Bioinformatics in pandemic Script

BIOINFORMATICS IN PANDEMIC
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INTRODUCTION
Although high-throughput techniques are an integral part of today’s drug and vaccine
discovery process, accelerating the process manifold, the introduction of a new drug
or vaccine in the market still takes 10–15 years and therefore requires a huge
investment [Plotkin, 2005]. Technological advancements, along with improved and
innovative strategies, could reduce the cost and the time required to develop a new
drug. Most infectious diseases are caused by viral and bacterial pathogens. An
increase of 58% in the mortality rate due to such infectious diseases has been reported
from 1980 to 1992 in the United States [Pinner et al., 1996]. According to the 2004
World Health Organization Report
[www.who.int/whr/2004/annex/topic/en/annex_2_en.pdf], 16.4 million people died
worldwide in that year from infectious diseases. Although several antibiotics are
currently available for each bacterial pathogen, the emerging drug-resistant strains of
such pathogens make them difficult to control, perhaps due to decades-old uses of
such drugs in human patients [Arias and Murray, 2009].
Drug target identification is the first step in the drug discovery process [Chan et
al., 2010]. Because of the availability of both pathogen and host–genome sequences,
it has become easier to identify drug targets at the genomic level for any given
pathogen [Allsop, 1998; Stumm et al., 2002; Meinke et al., 2004; Owa, 2007]. In recent
years, the strategies are shifting progressively from a generic approach to genomic
and metabolomic approaches to identify novel drug targets that are required to design
new defenses against antibiotic resistant pathogens. Tremendous advancements
have been made in target identification and drug discovery since the human genome
sequence became available [Lander et al., 2001; Venter et al., 2001].

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Use of computational approaches, with integrated genomics, proteomics,
transcriptomics, interactomics, signalomics, and metabolomics, are current trends in
target discovery for most human diseases, especially for cancer, cardiovascular,
neuroendocrine, and infectious diseases; they make the discovery process faster and
more cost effective. Currently, genomics and more specifically in silico comparative,
subtractive, and functional genomics are being widely used to identify novel drug and
vaccine targets in order to develop effective antibacterial agents and vaccines against
bacterial pathogens that are either resistant to existing antibacterial regimens or for
which a suitable vaccine is not available [Pucci, 2006].
WHAT IS PANDEMIC?
A pandemic is defined as “an epidemic occurring worldwide, or over a very wide
area, crossing international boundaries and usually affecting a large number of
people”. The classical definition includes nothing about population immunity, virology
or disease severity. By this definition, pandemics can be said to occur annually in each
of the temperate southern and northern hemispheres, given that seasonal epidemics
cross international boundaries and affect a large number of people. However,
seasonal epidemics are not considered pandemics.
A true influenza pandemic occurs when almost simultaneous transmission
takes place worldwide. In the case of pandemic influenza A(H1N1), widespread
transmission was documented in both hemispheres between April and September
2009. Transmission occurred early in the influenza season in the temperate southern
hemisphere but out of season in the northern hemisphere. This out-of-season
transmission is what characterizes an influenza pandemic, as distinct from a pandemic
due to another type of virus.

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Figure 1: Diagram representing the spread of a pandemic
Simultaneous worldwide transmission of influenza is sufficient to define an
influenza pandemic and is consistent with the classical definition of “an epidemic
occurring worldwide”. There is then ample opportunity to further describe the potential
range of influenza pandemics in terms of transmissibility and disease severity. The
emerging evidence for A(H1N1) is that transmissibility, as estimated by the effective
reproduction number (R, or average number of people infected by a single infectious
person) ranged from 1.2 to 1.3 for the general population but was around 1.5 in
children (Kathryn Glass, Australian National University, personal communication).
Some early estimates of R for pandemic influenza H1N1 2009 may have been
overestimated.
Severity, as estimated by the case fatality ratio, probably ranged from 0.01 to
0.03%. These values are very similar to those normally seen in the case of seasonal
influenza. However, the number of deaths was higher in younger people, a recognized
feature of previous influenza pandemics.

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It is tempting to surmise that the complicated pandemic definitions used by the
World Health Organization (WHO) and the Centers for Disease Control and Prevention
of the United States of America involved severity in a deliberate attempt to garner
political attention and financial support for pandemic preparedness. As noted by Doshi,
the perceived need for this support can be understood given concerns about influenza
A(H5N1) and the severe acute respiratory syndrome (SARS). However, conflating
spread and severity allowed the suggestion that 2009 A(H1N1) was not a pandemic.
It was, in fact, a classical pandemic, only much less severe than many had anticipated
or were prepared to acknowledge, even as the evidence accumulated.
In 2009 WHO declared a pandemic several weeks after the criteria for the
definition of a classical pandemic had been met. Part of the delay was no doubt related
to the nexus between the formal declaration of a pandemic and the manufacture of a
pandemic-specific vaccine. If a classical pandemic definition had been used, linking
the declaration to vaccine production would have been unnecessary. This could have
been done with a severity index and, depending on the availability and quality of the
emerging evidence on severity, a pandemic specific vaccine may have been deemed
unnecessary. Alternatively authorities may have decided to order vaccine in much
smaller quantities.
The response to A(H1N1) has been justified as being precautionary, but a
precautionary response should be rational and proportionate and should have
reasonable chances of success. We have argued that the population-based public
health responses in Australia and, by implication, elsewhere, were not likely to
succeed. Similarly, the authors of the draft report on the response to the International
Health Regulations during the 2009 pandemic note that what happened during the
pandemic reflected the activity of the virus and, by implication, not the interventions.

