Hae-Wol Cho

Expression of Interferon Inducible Genes Following Hantaan Virus Infection as a Mechanism of Resistance in A549 Cells

Hantaan virus (HTN) is a causative agent of hemorrhagic fever with renal syndrome (HFRS). Little is known of its pathogenesis or the molecular mechanisms underlying resistance to HTN infection. In the present study, DNA microarray technology was used to monitor changes in mRNA levels after HTN infection, to elucidate resistance mechanisms to viral infection by understanding virus–host interactions. We found that several interferon (IFN)-inducible genes were up-regulated in host cells infected with HTN. According to previous available data, IFNs have been reported to be inhibitory, but their mode of action has not been yet clear. In this study, the 2′,5′-oligoadenylated synthetase (OAS) and Mx1 genes, not a double-stranded RNA-dependent protein kinase R (PKR), of the IFN response pathways are associated with antiviral activity during HTN infection. Furthermore, A549 cells treated with IFN-α were protected against HTN infection. Taken together, these results confirmed that IFN plays a role in cellular defenses against HTN infection at an early stage of the infection and revealed the resistance mechanism for HTN infection.

Clinical Responses to Smallpox Vaccine in Vaccinia-Naive and Previously Vaccinated Populations: Undiluted and Diluted Lancy-Vaxina Vaccine in a Single-Blind, Randomized, Prospective Trial

We conducted a single-blind, randomized trial of 2 dilutions (1:1 or 1:10) of Lancy-Vaxina vaccine (Berna Biotech) in vaccinia-naive persons (n=36) and persons previously vaccinated >25 years ago (n=76). All vaccinees responded successfully to the vaccination. There were no significant differences in the size of the skin lesions, the number of adverse events, the amount of viral shedding, or the level of antibody responses between the undiluted (n=56) and diluted (n = 56) vaccine groups. Compared with vaccinia-naive persons, previously vaccinated persons exhibited significantly smaller and more rapidly evolving skin lesions and fewer adverse events. Previously vaccinated persons had significantly higher neutralizing antibody levels before the administration of the study vaccine than vaccinia-naive persons, and viral shedding from lesions in previously vaccinated persons was lower and diminished more rapidly than from lesions in vaccinia-naive persons.

Prediction of Residual Immunity to Smallpox, by Means of an Intradermal Skin Test with Inactivated Vaccinia Virus

BACKGROUND Intradermal skin testing with inactivated vaccinia virus was evaluated for its prediction of residual immunity to smallpox. METHODS An intradermal skin test was performed with heat-inactivated Lancy-Vaxina. Two days later, the subjects were vaccinated with Lancy-Vaxina. The skin lesions resulting from this vaccination were used as a surrogate marker of residual immunity to smallpox, and this surrogate marker was compared with the available indicators of susceptibility to smallpox. RESULTS Of the 83 subjects, 30 (36%) showed the typical primary response after vaccination (i.e., absence of residual immunity), whereas 34 (41%) showed the typical revaccinees response (i.e., presence of residual immunity); the remaining 19 (23%) had an indeterminate response and were excluded from the final analysis. The sensitivity and specificity of the intradermal skin test (induration size, >or=4 mm) for prediction of residual immunity to smallpox were 85% and 97%, respectively, whereas those of a positive vaccinia-specific interferon- gamma -producing T cell response (>or=9 spot forming cells/10(6) peripheral-blood mononuclear cells) were 32% and 63%, respectively, and those of a positive neutralizing antibody (titer, >or=1 : 8) were 79% and 80%, respectively. CONCLUSION The intradermal skin test appears to be a simple and reliable method for prediction of residual immunity to smallpox.

An HIV Type 1 Subtype B Founder Effect in Korea: gp160 Signature Patterns Infer Circulation of CTL-Escape Strains at the Population Level

HIV-1 subtype B predominates in the Republic of Korea. Phylogenetic analyses of sequences for complete nef genes and env gene fragments encoding the V3 loop have identified a major monophyletic Korean subclade that is distinct from Western subtype B sequences in the Los Alamos HIV Sequence Database. This was investigated further by sequence analysis of complete env genes recovered from the DNA of peripheral blood mononuclear cells for matched groups of Koreans, four patients per group, previously assigned as being infected with either Korean or Western strains. The phylogenetic classifications were confirmed and analysis of the translation products identified 32 amino acid signature pattern differences, dispersed throughout gp160, which differentiate the two subclades. Twenty-three of these positions map to epitopes recognized by HLA-I-restricted cytotoxic T-lymphocytes (CTL) as catalogued in the Los Alamos HIV Immunology Database. The remaining nine map at or close to sites predicted to be targets for immunoproteasomes that are involved in producing peptides that bind to MHC Class I. These results suggest that a founder effect in the Korean population is based on the spread of CTL-escape/host-adapted HIV-1 strains.

