Translational approach in emerging infectious disease treatment: an update
- *Corresponding Authors:
- Dhilleswara Rao V
Center for Excellence in Genomics
MKU, Tamil Nadu, India
- Dattatreya Adapa
Department of Microbiology
GITAM University, Andhra Pradesh, India
Accepted on May 22, 2017
While the rational understanding on the therapeutic and preventive care of epidemic diseases have enriched our knowledge, recent outbreak of complicated infectious diseases have presented newest challenges towards humankind. It started from the beginning of 19th century when disease infection from unknown origin preferred its host as human and mass mortality altered the socio-economic strata of various corners of the globe. For instance, human being witnessed some newly emerged global burdens such as HIV, Ebola hemorrhage fever, Zika Virus, Sever Acute Respiratory Syndrome (SARS) in the last century. Nevertheless, drastic changes in the environment, mutations in genetic composition and increased population extend the chances for new disease emergence. The inception of biomedical research has brought new diagnosis and treatment options; however, the outbreaks are being surprised and caused by new strains or modified strains. Translational biomedicine is a new context in this regard and raised the hope in integrated approaches to develop new diagnostic and treatment methods. In this review, we have summarized timely information about recently reported disease pathologies, which have challenged the world with mass mortality, and discussed about the causative agents, possible treatment strategies and future perspective for respective diseases.
Infectious diseases, Disease control, Virus infection, Translational medicine, Therapeutic challenges.
In recent past, the threats of infectious diseases have increased rapidly. Regardless the casualties, the infectious diseases can be classified into two categories: emerging and re-emerging diseases. According to the types of pathogen, Zoonotic diseases can be divided into three distinct categories: viral (rabies, yellow fever, HIV infection), bacterial (brucellosis, tuberculosis, anthrax) and parasitic (toxoplasmosis, cysticercosis, and leishmaniasis). However, the main sources of the origin of disease pathologies are wild and domestic animals . Available reports have related the association of infectious diseases and Zoonoses, which extends the host specific understanding of infectious disease. Interestingly, from the very first infectious disease i.e., Plague to the recent outbreak of HIV and Ebola, all are Zoonotic by transmission nature. It is estimated that nearly 75% of viruses and 50% of bacteria are associated with human zoonotic diseases. Zoonotic infection is the major cause of human illnesses, which accounts major causalities mainly in tropical regions. However, in 14% of the human pathogens, the route, etiology and mode of transmission are equivocal [2,3]. There are wide spectra of infectious diseases that emerged and re-emerged are related to travel. The majority of cases of malaria (Traveler’s Malaria) in the United States occur in individuals returning from travel abroad. Therefore, it is important to utilize the services of the specialized travel clinics .
As a context of eradication or prevention of infectious diseases, it is important to understand the biology of pathogens, hosts and the host-pathogen interactions. Identification of essential molecular events or biomarkers may provide strategies for development of new drugs or vaccine candidates. Some of the invertebrate models are reported as animal models for new drug design and discovery. This could be an alternative for the animal models; therefore, new technological approaches are required to utilize invertebrates such as amoeba, Drosophila, Zebrafish as laboratory organisms. These animal models have a unique feature that the whole genomes have been sequenced, which could provide new insights in the association of pathogen-host genetics . Another promising option is metagenomic approach that reveals the chemical diversity for discovery of resistant determinants in clinical and natural environment. As an alternative, metagenomic approach can be used as a potential source to explore the antimicrobial peptides, moreover, antibiotic resistance can also be tackled to reduce the infection and related mortality [6,7]. The manifestations of infectious diseases include both functional and physiological behaviors in immunology of infected individuals that are not clearly understood. The current diagnostic methods are not effective and time consuming procedures. The advancements in pharmacogenomics are believed to be the promising method in identification of adverse effects caused by the therapeutics used to treat the viral infections. More or less, these new technologies offer multidirectional diagnosis and treatment methods for these deadly diseases [8,9].
Zika Virus: The Re-emerged Challenge
Zika virus named after the ZIKA forest in Uganda where the virus was first isolated in 1947. Zika virus is member of Flavivirus family, like its close colleagues dengue, yellow fever, and West Nile fever of Flavivirus family, transmitted through infected Aedes aegypti. There are evidences for the outbreak of Zika virus in 2007 and 2013 in Africa and Southeast Asia but they are not considerably large. In July 2016, the large outbreak reported in USA [10-12]. Most of the cases in the US are travel related or individual exposure to the Zika affected countries [13,14].
Reports suggested that Zika virus infection is associated with neurological abnormalities. It also influences the neurological birth complications after affecting pregnant women in the ground zero zone. It is interesting that, Zika virus is able to cross the blood brain barrier and had a greater affinity to the nervous system. Most of the reported incidences of Zika infection in USA and Latin America are associated with microcephaly or Guillain-Barre syndrome. Solomon et al. reviewed the published data by Center for Disease Control and Prevention and reported that 1-4% of the reported cases are microcephaly, 29% are associated with fetal abnormalities . Nguyen et al. reported that, till August 2016, 11,528 Zika virus cases were confirmed in USA, out of which 1396 were pregnant women and 33 were Guillain-Barre syndrome cases . Diop et al. investigated the epidemiology of Zika virus in a systemic review and reported the endemic epidemiology of Zika virus in Africa, Asia and South and Central America. The study also concluded that there are many travel related infection incidences and diseases pathologies are reported in the Europe and North America . Notwithstanding to the fact that, the mutations also play a key role in re-emerging or emerging infections, and in Zika virus perspective, it appears to have specific mutations in the genetic composition. Wickramasinghe and Steele reviewed the panspermia hypothesis, evolutionary bursts and genome structure of Zika virus. According to the literature available on Zika outbreaks at various times, it is believed that the genome structure has changed at significant levels. Evidences suggested that there is no incidence of microencephaly in the cases reported before 2000, but the recent outbreak is predominant in microencephaly. This is a clear indication for the role of mutations in emerging diseases and new human phenotypes of causative agents .