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Risk is assessed by anticipation of severity and precaution should be calibrated
to risk. As Doshi has argued, we need to redefine pandemic influenza. We can
then describe the potential severity range of future pandemics. Finally, we need to use
evidence to assess severity early to anticipate risk. [WHO bulletin].
The approach of reductive genomics
Subtractive genomics is the process in which the subtraction of sequences
between host and the pathogen proteome which helps in providing information for a
set of proteins which are essential to pathogen but are not present in the host.
Subtractive genomics plays an important role in identification of potential drug targets.
These targets are those proteins which are considered essential for the survival of the
organism [Dutta et al., 2006].
Subtractive genomics studies applied in 3 types of cases
i. Multi-Drug resistant pathogenic organism:
Salmonella enterica serovar typhi is a human-specific gram-negative pathogen
causing enteric typhoid fever, a severe infection of the Reticuloendothelial system.
Infection of S. typhi leads to the development of typhoid, or enteric fever. This
disease is characterized by the sudden onset of a sustained and systemic fever,
severe headache, nausea, and loss of appetite. [Everest et al. 2001]. Worldwide,
typhoid fever affects roughly millions of people annually, causing deaths. The early
administration of antibiotic treatment has proven to be highly effective in eliminating
infections, but indiscriminate use of antibiotics has led to the emergence of
multidrug-resistant strains of S. enterica serovar Typhi.
Listeriosis, the infectious disease caused by Listeria monocytogenes causes serious
localized and generalized infections in humans especially among pregnant women,
the elderly or individuals with a weakened immune system. In serious cases,
it can lead to brain infection and even death. Several symptoms are ranged from

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flu-like illness to severe complications including meningitis, septicemia,
spontaneous abortion or listeriosis of the newborn (FAO/WHO, 2002). The
prolonged and uncontrolled use of antibiotics in treatment against many pathogens
has caused the multiple drug resistance. [WHO,2002].
ii. Pathogenic organisms with No effective drugs available:
The Leishmania donovani is an intracellular parasite causing kala azar disease, which
is almost always fatal if left untreated. As there is no effective medicine available so
far, leishmaniasis infection is a worldwide public health challenge.
Botulism (Latin, botulus, "sausage") also known as botulinus intoxication is a rare but
serious paralytic illness caused by botulinum toxin, which is produced by the bacterium
Clostridium botulinum. Severe botulism leads to reduced movement of the muscles of
respiration, and this may be experienced as dyspnea (difficulty breathing), but when
severe can lead to respiratory failure which may lead to coma and eventually
death if untreated. Clostridium botulinum would normally be harmless to humans, but
it can infect by a virus, the viral DNA gets integrated into the bacterial genome, causes
the host to produce toxins. Neurotoxin production is the unifying feature of the species
C. botulinum. Seven types of toxins have been identified and allocated a letter
(A-G). Organisms genetically identified as other Clostridium species have caused
human botulism, Clostridium butyricum producing type E toxin and Clostridium baratii
producing type F toxin. The ability of C. botulinum to naturally transfer neurotoxin
genes to other clostridia is concerning, especially in the food industry where
preservation systems are designed to destroy or inhibit only Clostridium botulinum but
no other Clostridium species. [Tomb et al., 1997].
iii. Pathogenic organism with no virulence factor identified:
Streptococcus Suis are a Gram-positive, facultative anaerobe coccus, possessing
cell wall antigenic determinants. S. suis is responsible for a wide variety of porcine
disease syndromes, such as meningitis, septicae.mia, arthritis and endocarditis.It has
more than 35 serotype which are responsible in the cause of serious infections in

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humans [Higgins et al., 1998]. Since no critical virulence factor is well known in
the pathogen they applied in silico subtractive proteomics approach to identify
potent drug targets in S. suis so that new drugs can be tailored to resist this zoonotic
emerging disease.
Figure 2: Diagram representing the application of bioinformatics in vaccine and drug discovery path.
Application of Bioinformatics

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Conclusion:
The result analysis shows that subtractive genomics approach can be successfully
applied to identify drug targets in a pathogenic organisms which is specific for that
organisms and hence drugs against it cannot show cross reactions with human
proteins. Wet lab analysis of the derived essential organism specific targets
obtained from the above said studies can enhance the drug development process.
Bioinformatics can aid in identification of drug or vaccine targets at the earliest with
least resources and economy

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