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Viral Gastroenteritis in Ghana

Viral Gastroenteritis in Ghana

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An essay for the 2012 Undergraduate Awards (International Programme) Competition by Chuan-jay Jeffrey Chen. Originally submitted for Junior Independent Work at Princeton University, with lecturer Adel Mahmoud in the category of Medical Sciences
An essay for the 2012 Undergraduate Awards (International Programme) Competition by Chuan-jay Jeffrey Chen. Originally submitted for Junior Independent Work at Princeton University, with lecturer Adel Mahmoud in the category of Medical Sciences

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Published by: Undergraduate Awards on Aug 31, 2012
Copyright:Attribution Non-commercial

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10/27/2013

 
 ABSTRACT
Diarrheal diseases cause significant morbidity and mortality worldwide, particularlyamong children under age 5. Most of the 2.5 million annual diarrhea-related deaths occurin developing countries. In these settings, poor sanitation practices promote the spread of diarrheal diseases. Furthermore, access to sufficient medical care and oral rehydrationtreatment is extremely limited, and patients with diarrhea place a disproportionately largeburden on hospitals and health systems.Rotaviruses are the leading cause of acute gastroenteritis, a medical conditioncharacterized by diarrhea and vomiting resulting from inflammation of the gastrointestinaltract. Two live-attenuated oral rotavirus vaccines, Rotateq (Merck & Co.) and Rotarix(GlaxoSmithKline) have proven to be highly effective against severe rotavirusgastroenteritis in developed settings throughout Europe and the Americas. However, bothvaccines prove to be less effective in developing countries in sub-Saharan Africa, Southeast Asia, and Latin America. A likely explanation for this efficacy gap is the increased diversityof rotavirus strains in developing countries that are not included in the currently availablevaccines, which were designed for use in developed countries. Noroviruses are the next leading cause of viral gastroenteritis worldwide. As protection against rotavirus infectionincreases with the introduction of vaccines, it is a possibility that noroviruses may soonsupersede rotaviruses as the most prominent diarrhea-causing agent.In April 2012, health officials in Ghana introduced Rotarix, a monovalent rotavirusvaccine, into the national immunization program. This paper proposes the use of serological and molecular biology techniques to investigate the epidemiology of rotavirusserotypes as well as the impact of the vaccine on prevalent rotavirus strain types. Anothergoal is evaluate the changes in rotavirus gastroenteritis disease burden in Ghana after theintroduction of the vaccine. The ultimate aim of this research is to evaluate the hypothesisthat uncommon rotavirus strains in developing countries reduce vaccine efficacy. Thispaper also proposes to evaluate the epidemiology of norovirus in Ghana. These results willhelp elucidate the causes of the efficacy gap of the rotavirus vaccine between developingand developed countries as well as the potential for further viral gastroenteritisintervention.
 
 
1
Viral Gastroenteritis in Ghana
BACKGROUND & SIGNIFICANCE
 Diarrhea is the passage of loose or liquid stools at a rate that is more frequent thannormal—typically 3 or more times per day.
1
The loss of vital fluids and electrolytes throughdiarrhea can cause severe dehydration, leading to death if left unmanaged. The WorldHealth Organization (WHO) ranks diarrheal diseases as the 5
th
leading cause of mortalityworldwide, with an estimated 2.5 million deaths each year.
2
Over half of these deaths(1.3-1.8 million) occur in children younger than 5 years old, making diarrhea the 2
nd
 leading killer of children globally.
3,4
Of these 1.3 million deaths, 80% are under 2 years old.While there are many causes of diarrhea, it is often a symptom of an infection in thegastrointestinal tract.
1
A variety of pathogens—ranging from bacteria to viruses toprotozoa to helminths—can cause acute gastroenteritis, a medical condition characterizedby inflammation of the gastrointestinal tract.
5
This inflammation results in diarrhea,vomiting, abdominal pain, and often fever. Most pathogens that cause diarrhea aretransmitted from person to person through the fecal-oral route by vehicles such as waterand food. In many developing nations, poor sanitation facilities and practices promote thespread of diarrheal diseases.
6
Moreover, access and use of rehydration therapy is limited inthese countries.
7
Unsurprisingly, of the 1.3 million deaths among children caused bydiarrhea each year, about 800,000 occur in Africa.
4
 