As of now, there is no screening method or potential therapeutic vaccines reported. To prevent and control Zika virus, it is important to understand pathogenesis, circulation, mode of transmission, vector biology, risk factors and associated disorders and the impact of environmental changes. Awasthi reported that the discovery of fifth serotype of dengue virus has successfully completed the phage III trails and available in Brazil. Vaccine Research Center (VRC), National Institute of Allergy and Infectious Disease (NIAID) and other organizations are working to find effective vaccine candidates against Zika . Recently, Bharat Biotech from India has claimed the invention of Zika vaccine under the trade name of ZIKAVAC™ and successfully completed the initial trial procedure , which could be promising for future therapeutics against Zika infection pathology
Studies have shown that, identification of E protein regions may provide targets for developing of new vaccines. Weltman used information entropy (H) and predicted B cell epitope score to determine the E protein and epitope prediction provide information for potential vaccine design. This computerassisted study facilitates development of an anti-ZIKV vaccine, one with a lowered susceptibility to viral mutational escape . In another report, Ceron-Carrasco et al. summarized the application of computational drug discovery techniques in development of vaccine for the Zika. Advanced virtual screening tests docking techniques, blind docking simulations, Ligand-based virtual screening, etc., have been shown potential to provide valuable solutions and array of panels for biological problems. It is believed that integrated approaches are available for novel drug designing and developing in the context of Zika virus ..
Methicillin-Resistant Staphylococcus aureus: Common Infection of Community
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common infectious diseases first reported in 1960s in United Kingdom, but soon after, large hospital outbreaks reported in the UK in 1970s. MRSA has become endemic due to simpler ways of infection. It is reported that the disease is community based infection, hospital-onset and healthcareassociated community infection. In 1968, the first hospital outbreak of MRSA was reported in Boston, USA. Later the infection became endemic in the United States. The reports suggested that the percentage of MRSA patients in US hospitals increased from 2.4% in 1975 to 29% in 1991 [21-23]. Furthermore, approximately 125,969 MRSA hospitalized cases per year were reported in between 1999 to 2000, in the United States. Between 1998 and 2003, the average percentage of MRSA cases increased and reported 51.6% as ICU infected cases and 42% as non-ICU infected cases [24,25]. Williams summarized some statistical data from the literature and concluded that percentage of MRSA isolates increased from 35.9% in 1992 to 64.4% in 2003 and there were around 94,000 MRSA cases reported out of which 18,000 deaths occurred in 2005 . Another study by Taniguchi et al. showed that antibiotic resistance has greatly increased in the second half of the period. Moreover, the study showed that there is regional difference in antibiotic susceptibility for CA-MRSA .
Available information on the respective issue suggested that, MRSA infection is largely due to the hospital setup and poorly maintained ICU conditions, which causes simple skin infection to life threating infections such as pneumonia, osteomyelitis, etc. . It is believed that there is an association between MRSA and minimum inhibitory concentration. This indicated that it is essential to investigate whether such a discrepancy exists between different MIC measurement methods. Kitano et al. reported various MIC measurement options by using ‘Broth microdilution method’. The study also concluded that MicroScan® prompt method and the MicroScan® turbidity method had fewer discrepancies . In another study, Chaudhary et al. demonstrated that combining ceftriaxone with vancomycin in presence of VRP1020 significantly reduces the MIC and MBEC values against strong biofilm producing MRSA isolates. The study also reported that Linezolid is the second best option after Vancoplus . For the detection of simple microbiological tests take more time to yield the results. Therefore, there is a great need of developing new, efficient, cost-effective and rapid detecting system for screening. Ikeuchi et al. developed a simplified electrochemical method to detect the mecA Gene . Khan et al. reported that, organic nonalkaloid extract derived from R. stricta have antibacterial activities against MRSA. The study successfully showed inhibition of growth in the zone of inhibition ranging between 6 and 19 mm. This study provides new insights in the development of novel drugs .
HIV and AIDS: Global Burden of the History
Over the past three decades, Acquired Immune Deficiency Syndrome (AIDS) came into light as a global epidemic, paving to numerous scientific advances to treat AIDS, which included the identification of Human Immunodeficiency Virus (HIV) disease mechanisms and the introduction of Antiretroviral Therapy (ART) . HIV has maintained its status of being a grave public health problem during these decades firming its position as lethal emerging infection even after the incredible advances in therapeutic regimens and treatment. Since first discovery of HIV long back in the year 1983, there had been spectacular progress in understanding the complex biology of the virus . There is a proverb by Benjamin Franklin that, “An ounce of prevention is worth a pound of cure”, which holds true sense for HIV therapeutics. The virus finds it way of transmission through direct contact of body fluids, which mainly includes blood, semen, vaginal secretions and breast milk. In the developed countries like the United States of America (USA) the risk behaviors like unprotected sex and the sharing of needles and syringes among drug users are the major causes of HIV infection .