Antigenic characterization of severe acute respiratory syndrome-coronavirus nucleocapsid protein expressed in insect cells: The effect of phosphorylation on immunoreactivity and specificity

Abstract The nucleocapsid (N) protein of severe acute respiratory syndrome-coronavirus (SARS-CoV) is involved in the pathological reaction to SARS and is a key antigen for the development of a sensitive diagnostic assay. However, the antigenic properties of this N protein are largely unknown. To facilitate the studies on the function and antigenicity of the SARS-CoV N protein, 6× histidine-tagged recombinant SARS-CoV N (rSARS-N) with a molecular mass of 46 and 48kDa was successfully produced using the recombinant baculovirus system in insect cells. The rSARS-N expressed in insect cells (BrSARS-N) showed remarkably higher specificity and immunoreactivity than rSARS-N expressed in E. coli (ErSARS-N). Most of all, BrSARS-N proteins were expressed as a highly phosphorylated form with a molecular mass of 48kDa, but ErSARS-N was a nonphosphorylated protein. In further analysis to determine the correlation between the phosphorylation and the antigenicity of SARS-N protein, dephosphorylated SARS-N protein treated with protein phosphatase 1 (PP1) remarkably enhanced the cross-reactivity against SARS negative serum and considerably reduced immunoreactivity with SARS-N mAb. These results suggest that the phosphorylation plays an important role in the immunoreactivity and specificity of SARS-N protein. Therefore, the BrSARS-N protein may be useful for the development of highly sensitive and specific assays to determine SARS infection and for further research of SARS-N pathology.

Avian influenza a (H5N1) virus antibodies in poultry cullers, South Korea, 2003-2004.

Transmission of influenza (H5N1) virus from birds to humans is a serious public health threat. In South Korea, serologic investigation among 2,512 poultry workers exposed during December 2003–March 2004 to poultry with confirmed or suspected influenza (H5N1) virus infection found antibodies in 9. Frequency of bird-to-human transmission was low.

Cell-Mediated Immune Responses to Smallpox Vaccination

ABSTRACT We report that vaccine dilution (1:1 or 1:10) and previous vaccinia virus vaccination status had no significant effect on cell-mediated immune responses (i.e., the immediate vaccinia virus-specific gamma interferon-producing T-cell response measured by enzyme-linked immunospot assay) 1 month after smallpox vaccination (Lancy-Vaxina; Berna Biotech, Switzerland).

Preparation and characterization of a novel monoclonal antibody specific to severe acute respiratory syndrome-coronavirus nucleocapsid protein.

Abstract Severe acute respiratory syndrome-coronavirus nucleocapsid (SARS-CoV N) protein has been found to be important to the processes related to viral pathogenesis, such as virus replication, interference of the cell process and modulation of host immune response; detection of the antigen has been used for the early diagnosis of infection. We have used recombinant N protein expressed in insect cells to generate 17 mAbs directed against this protein. We selected five mAbs that could be used in various diagnostic assays, and all of these mAbs recognized linear epitopes. Three IgG2b mAbs were recognized within the N-terminus of N protein, whereas the epitope of two IgG1 mAbs localized within the C-terminus. These mAbs were found to have significant reactivity with both non-phosphorylated and phosphorylated N proteins, which resulted in high reactivity with native N protein in virus-infected cells; however, they did not show cross-reactivity with human coronavirus. Therefore, these results suggested that these mAbs would be useful in the development of various diagnostic kits and in future studies of SARS-CoV pathology.