Rotavirus: Profile of a Leading International Killer 
The leading causes of severe acute gastroenteritis are viral. Globally, rotavirus aloneaccounts for about 40% of all cases of diarrheal diseases in children under age 5 that leadto hospital admission.
8
Overall, rotavirus infection is responsible for over 2 millionhospitalizations and an estimated 527,000 deaths worldwide each year.
9,10
Out of thesedeaths, nearly 240,000 are believed to occur in sub-Saharan Africa.
11
The rotavirus diseaseburden and mortality limit the economic development of resource-limited countries; it would thus be beneficial for developing nations like Ghana to reduce rotavirus infectionsthrough vaccination. However, many challenges stand in the way of doing so.Rotaviruses comprise a genus within the family
Reoviridae
(reviewed in [12]) that consists of icosahedral RNA viruses.
12,13
The rotavirus virion is a 100 nm non-envelopedparticle that is made up of 3 protein layers surrounding the genome (Figure 1A-B).
14
Theinnermost is made up of the core shell protein VP2, with the RNA polymerase VP1 and theRNA capping enzyme VP3 attached to the interior side.
15–17
Contained inside of this core isthe genome, which consists of 11 segments of double-stranded RNA (dsRNA). Theintermediate layer is solely made up of VP6. The outer layer consists mostly of the VP7glycoprotein but also contains spikes of the VP4 attachment protein. In the gastrointestinaltract of the infected host, trypsin-like proteases cleave VP4 to yield VP5* and VP8*.
18
VP5*
 
 
2
Viral Gastroenteritis in Ghana
forms the base and stalk of the spike, while VP8* forms the tip (Figure 1C).
14
Together,VP5* and VP8* allow the virus to interact with and penetrate enterocytes in the intestine.
18
 
Figure 1.
Rotavirus protein capsid structure. A: View of the intact triple-layered rotavirus virion. VP4 spikesproject from the VP7 outer capsid shell. B: View of a cut-away of the rotavirus virion, revealing the VP6intermediate layer and the VP2 inner core shell. Contained within the core shell are the 11 dsRNA segmentsthat comprise the rotavirus genome. C: Magnified view focusing on the VP4 spike protein and revealing thedistinct VP8* and VP5* regions.
Figure adapted from [12] with permission.
Rotaviruses are typically classified by serotype and group. Serotype classificationcurrently uses a binary (G/P) system, which is determined by the antigenic propertiesconferred by the proteins in the outer layer of the virion: VP7 (G for Glycoprotein) and VP4(P for Protease-sensitive). Historically, serotype classification was based on the antigenicepitopes of different reference antisera.
19
More recently, the determination of G/P typeshas more often used a genotyping system based on analysis using reverse transcriptionpolymerase chain reaction (RT-PCR) or cDNA libraries.
20,21
Currently, in total, 27 Ggenotypes (G1-G27) and 35 P genotypes (P[1]-P[35]) have been described.
22
It is largelyunknown whether each genotype corresponds to antigenically distinct G/P serotypes.A limitation of the current classification system is that it depends only on 2 genesencoding the 2 outer capsid proteins: VP7 (G) and VP4 (P). However, the rotavirus genomeconsists of 12 total genes, as each dsRNA segment contains a single gene except segment 11,which contains 2 (Figure 2).
23
The current classification system thus ignores 10 genes that code for 4 structural proteins (VP1-3, VP6) and 6 non-structural proteins (NSP1-6). Thesenon-structural proteins support a number of viral functions in the host cell such as genomereplication, viral gene expression, and particle assembly.
12
For example, NSP1 acts as aninterferon antagonist, thus directly regulating the host immune system.
24
NSP4 acts as anenterotoxin. It works by stimulating inositol 1,4,5-trisphosphate (IP
3
) production inintestinal cells, causing an influx of Ca
2+
across the plasma membrane as well as the releaseof Ca
2+
from intracellular sources. This increase in intracellular Ca
2+
concentration causes

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