It is recently reported that USA has about nearly 1.2 million people living with HIV infection, with a proportion that one in seven people are unaware of their diseased condition . Even though the size of the epidemic is relatively small when compared to the total population of USA, it is heavily concentrated within several key affected populations located geographically in the Southern states which estimate nearly 49% of all new HIV infection cases occurring. Marked from the beginning of the epidemic nearly 659,000 people have died due to AIDS-related illnesses in the USA . The major affected populations can be easily grouped by transmission category i.e. men who have sex with men (MSM), also by race .
A complex set of economic and socioeconomic factors drive risk to these populations, including a lack of access to care, discrimination, homophobia, stigma and poverty . USA is the greatest national funder for HIV research globally, but still faces the major HIV epidemic by itself discovering nearly 50000 new infections each year. USA lacked a comprehensive plan on HIV prevention until 2010, when President Barak Obama created a National HIV/AIDS Strategy. In accordance with the latest strategies released in 2015, it mainly focused on four main aims-firstly, reducing new HIV infection, secondly increasing the access to care and improving the lifestyle of those individuals living with the HIV, thirdly reducing HIV health inequalities and finally achieving a coordinated national response to the epidemic .
The reports and statistics of many national and international organizations suggested HIV and AIDS as a predominant challenge to the world in the past century; therefore, it requires an emergency to find early detection and treatment methods for this disease . Over the past two decades, advancements in the biomedical research offered new insights in the diagnosis and treatment options. Initially, researchers used to suggest simple chemicals to improve the quality of life of an HIV positive patient. On the other hand, there were reports for the mutants HIV and many co-infections such as tuberculosis, fungal and viral pneumonia . Such incidents have motivated the research communities to find better ways to treat the disease. Notable breakthrough research on HIV infection was reported in 2008, which stated about the molecular structure of HIV virus and the discovery was awarded Noble Prize [42,43]. The discovery of Anti-retroviral therapy [44-46], which is believed to be the best available therapeutic option, however, need further understanding of the disease, which leads to the discovery of Highly Activated Anti-retroviral Therapy (HAART) [47-52]. Nevertheless, Neuro AIDS also reported as equal burden to the world, for which personalized nanomedicine [53-57] and advanced theranostic methods [56-58] are available now to cross the blood brain barrier and treat the Neuro-AIDS [59-61].
H1N1: The Altered Re-Emergency
The influenza virus, commonly known as ‘Swine flu’ is a type of acute respiratory disease caused by influenza ‘A’ virus belonging to the Orthomyxoviridae family. The primary clinical symptoms of the viral infection are fever and acute respiratory distress. It also infects many animal species including birds, seals, whales, humans, horses and swine . Under normal conditions, the virus does not infect humans. However, a different strain of influenza virus called ‘variant virus’, which affect via circulation of the sporadic human infections. These variant strains are denoted by adding the letter ‘v’ to the end of the virus subtype designation. Human infections with H1N1v, H3N2v and H1N2v viruses have been detected in USA .
Sundar et al. built a model that enabled them to produce improvised estimate cases, hospitalizations, and death tolls that could be frequently updated as new information . In USA, the cases of H1N1 are spreading rapidly, particularly in Texas, New York, Utah, and California. Early reports suggested that most of the cases are due to travel to Mexico and most of the reported cases are students . During the last pandemic outbreak in 2009, CDC reported 1 death and 286 confirmed cases of H1N1 Flu across the 36 states. Among which, 35 cases of hospitalizations took place and several secondary factors have been recognized that assisted in the rise of victim numbers in the preceding days. The CDC and government officials had expressed their cautious optimism about the severity and the spread of H1N1 . Since the last pandemic in 2009, the cases of influenza has not disappeared completely, despite of several national prevention programs conducted in many countries. According to the reports of World Health Organization (WHO) , on 2015-2016 influenza incident in December, nearly 35,732 samples were analysed, in which 89% of them were classified as influenza A and the rest 11% were classified as influenza B. Out of the number of virus classified as type A, 93.3% were influenza A (H1N1) and approximately 6.7% were influenza A (H3N2). Half-a-year later, during the month of June, more than 55,586 samples were analysed showing a shift among the statistical values. Nearly 60.1% were classified as influenza A and 39.9% as influenza B. Out of the viruses classified as influenza A, 86.2% were influenza A (H1N1) and 13.8% were influenza A (H3N2) [68-71]. On a better note, this year, the number of cases of influenza has remained within the expected range but there is higher possibility of an increase in the number of cases due to the circulation of new viral variants, which might increase the threat of the disease [72-75].
Seven years down from the last pandemic outbreak of influenza virus (AH1N1), which remained being the highest incidence, provided a new way to vaccination, where particle of influenza AH1N1 strain was represented as the source antigen in all vaccines against influenza, irrespective of trivalent or quadrivalent. This led to a query about still existing incident of this virus, which having no substantial changes that permits a change in the composition of currently available vaccines. Vega-Sánchez et al. highlighted this dilemma in their work, which discussed the effect of the substrate used for production of vaccines, on the structural characteristics of influenza virus and there by proposing alternatives for the advancement of improved vaccines against this disease. The reason underlying such distinct behavior is due to the absence of significant changes in the nucleotide sequence of the Hemagglutinin (HA). Nevertheless, the effectiveness of the vaccine has not been as expected; therefore, at present new improvements against the existing vaccines remain under investigation [76-79].
