- Ectromelia Virus Disease Characterization in the BALB/c Mouse: A Surrogate Model for Assessment of Smallpox Medical Countermeasures. [Journal Article]
- Viruses 2016; 8(7)
In 2007, the United States- Food and Drug Administration (FDA) issued guidance concerning animal models for testing the efficacy of medical countermeasures against variola virus (VARV), the etiologic agent for smallpox. Ectromelia virus (ECTV) is naturally-occurring and responsible for severe mortality and morbidity as a result of mousepox disease in the murine model, displaying similarities to variola infection in humans. Due to the increased need of acceptable surrogate animal models for poxvirus disease, we have characterized ECTV infection in the BALB/c mouse. Mice were inoculated intranasally with a high lethal dose (125 PFU) of ECTV, resulting in complete mortality 10 days after infection. Decreases in weight and temperature from baseline were observed eight to nine days following infection. Viral titers via quantitative polymerase chain reaction (qPCR) and plaque assay were first observed in the blood at 4.5 days post-infection and in tissue (spleen and liver) at 3.5 days post-infection. Adverse clinical signs of disease were first observed four and five days post-infection, with severe signs occurring on day 7. Pathological changes consistent with ECTV infection were first observed five days after infection. Examination of data obtained from these parameters suggests the ECTV BALB/c model is suitable for potential use in medical countermeasures (MCMs) development and efficacy testing.
- Vacca pox to pexa vec: John Hunter's and Edward Jenner's contribution to oncolytic virotherapy. [Journal Article, Review]
- J Surg Res 2016 Jul; 204(1):228-31.
- [THE USE OF THE MODEL MOUSE ICR--VARIOLA VIRUS FOR EVALUATION OF ANTIVIRAL DRUG EFFICACY]. [English Abstract, Journal Article, Research Support, Non-U.S. Gov't]
- Vopr Virusol 2016; 61(2):79-84.
Mice of the ICR outbred population were infected intranasally (i/n) with the variola virus (VARV, strain Ind-3a). Clinical signs of the disease did not appear even at the maximum possible dose of the virus 5.2 lg PFU/head (plaque-forming units per head). In this case, 50% infective dose (ID50) of VARV estimated by the presence or absence of the virus in the lungs three days after infection (p.i.) was equal to 2.7 ± 0.4 lg PFU/head. Taking into account the 10% application of the virus in the lungs during the intranasal infection of the mice, it was adequate to 1.7 lg PFU/lungs. This indicates a high infectivity of the VARV for mice comparable to its infectivity for humans. After the i/n infection of mice with the VARV at a dose 30 ID50/ head the highest concentration of the virus detected in the lungs (4.9 ± 0.0 lg PFU/ml of homogenate) and in nasal cavity tissues (4.8 ± 0.0 lg PFU/ml) were observed. The pathomorphological changes in the respiratory organs of the mice infected with the VARV appeared at 3-5 days p.i., and the VARV reproduction noted in the epithelial cells and macrophages were noticed. When the preparations ST-246 and NIOCH-14 were administered orally at a dose of 60 μg/g of mouse weight up to one day before infection, after 2 hours, 1 and 2 days p.i., the VARV reproduction in the lungs after 3 days p.i. decreased by an order of magnitude. Thus, outbred ICR mice infected with the VARV can be used as a laboratory model of the smallpox when evaluating the therapeutic and prophylactic efficacy of the antismallpox drugs.
- [EVALUATION OF THE HUMAN SENSITIVITY TO SMALLPOX VIRUS BY THE PRIMARY CULTURES OF THE MONOCYTE-MACROPHAGES]. [English Abstract, Journal Article]
- Vopr Virusol 2016; 61(2):69-73.
Studies of the primary cultures of granulocytes, mononuclear, and monocyte-macrophage cells derived from human blood were performed using variola virus (VARV) in the doses of 0.001-0.021 PFU/cell (plaques-forming units per cell). Positive dynamics of the virus accumulation was observed only in the monocyte-macrophages with maximum values of virus concentration (5.0-5.5 Ig PFU/ml) mainly within six days after the infection. The fact of VARV replication in the monocyte-macrophages was confirmed by the data of electron microscopy. At the same time, virus vaccines when tested in doses 3.3 and 4.2 Ig PFU/ml did not show the ability to reproduce in these human cells. The people sensitivity to VARV as assessed from the data obtained on human monocyte-macrophages corresponded to -1 PFU (taking into account the smooth interaction of the virus in the body to the cells of this type), which is consistent to previously found theoretical data on the virus sensitivity. The human susceptibility to VARV assessed experimentally can be used to predict the adequacy of developed smallpox models (in vivo) based on susceptible animals. This is necessary for reliable assessment of the efficiency of development of drugs for treatment and prophylaxis of the smallpox.
- Paediatric Virology in the Hippocratic Corpus. [JOURNAL ARTICLE]
- Exp Ther Med 2016 Aug; 12(2):541-549.