Outbreak of Middle East Respiratory Syndrome in Korea

It was a total surprise to everybody! Since late May 2015, we have observed an imported pathogen make a huge impact on the general public and economy of the Republic of Korea, which has one the most advanced medical and public health systems in the world. Nobody expected Korea to be in second place on the list of countries with the highest incidence of Middle East respiratory syndrome (MERS), right after Saudi Arabia. The Korea Centers for Disease Control and Prevention (KCDC) has been at the center of this unprecedented event. We have seen the incredible commitment of the members of the Division of Epidemic Intelligence Service in the KCDC, and of the MERS outbreak investigation team. This editorial is a record of what the virus fighters have experienced in the past 2 months. Before we review the whole picture, we would like to give our sincere homage to their professional attitude and heroic sacrifices. We would also like to acknowledge the efforts of medical staff in treating infected patients and of public health officials in tracing contacts.

A Tale of Two Fields: Mathematical and Statistical Modeling of Infectious Diseases

The managing editor of Osong Public Health and Research Perspectives (PHRP) attended the Casablanca International Workshop in Mathematical Biology: Analysis and Control, Morocco, June 20–24, 2011. PHRP was welcomed by the community, especially by the infectious disease-modeling group. They welcomed a new public health journal that contains articles for applied mathematical modelers. It is an asset to have such strong supporters for PHRP. Mathematical models for public health experts are varied. The classical disease-transmission model was created by Kermack-McKendrick in 1927 [1]. In this model, disease transmission is conveniently conceptualized as passage among members of a population by moving among compartments. Actually, this is a special case of the Susceptible-Infectious-Removed (SIR) compartmental model. SIR functions well for infectious or communicable diseases with immunity against re-infection or disease with no immunity. Another model divides I-class into two classes with an exposed period between being infected and becoming infectious, which yields Susceptible-Exposed-Infectious-Removed (SEIR) and Susceptible-Exposed-Infectious-Susceptible (SEIS). We can consider Susceptible-Infectious-Removed-Susceptible (SIRS) models with temporary immunity [1]. In the simple Susceptible-Infected-Susceptible model, the deterministic dynamic structure shows us a great deal about the behavior of stochastic paths and brings to our attention questions that pertain to the stochastic model: What is the nature of the stochastic path as it varies near the deterministic equilibrium? Starting from the deterministic equilibrium, what is the distribution of time until the stochastic hits zero? We should point out that the stochastic models that we have discussed here are simple ones, involving no more than two linked stochastic equations [2]. The basic reproduction number R0 is the number of secondary infections caused by a single infective agent introduced in an entirely susceptible population over the course of the infection of this single infective and determines whether there is an epidemic in a population [1]. Stochastic modeling with compartmental stochastic models is often utilized. The dynamics of an Ordinary Differential Equation system informs us of the deterministic skeleton on which the behavior of corresponding stochastic systems are built [2]. Statistical modeling has two tracks to reach conclusions from data. One assumes that the data are generated by a given stochastic data model, whereas the other uses algorithmic models and treats the data mechanism as unknown. Logistic regression is frequently used in public health because it produces a linear combination of the variables with weights that give an indication of the variable importance. The end is a neat result of how the prediction variables affect the response variable plus confidence intervals for the weights. Assume also that each one with a different approach to data modeling fits a model to the same dataset and that each one applies standard goodness-of-fit test, looks at residuals, etc, and is convinced that their model fits the data. Yet the two models give different pictures of nature’s mechanism and lead to different conclusions [3]. Computer-generated simulation is becoming increasingly important in inference of given data, but still one of the most hackneyed methods to estimate disease-related phenomena is multiple regression [4]. In this issue two modeling approaches are presented. A compartmental deterministic mathematical model was introduced to predict the evolution of obesity in a population and to propose strategies to reduce its incidence. The authors took obesity as an epidemic and developed a model based on Susceptible-Infected-Susceptible transmission. Obesity was regarded as an infectious disease caused by social peer pressure or social contact. These social contacts had influences on the probability of transmission of a sedentary lifestyle and unhealthy nutritional habits. From these considerations they proposed an epidemiologic-type model to study the epidemic evolution of obesity [5]. Statistical modeling was adopted to estimate seasonal influenza patients in Korea using sentinel surveillance data. This report followed the traditional statistical modeling track. The authors present two regression models: first, they estimated monthly reporting rates (W1) from sentinel clinics of the influenza surveillance system, and then estimated hospital-visit patient numbers for the sentinel clinics. They also estimated weight of scale of treatment of national hospital/clinics to sentinel hospital/clinics (W2). The weight by month and province (W3) was estimated as the last step. The authors obtained the final number of influenza patients with multiple linear regression models using the above weights [6].