Change in the surveillance pattern for detecting cases of influenza-like illness, resulted a spike increase in the percentage cases tested positive for influenza. Out of these positive cases, one third are due to novel strains, but a substantial number of cases are due to strains that are not subtyped [80,81]. The current trends of research on developing vaccines for influenza focus on achieving an acceptable platform that could be generated in a short time period with a higher performance rate. In addition, it also guarantees to confer adequate immunity to the patient. In the quest of such advancement, the researchers are aiming to develop cells or systems with specific enzymatic machinery identical to that of humans, helping the biosynthesis of vaccines against the virus .
Ebola Virus: Stranger at the Door Step
After witnessed few deadly infectious diseases the world consciously switching new biomedical research fields to protect the humankind from emerging infections. However, there are very rare burdens challenging the technological advancements by causing high mortality. Ebola hemorrhagic fever (Ebola virus) is such kind, which is completely a strange virus infection and first reported in West Africa in 2014 and spread to various countries within no time. According to the source and data from the various public health agencies Ebola is the most deadly disease reported in the last decade. On 8th August 2014 the World Health Organization declared the Ebola outbreak as a community health disaster of international concern and the diseases demands collective response . Over the past four decades, Ebola virus infections are reported periodically, but, as far as the mortality is concerned, early 1990s outbreak was the most worst and reported in Congo, Sudan, Uganda, Gabon and Congo-Brazzaville. However, the recent outbreak is undoubtedly a surprise and unpredictable because the virus was silent for last 13 years 1980 to 1993 [83-89]. The interesting fact that the infected virus is different from outbreak to outbreak and country to country, for instance, the first outbreak was reported in 1976 in Congo and Sudan which is caused by two distinct species of Ebola viruses . The vast diversity of the virus population and availability of wide range of hosts, both human and non-human primates are the major reasons for the frequent outbreaks in Africa .
Overall, in between 1976 and 2014, twenty-four were reported and the virus captured the attention due to the high fatality rate, which is estimated as more than 90% in each outbreak . The mode of transmission is another advantage; Ebola could transmit through simple contact of blood, body fluids and skin of the infected patients, even after the death because the Ebola victims are most contagious after death and the viral load in the blood is high [93-96].
There are no FDA approved treatments or vaccines available to prevent the disease. However, the life-threating virus enforces the necessity of developing new vaccine candidates. Several vaccines are being tested and reported immune side effects; therefore, improvement is needed with better outcomes. Peptide vaccines are one of the possible options, which combine the desired immune response with minimal side effects. Abu-haraz AH et al. conducted a study to develop multi-epitope peptide prediction by using immunoinformatics approaches and successfully reported three epitopes as peptide vaccines for B cell against Sudan Ebola Virus, for which in vivo and in vitro clinical validation is required . We have strong molecular knowledge on the virus but there is no potential vaccine or remedy developed yet. By using the molecular approaches, Dash et al. attempted to develop an epitope based peptide vaccine against Ebola. It used a combination of B-cell and T-cell predictions followed by molecular docking and dynamic stimulation approach. The study reported a potential peptide region HKEGAFFLY (ranging from 186 to 220 and the sequence HKEGAFFLY from the positions of 154-162) which helps in development of potential defensive system against EBOV . In many cases, Virus like particles and recombinant viral vectors provided potential vaccine candidates, with this advantage; Schweneker et al. constructed a modified vaccinia virus Ankara-Bavarian Nordic® to generate Ebola like virus particles. Moreover, the study successfully reported that the MVA-BN-EBOV-VLP efficiently induced EBOV-specific humoral and cellular immune responses in vaccinated mice . This study provides basic knowledge on development of multivalent virus like particle modified vaccine candidates. Of course, very few studies reported positive note on vaccine development; various approaches such as plant made vaccines , viral vector and dose dependent cell dynamic models , transcriptomic analysis , and genomic-based vaccine development  are under clinical trials and hopefully passed the clinical validations. In a technical point of view, approaches that are available to develop vaccines for emerging infectious diseases are not effective and sustainable; however, the advent technologies offer opportunities to develop new vaccine candidates. So far, independent researchers, private sector, national and international organizations have made several attempts to develop vaccines against emerging diseases such as Ebola, but there is a need for global governance to make attractive global approach .
Translational Approaches Raising the Hope
As discussed above the available techniques and methods to treat the infectious diseases are effective but not sufficient because most of the pathogens are getting resistance to the drugs and changing the genetic compositions rapidly. This clearly indicates that the need of integrated approaches to understand the basic concepts that could convert to clinical applications to improve the patient care. Over the past two decades, we witnessed technological evolution in science after the development of high throughput technologies and next generation sequencing methods. Genomics, proteomics, metabalomics and bioinformatics tools have become predominant in analyzing and applying large data to solve the biological questions . The aim of translational research strategy is to combine the basic research results with high throughput technologies by which the clinical infectious disease practice improve the disease management . In recent times, the molecular genomics approaches and microRNA-based studies reported promising methodologies in infectious disease treatment more particularly in virus based infectious diseases [107,108]. The early 21st century has seen remarkable developments in infectious diseases treatment methods in combination of technology and computational methods. Genomics, bio-informatics and systems biology improved the opportunities in understanding the complex biological systems in vivo, in vitro and in silico models which are creating more opportunities and raising the hope for multifaceted future research [109,110].