Hippocrates (Island of Kos, 460 B.C.-Larissa, 370 B.C.) is the founder of the most famous Medical School of the classical antiquity. In acknowledgement of his pioneering contribution to the new scientific field of Paediatric Virology, this article provides a systematic analysis of the Hippocratic Corpus, with particular focus on viral infections predominating in neonates and children. A mumps epidemic, affecting the island of Thasos in the 5th century B.C., is described in detail. 'Herpes', a medical term derived from the ancient Greek word 'ἕρπειν', meaning 'to creep' or 'crawl', is used to describe the spreading of cutaneous lesions in both childhood and adulthood. Cases of children with exanthema 'resembling mosquito bites' are presented in reference to varicella or smallpox infection. A variety of upper and lower respiratory tract viral infections are described with impressive accuracy, including rhinitis, pharyngitis, tonsillitis, laryngitis, bronchiolitis and bronchitis. The 'cough of Perinthos' epidemic, an influenza-like outbreak in the 5th century B.C., is also recorded and several cases complicated with pneumonia or fatal outcomes are discussed. Hippocrates, moreover, describes conjunctivitis, otitis, lymphadenitis, meningoencephalitis, febrile convulsions, gastroenteritis, hepatitis, poliomyelitis and skin warts, along with proposed treatment directions. Almost 2,400 years later, Hippocrates' systematic approach and methodical innovations can inspire paediatric trainees and future Paediatric Virology subspecialists.
- Modulation of PD-L1 and CD8 Activity in Idiopathic and Infectious Chronic Inflammatory Conditions. [JOURNAL ARTICLE]
- Appl Immunohistochem Mol Morphol 2016 Jul 19.
Programmed death-ligand 1 (PD-L1) can reduce the immune response by inhibiting CD8 T-cell proliferation and cytotoxic activity. We studied a series of human viral (molloscum, human papillomavirus, herpes simplex, cytomegalovirus, Epstein-Barr virus, smallpox) and bacterial infections (Helicobacter pylori) for the in situ expression of PD-L1, mononuclear cell infiltration, and CD8 activity and compared this to noninfectious idiopathic inflammatory conditions to better define which immune responses may be more highly correlated with an infectious agent. Each viral and bacterial infection showed an increased PD-L1 expression that was most prominent in the mononuclear cell/CD8+ infiltrate surrounding the infection. However, the CD8 cells were mostly quiescent as evidenced by the low Ki67 index and minimal granzyme expression. Using a melanoma mouse model, acute reovirus infection increased PD-L1 expression, but decreased CD8 cytotoxic activity and Treg (FOXP3) cell numbers. In comparison, idiopathic noninfectious chronic inflammatory processes including lichen sclerosis, eczema, Sjogren's disease, and ulcerative colitis showed a comparable strong PD-L1 expression in the mononuclear cell infiltrates but much greater Treg infiltration. However, this strong immunosuppressor profile was ineffective as evidenced by strong CD8 proliferation and granzyme expression. These data suggest that viral and bacterial infections induce a PD-L1 response that, unlike noninfectious chronic inflammatory conditions, dampens the activity of the recruited CD8 cells which, in turn, may enhance the ability of anti-PD-L1 therapy to eliminate the infectious agent.
- Beyond Primates: Research Protections and Animal Moral Value. [Journal Article]
- Hastings Cent Rep 2016 Jul; 46(4):28-30.
Should monkeys be used in painful and often deadly infectious disease research that may save many human lives? This is the challenging question that Anne Barnhill, Steven Joffe, and Franklin G. Miller take on in their carefully argued and compelling article "The Ethics of Infection Challenges in Primates." The authors offer a nuanced and even-handed position that takes philosophical worries about nonhuman primate moral status seriously and still appreciates the very real value of such research for human welfare. Overall, they argue for an extension and revision of the recommendations regarding chimpanzee research offered by the Institute of Medicine in 2011; the practical upshot of their argument would allow for infection challenge research for promising interventions for Ebola and Marburg virus diseases but not for smallpox or the common cold. The IOM recommendations regarding chimpanzee research put in motion an exceptionalist policy for this great ape population. Barnhill and colleagues' proposal would enlarge the scope of that exceptionalism to embrace NHPs other than great apes. But is such exceptionalism warranted? It is not obvious to me either that the more sophisticated capacities of a species as a whole give it greater ethical protections or that less intellectually or socially sophisticated animals ought to therefore receive less protection when it comes to painful experimental interventions.
- Emerging diseases - The monkeypox epidemic in the democratic repubic of the congo. [EDITORIAL]
- Clin Microbiol Infect 2016 Jul 9.
- Adventures of a Female Medical Detective: In Pursuit of Smallpox and AIDS. [JOURNAL ARTICLE]
- Clin Infect Dis 2016 Jul 8.
- British merchant seafarers 1900-2010: A history of extreme risks of mortality from infectious disease. [JOURNAL ARTICLE]
- Travel Med Infect Dis 2016 Jul 7.
This study established trends in major infectious disease mortality in British merchant shipping from 1900 to 2010 as compared with the British male working population and the Royal Navy.A population mortality study of six infectious diseases using annual government mortality returns and death inquiry files for British merchant shipping and the Royal Navy, and official mortality data for the general male working aged population.Relative mortality risks for each disease were increased significantly in British merchant shipping when compared with the general population; malaria by 58.2 fold, yellow fever (6276), typhoid (9.5), cholera (1734), dysentery (20.6) and smallpox (142). For all six diseases combined, relative mortality risks were 21.5 compared with the general population and 3.5 compared with the Royal Navy. Mortality trend patterns varied between diseases, but reductions in mortality in British merchant shipping consistently lagged many years behind those in both the British general population and the Royal Navy.Merchant seamen were at far higher risk of death than probably any other occupational group of the population. Much of these excess risks came from exposure to infection in unhygienic and tropical ports, although some was a result of neglect of feasible preventative measures.