacteria, albeit unusual types (Mycoplasma is a type of bacteria without a cell wall and Chlamydias are intracellular parasites). As the conditions caused by these agents have different courses and respond to different treatments, the identification of the specific causative pathogen is important.

Cause
The most common causative organisms are (often intracellular living) bacteria:[6] Chlamydophila pneumoniae Mild form of pneumonia with relatively mild symptoms. Chlamydia psittaci Causes psittacosis. Coxiella burnetii Causes Q fever. Francisella tularensis Causes tularemia. Legionella pneumophila Causes a severe form of pneumonia with a relatively high mortality rate, known as legionellosis or Legionnaires' disease. Mycoplasma pneumoniae [12] Usually occurs in younger age groups and may be associated with neurological and systemic (e.g. rashes) symptoms. "Klebsiella pneumoniae" Mostly seen in immunocompromised patients. Atypical pneumonia can also have a fungal, protozoan or viral cause.[13][14] In the past, most organisms were difficult to culture. However, newer techniques aid in the definitive identification of the pathogen, which may lead to more individualized treatment plans.

Viral
When comparing the bacterial-caused atypical pneumonias with these caused by real viruses (excluding bacteria that were wrongly considered as viruses), the term "atypical pneumonia" almost always implies a bacterial etiology[citation needed] and is contrasted with viral pneumonia. Known viral causes of atypical pneumonia include Respiratory Syncytial Virus (RSV), Influenza A and B, Parainfluenza, Adenovirus, severe acute respiratory syndrome (SARS)[15] and measles

Hemagglutinin (influenza)
Influenza hemagglutinin (HA) or haemagglutinin (British English) is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein. It is

responsible for binding the virus to the cell that is being infected. HA proteins bind to cells with sialic acid on the membranes, such as cells in the upper respiratory tract or erythrocytes.[1] The name "hemagglutinin" comes from the protein's ability to cause red blood cells (erythrocytes) to clump together ("agglutinate") in vitro

Subtypes
There are at least 17 different HA antigens. These subtypes are named H1 through H17. H16 was discovered only in 2004 on influenza A viruses isolated from blackheaded gulls from Sweden and Norway. The most recent H17 was discovered in 2012 in fruit bats.[3][4] The first three hemagglutinins, H1, H2, and H3, are found in human influenza viruses. Viral neuraminidase (NA) is another protein found on the surface of influenza. Influenza viruses are characterised by the type of HA and NA that they carry; hence H1N1, H5N2 etc. A highly pathogenic avian flu virus of H5N1 type has been found to infect humans at a low rate. It has been reported that single amino acid changes in this avian virus strain's type H5 hemagglutinin have been found in human patients that "can significantly alter receptor specificity of avian H5N1 viruses, providing them with an ability to bind to receptors optimal for human influenza viruses". [5][6] This finding seems to explain how an H5N1 virus that normally does not infect humans can mutate and become able to efficiently infect human cells. The hemagglutinin of the H5N1 virus has been associated with the high pathogenicity of this flu virus strain, apparently due to its ease of conversion to an active form by proteolysis.

Function and mechanism

HA has two functions. Firstly, it allows the recognition of target vertebrate cells, accomplished through the binding to these cells' sialic acid-containing receptors. Secondly, once bound it facilitates the entry of the viral genome into the target cells by causing the fusion of host endosomal membrane with the viral membrane.[9] HA binds to the monosaccharide sialic acid which is present on the surface of its target cells, which causes the viral particles to stick to the cell's surface. The cell membrane then engulfs the virus and the portion of the membrane that encloses it pinches off to form a new membrane-bound compartment within the cell called anendosome, which contains the engulfed virus. The cell then attempts to begin digesting the contents of the endosome by acidifying its interior and transforming it into alysosome. However, as soon as the pH within the endosome drops to about 6.0, the original folded structure of the HA molecule becomes unstable, causing it to partially unfold and release a very hydrophobic portion of its peptide chain that was previously hidden within the protein.[10] This so-called "fusion peptide" acts like a molecular grappling hook by inserting itself into the endosomal membrane and locking on. Then, when the rest of the HA molecule refolds into a new structure (which is more stable at the lower pH), it "retracts the grappling hook" and pulls the endosomal membrane right up next to the virus particle's own membrane, causing the two to fuse together. Once this has happened, the contents of the virus, including its RNA genome, are free to pour out into the cell's cytoplasm

Structure
HA is a homotrimeric integral membrane glycoprotein. It is shaped like a cylinder, and is approximately 13.5 nanometres long. The three identical monomers that constitute HA are constructed into a central helix coil; three spherical heads contain the sialic acid binding sites. HA monomers are synthesized as precursors that are then glycosylated and cleaved into two smaller polypeptides: the HA1 and HA2 subunits. Each HA monomer consists of a long, helical chain anchored in the membrane by HA2 and topped by a large HA1 globule.

Neutralizing antibodies
Since hemagglutinin is the major surface protein of the influenza A virus and is essential to the entry process, it is the primary target of neutralizing antibodies. Neutralizing antibodies against flu have been found to act by two different mechanisms, mirroring the dual functions of hemagglutinin: 1. Inhibition of attachment to target cells 2. Inhibition of membrane fusion (entry) Most commonly, antibodies against hemagglutinin act by inhibiting attachment. This is because these antibodies bind near the top of the hemagglutinin "head" (blue region in figure at right) and physically

block the interaction with sialic acid receptors on target cells. In contrast, some antibodies have been found to have no effect on attachment. Instead, this latter group of antibodies acts by preventing membrane fusion. Most of these antibodies, like the human antibodies F10,[11] FI6,[12] CR6261, recognize sites in the stem/stalk region region (orange region in figure at right), far away from the receptor binding site.[13][14] The stem (also called HA2), contains most of the membrane fusion machinery of the hemagglutinin protein, and antibodies targeting this region block key structural changes that drive the membrane fusion process. However, at least one fusion-inhibiting antibody was found to bind closer to the top of hemagglutinin, and is thought to work by cross-linking the heads together, the opening of which is thought to be the first step in the membrane fusion process.

Legionella pneumophila
Legionella pneumophila is a thin, aerobic, pleomorphic, flagellated, non-spore forming, Gramnegative bacterium of the genus Legionella.[1][2] L. pneumophila is the primary human pathogenic bacterium in this group and is the causative agent of legionellosis or Legionnaires' disease.

Characterization
L. pneumophila is a gram-negative, non-encapsulated, aerobic bacillus with a single, polar flagellum often characterized as being a coccobacillus. It is aerobic and unable to hydrolyse gelatin or produce urease. It is also non-fermentative. L. pneumophila is neither pigmented nor does it autofluoresce. It is oxidase- and catalase-positive, and produces beta-lactamase. L. pneumophila has a colony morphology that is gray-white with a textured, cut-glass appearance; it also requires cysteine andiron to thrive. It will grow on yeast extract in "opal-like" colonies.

Pathogenesis
In humans, L. pneumophila invades and replicates in macrophages. The internalization of the bacteria can be enhanced by the presence of antibody and complement, but is not absolutely required. Internalization of the bacteria appears to occur through phagocytosis however L. pneumophilais also capable of infecting non-phagocytic cells through an unknown mechanism. A rare form of phagocytosis known as coiling phagocytosis has been described for L. pneumophila however this is not dependent on the Dot/Icm secretion system and has been observed for other pathogens. [6] Once internalized, the bacteria surround themselves in a membrane-bound vacuole that does not fuse with lysosomes that would otherwise degrade the bacteria. In this protected compartment, the bacteria multiply.