Epidemic and pandemic infectious disease events have been evident throughout the known history of human succession. Progress in medical science has made us less vulnerable to their devastation now-a-days. In many countries, standard operating procedures and protocols for data exchange, during the outbreak are not settled between human and animal health services. Therefore, vaccine designing for vector transmitted diseases should be targeted through common procedures and protocols, which further will help in disease related data exchange and proper understanding of the disease. Nonetheless, human and veterinary health professionals fail to acknowledge and understand the correlation between human and animal health. The effective treatment, control and eradication of these diseases require an interactional understanding between humans, animals and the environment. By learning, threats, which are posed by emerging infectious diseases, could be reduced.
The high-end technological approaches used to combat infectious diseases are getting more improvised with time and awareness. Individual concern is playing a critical role in preventing and controlling infection. Though, therapeutic care for critical infectious diseases are providing appreciable assistance in recovery and eradication of causative agent but, self-health concern holds the key to secure life from such epidemiological issues. Medicine can only provide limited measures for a particular disease but a healthy immune system is always considered as the best defense ever.
- Gulich GA. Transmission and control options of Zika virus. J Infect Dis Ther 2016; 4: e278.
- Rothschild B. Emerging infectious diseases and primate zoonoses. J Primatol 2015; 4: e130.
- Efird JT. Emerging infectious diseases: assessing the risk of zoonotic exposures. Trop Med Surg 2013; 1: e105.
- Rapose A. Travel to tropical countries: a review of travel-related infectious diseases. Trop Med Surg 2013; 1: e128.
- Sardi JDCO. Use of invertebrate animals as model to investigate infectious diseases and toxicity of new drugs. Clin Microbiol 2016; 5: e133.
- Pushpanathan M, Gunasekaran P, Rajendhran J. Mechanisms of the antifungal action of Marine Meta Genome-derived Peptide MMGP1, against Candida albicans. PLoS One 2013; 8: e69316.
- Muthuirulan P. Chasing new drugs against infectious diseases: a herculean task. J Clin Case Rep 2016; 6: e859.
- d'Arminio MA, Lepri AC, Rezza G, Pezzotti P, Antinori A. Insights into the reasons for discontinuation of the first highly active antiretroviral therapy regimen in a cohort of antiretroviral naive patients. AIDS 2000; 14: 499-507.
- Aceti A. Pharmacogenomics for infectious diseases. J Med Microb Diagn 2016; 5: e223.
- Konda S, Dayawansa S, Huang J. The evolution and challenge of the zika virus and its uncharted territory in the neurological realm. J Neuroinfect Dis 2016; 7: e215.
- Arora, Neelima, Amit K. Banerjee, Mangamoori LN. Zika virus: an emerging arboviral disease. Fut Virol 2016; 11: 395-399.
- Solomon IH, Milner DA, Folkerth RD. Neuropathology of Zika virus infection. J Neuroinfect Dis 2016; 7: e220.
- Diop D, Rambe DS, Sanicas M. Zika: what we know and don't know. Pan Afr Med J 2016; 24: 33.
- Nguyen KK, O’Brien BE, Steele RW. Zika virus: the new rubella epidemic. J Neurol Neurophysiol 2016; 7: e390.
- Wickramasinghe NC, Steele EJ. Dangers of adhering to an obsolete paradigm: could Zika virus lead to a reversal of human evolution. Astrobiol Outreach 2016; 4: e147.
- Awasthi S. Zika virus: prospects for the development of vaccine and antiviral agents. J Antivir Antiretrovir 2016; 8: e130.
- Weltman JK. Computer-assisted vaccine design by analysis of zika virus e proteins obtained either from humans or from Aedes mosquitos. J Med Microb Diagn 2016; 5: e235.
- Ceron CJP, Coronado PT, Imbernon TB, Banegas LAJ, Ghasemi F. Application of computational drug discovery techniques for designing new drugs against Zika virus. Drug Des 2016; 5: e131.
- Barrett FF, McGehee RF, Finland M. Methicillin-resistant Staphylococcus aureus at Boston city hospital: bacteriologic and epidemiologic observations. N Engl J Med 1968; 279: 441-448.
- Panlilio, Culver DH, Gaynes RP, Banerjee S, Henderson BS, Tolson JS, Martone WJ. National Nosocomial Infections Surveillance System. Am J Infect Control 1991; 13: 582-586.
- Honigsberg HRN. Global health report-community acquired Methicillin-Resistant Staphylococcus Aureus. J Health Edu Res Dev 2016; 4: e159.
- Kuehnert MJ, Hill HA, Kupronis BA, Tokars JI, Solomon SL, Jernigan DB. Methicillin-Resistant Staphylococcus aureus hospitalizations, United States. Emerg Infect Dis 2005; 11: 868-872.
- Division of Healthcare Quality Promotion, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Public Health Service, U.S. Department of Health and Human Services. National Nosocomial Infections Surveillance (NNIS) system report, data summary from January 1992 through June 2003, issued August 2003. Am J Infect Control 2003; 31: 481-498.
- Williams LL. Should the federal government focuses more attention on the surveillance of methicillin-resistant Staphylococcus Aureus from food sources. Medicinal Aromatic Plants 2012; 1: e117.
- Taniguchi J, Yoshinaga M, Kucho Y, Watanabe M, Kushida C. Longitudinal changes in clinical epidemiology and drug sensitivity of community associated methicillin-resistant Staphylococcus aureus in a tertiary hospital in Japan. J Infect Dis Ther 2014; 2: e172.
- Zaghloul MZ. Methicillin-resistant Staphylococcus aureus. J Med Microb Diagn 2016; 5: e131.
- Kitano Y, Fujitani S, Wakatake H, Yanai M, Umekawa S. The discrepancy of the minimum inhibitory concentration results for methicillin-resistant staphylococcus aureus by various measurement methods: a comparison of etest® and microdilution methods for vancomycin, teicoplanin, linezolid, daptomycin and quinupristin-dalfopristin. Emerg Med 2015; 5: e286.
- Chaudhary M, Payasi A. Battling the methicillin-resistant staphylococcus aureus biofilm challenge with vancoplus. J Microb Biochem Technol 2014; 10: e001.
- Ikeuchi T, Seki M, Akeda Y, Yamamoto N, Hamaguchi S. PCR-based method for rapid and minimized electrochemical detection of meca gene of methicillin-resistant Staphylococcus aureus and methicillin-resistant staphylococcus epidermidis. Gen Med 2015; 3: e215.
- Khan R, Baeshen MN, Saini KS, Bora RS, Al-Hejin AM. Antibacterial activity of rhazya stricta non-alkaloid extracts against methicillin-resistant Staphylococcus aureus. Biol Syst 2016; 5: e157.
- Betina HSM, Samara ERS, Vidiana TC, AlineDC, Barbara AF, Valdete MK. Care management: perspectives from managers, professionals and users of a specialized service facility focused on human immunodeficiency virus/acquired immune deficiency syndrome. J Nurs Care 2016; 5: e369.
- Arpan A, Salil V, Harsh P, Rabindranath M, Minal W, Pratap NM. Human immunodeficiency virus: discovery to drug resistance-a review update. Biol Syst Opn Acc 2016, 5: e154.
- Ines P, Cristina L, Ana M. Treatment of human immunodeficiency virus-1: current challenges and future perspectives. J AIDS Clin Res 2016, 7: e603.
- CDC. Today’s HIV/AIDS Epidemic 2015.
- CDC. HIV Surveillance Report 2013.
- CDC. Today’s HIV/AIDS Epidemic 2015.
- The White House. The National HIV/AIDS Strategy: Updated to 2020, 2015.
- Meirelles BHS, Suplici SER, Costa VT, Colaco AD, Forgearini BAO. Care management: perspectives from managers, professionals and users of a specialized service facility focused on human immunodeficiency virus/acquired immune deficiency syndrome. J Nurs Care 2016; 5: e369.
- Cardenas GJ, Arunabh T, Mangala N, Prashant M, Rakesh DS. Review of radiologic infectious and non-infectious pulmonary complications in human immunodeficiency virus patients. J Pulm Respir Med 2015; 5: e260.
- Rao VD, Kumar NBP. Physiology and medicine: the gifted saga of the last decade. Anat Physiol 2016; 6: e234.
- Aziz N, Butch AW, Quint JJ, Detels R. Association of blood biomarkers of bone turnover in HIV-1 infected individuals receiving anti-retroviral therapy. J AIDS Clin Res 2014; 5: e360.
- Nsimba SED, Irunde H, Comoro C. Barriers to arv adherence among HIV/AIDS positive persons taking anti-retroviral therapy in two Tanzanian regions 8-12 months after program initiation. J AIDS Clinic Res 2010; 1: e111.
- Nemaura T, Dhoro M, Nhachi C, Kadzirange G, Chonzi P. Evaluation of the prevalence, progression and severity of common adverse reactions associated with anti-retroviral therapy and anti-tuberculosis treatment in outpatients in Zimbabwe. J AIDS Clin Res 2013; 4: e203.
- Lu DY, Yarla NS, Xu B, Ding J, Lu TR. HAART in HIV/AIDS treatments, future trends. Infect Disord Drug Targets 2017; 17: 140-146.
- Prifti E. The impact of HAART in the gastrointestinal tract. J Gastrointest Dig Syst 2016; 6: e438.
- Therese N, Edmond KY, Rodrique DN, Hortense GK, Frederick K. Comparison of intestinal parasitic infection among adults with or without HIV/AIDS in Yaounde and effect of HAART and CD4 cells counts. J Bacteriol Parasitol 2015; 6: e208.
- Kandi V. HIV patient care: an overview n management of complications arising from highly active antiretroviral therapy (HAART). J Pat Care 2016; 2: e110.
- Kumar A, Kilaru KR, Roach TC. Immunological and virological outcomes at 5 years in HIV infected adults who start HAART at a CD4 cell count of less than 200 in Barbados. J AIDS Clin Res 2015; 6: e406.
- Chapp AU, Onyire NB, Orji ML, Onwe OE, Ojukwu JU. Assessment of rate of adherence to highly active antiretroviral therapy (HAART) among HIV infected children attending the infectious disease clinic of federal teaching hospital Abakaliki. J Child Adolesc Behav 2016; 4: e269.
- Ines P, Cristina L, Ana MM. Treatment of HIV-1: current challenges and future perspectives. J AIDS Clin Res 2016; 7: e603.
- Sagar V, Kanthikeel PS, Pottathil R, Saxena SK, Nair M. Towards nanomedicines for neuroaids. Rev Med Virol 2014; 24: 103-124.
- Rao VD. Personalized nanomedicine: not just a tool but towards an excellence. Transl Biomed 2016, 7: e2.
- Jayant RD, Nair M. Role of biosensing technology for neuroaids management. J Biosens Bioelectron 2016; 7: e141.
- Santosh K. Role of Cytochrome P450 systems in substance of abuse mediated HIV-1 pathogenesis and NeuroAIDS. J Drug Metab Toxicol 2012; 3: e102.
- Nair M, Jayant RD, Kaushik A, Sagar V. Getting into the brain: potential of nanotechnology in the management of NeuroAIDS. Adv Drug Deliv Rev 2016; 103: 202-217.
- Yndart A, Kaushik A, Agudelo M, Raymond A, Atluri VS. Investigation of Neuropathogenesis in HIV-1 clades B and C infection associated with IL-33 and ST2 regulation. ACS Chem Neurosci 2015; 6: 1600-1612.
- Jayant RD, Atluri VS, Agudelo M, Sagar V, Kaushik A. Sustained-release nanoart formulation for the treatment of neuroAIDS. Int J Nanomedicine 2015; 10: 1077-1093.
- Saxena SK, Gupta A, Bhagyashree K, Saxena R, Arora N, Banerjee AK, Tripathi AK, Chandrasekar MJ, Gandhi N, Nair MP. Targeting strategies for human immunodeficiency virus: a combinatorial approach. Mini Rev Med Chem 2012; 12: 236-254.
- Prakash N, Devangi P, Madhuuri K, Khushbu P, Deepali P. Phylogenetic analysis of H1N1 Swine Flu Virus isolated in India. J Antivir Antiretrovir 2011, 3: e011.
- Sundar SS, David LS, Rebekah HB, Vimalanand SP, Finelli L. Estimating the Burden of 2009 Pandemic Influenza A (H1N1) in the United States (April 2009-April 2010). Clin Infect Dis 2011; 82: e012.
- Queens School At Flu Epicenter Reopens. CBS News 2009.
- Harris G, Malkin E. Health Officials Begin to Ease Public Alerts About Swine Flu. The New York Times 2009.
- WHO. Influenza update No 254. World Health Organization Geneva Switzerland 2016.
- ECDC. Surveillance Report Influenza Virus Characterisation SummaryEurope. Eur Centre Dis Prev Contr 2016.
- FDA. Complete List of Vaccines Licensed for Immunization and Distribution in the US. US Food and Drug Administration, USA 2016.
- Early estimates of seasonal influenza vaccine effectiveness-United States, January 2013. MMWR Morb Mortal Wkly Rep 2013; 62: 32-35.
- Shaik IK, Narain JP. Pandemic disease swine flu: H1N1 virus clinical and prevention aspects. J Pharmacy Pharm Sci 2015; 4: 1-6.
- Novel influenza A (H1N1) virus infections among health-care personnel-United States, April-May 2009. MMWR Morb Mortal Wkly Rep 2009; 58: 641-645.
- WHO. Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO 11 August 2009.
- WHO. WHO guidelines for pharmacological management of pandemic (H1N1) influenza andotherinfluenzaviruses 2010.
- Jose CVS, Flores VMA, Bravo MJ. The future of influenza vaccines: developing tools to match glycosylation patterns relevant for protection. J Vaccines Vaccin 2016; 7: e335.
- Lorenzo MM, Fenton MJ. Immunobiology of influenza vaccines. Chest 2013; 143: 502-510.
- Gaglani M, Pruszynski J, Murthy K, Clipper L, Robertson A. Influenza vaccine effectiveness against 2009 Pandemic Influenza A (H1N1) virus differed by vaccine type during 2013-2014 in the United States. J Infect Dis 2016; 213: 1546-1556.
- Delany I, Rappuoli R, Degregorio E. Vaccines for the 21st century. EMBO Mol Med 2014; 6: 708-720.
- 2008-2009 Influenza Season Week 53 ending January 3, 2009.
- 2008-2009 Influenza Season Week 18 ending May 9, 2009.
- Briand S, Bertherat E, Cox P, Formenty P, Kieny MP. The international Ebola emergency. N Engl J Med 2014; 371: 1180-1183.
- Joshi RM. Ebola Virus Disease (EVD): an unprecedented major outbreak in West Africa. Clin Microbial 2014; 3: e119.
- Heymann DL, Weisfeld JS, Webb PA, Johnson KM, Cairns T. Ebola hemorrhagic fever: Tandala, Zaire, 1977-1978. J Infect Dis 1980; 142: 372-376
- Amblard J, Obiang P, Edzang S, Prehaud C, Bouloy M. Identification of the Ebola virus in Gabon in 1994. Lancet 1997; 349: 181-182.
- Lamunu M, Lutwama JJ, Kamugisha J, Opio A, Nambooze J. Containing a haemorrhagic fever epidemic: the Ebola experience in Uganda (October 2000-January 2001). Int J Infect Dis 2004; 8: 27-37.
- Onyango CO, Opoka ML, Ksiazek TG, Formenty P, Ahmed A. Laboratory diagnosis of Ebola hemorrhagic fever during an outbreak in Yambio, Sudan, 2004. J Infect Dis 2007; 196: 193-198.
- Towner JS, Sealy TK, Khristova ML, Albarino CG, Conlan S. Newly discovered Ebola virus associated with hemorrhagic fever outbreak in Uganda. PLoS Pathog 2008; 4: 212.
- Leroy EM, Epelboin A, Mondonge V, Pourrut X, Gonzalez JP. Human Ebola outbreak resulting from direct exposure to fruit bats in Luebo, democratic republic of Congo, 2007. Vector Borne Zoonotic Dis 2009; 9: 723-728.
- Muyembe TJJ, Mulangu S, Masumu J, Kayembe JM, Kemp A. Ebola virus outbreaks in Africa: past and present. Onderstepoort J Vet Res 2012; 79: e451.
- Feldmann H, Geisbert TW. Ebola haemorrhagic fever. Lancet 2011; 377: 849-862.
- Gebretadik FA, Seifu MF, Gelaw BK. Review on Ebola virus disease: its outbreak and current status. Epidemiology 2015; 5: e204.
- James J, Charlotte F, Daniel K, Carafano J. The Ebola Outbreak of 2013-2014: An Assessment of U.S. Actions. Special Report No.166 2015.
- Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M. Assessment of the risk of Ebola virus transmission from bodily fluids and fomites. J Infect Dis 2007; 196: 142-147.
- Ethiopian Public Health Institute. Ebola viral disease interim Guideline. Addis Ababa Ethiopia 2014; 1-83.
- Weingartl HM, Nfon C, Kobinger G. Review of Ebola virus infections in domestic animals. Dev Biol 2013; 135: 211-218.
- Abu AH, Abdelrahman KA, Ibrahim MS, Hussien WH, Mohammed MS. Multi Epitope Peptide vaccine prediction against sudan Ebola virus using immune informatics approaches. Adv Tech Biol Med 2017; 5: e203.
- Das R, Junaid M, Akash MF, Islam A, Hosen SZ. In silico-based vaccine design against Ebola virus glycoprotein. Adv Appl Bioinform Chem 2017; 10: 11-28.
- Schweneker M, Laimbacher AS, Zimmer G, Wagner S, Schraner EM, Wolferstatter M, Klingenberg M, Dirmeier U, Steigerwald R, Lauterbach H, Hochrein H, Chaplin P, Suter M, Hausmann J. Recombinant modified vaccinia virus Ankara generating Ebola virus like particles. J Virol 2017; 17: 343.
- Rosales MS, Nieto GR, Angulo C. A perspective on the development of plant-made vaccines in the fight against Ebola virus. Front Immunol 2017; 8: e252.
- Dahlke C, Kasonta R, Lunemann S, Krahling V, Zinser ME, Biedenkopf N, Fehling SK, Ly ML, Rechtien A, Stubbe HC, Olearo F, Borregaard S, Jambrecina A, Stahl F, Strecker T, Eickmann M, Lutgehetmann M, Spohn M, Schmiedel S, Lohse AW, Becker S, Addo MM. Dose-dependent T-cell dynamics and cytokine cascade following rVSV-ZEBOV immunization. E Bio Med 2017; 19: 128-138.
- Menicucci AR, Sureshchandra S, Marzi A, Feldmann H, Messaoudi I. Transcriptomic analysis reveals a previously unknown role for CD8+ T-cells in rVSV-EBOV mediated protection. Sci Rep 2017; 7: e919.
- Dudas G, Carvalho LM, Bedford T, Tatem AJ, Baele G. Virus genomes reveal factors that spread and sustained the ebola epidemic. Epidemics 2017; 544: 1755-4365.
- Bloom DE, Black S, Rappuoli R. Emerging infectious diseases: a proactive approach. Proc Natl Acad Sci USA 2017; 114: 4055-4059.
- Fontana JM, Alexander E, Salvatore M. Translational research in infectious disease: current paradigms and challenges ahead. Transl Res 2012; 159: 430-453.
- Tacconelli E, Peschel A, Autenrieth IB. Translational research strategy: an essential approach to fight the spread of antimicrobial resistance. J Antimicrob Chemother 2014; 69: 2889-2891.
- Coloma J, Harris E. Molecular genomic approaches to infectious diseases in resource-limited settings. PLoS Med 2009; 6: e1000142.
- Shinde SP, Banerjee AK, Arora N, Murty US, Sripathi VR, Pal-Bhadra M, Bhadra U. Computational approach for elucidating interactions of cross-species miRNAs and their targets in Flaviviruses. J Vector Borne Dis 2015; 52: 11-22.
- Aderem A, Adkins JN, Ansong C, Galagan J, Kaiser S. A systems biology approach to infectious disease research: innovating the pathogen-host research paradigm. Mbio 2011; 2: e00325-10.
- Witkamp RF. Genomics and systems biology-how relevant are the developments to veterinary pharmacology, toxicology and therapeutics? J Vet Pharmacol Ther 2005; 28: 235-245.