The newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes a severe respiratory infection with a high mortality rate (~35%). MERS-CoV has been a global threat due to continuous outbreaks in the Arabian peninsula and international spread by infected travelers since 2012. From May to July 2015, a large outbreak initiated by an infected traveler from the Arabian peninsula swept South Korea and resulted in 186 confirmed cases with 38 deaths (case fatality rate, 20.4%). Here, we show the rapid emergence and spread of a mutant MERS-CoV with reduced affinity to the human CD26 receptor during the South Korean outbreak. We isolated 13 new viral genomes from 14 infected patients treated at a hospital and found that 12 of these genomes possess a point mutation in the receptor-binding domain (RBD) of viral spike (S) protein. Specifically, 11 of these genomes have an I529T mutation in RBD, and 1 has a D510G mutation. Strikingly, both mutations result in reduced affinity of RBD to human CD26 compared to wild-type RBD, as measured by surface plasmon resonance analysis and cellular binding assay. Additionally, pseudotyped virus bearing an I529T mutation in S protein showed reduced entry into host cells compared to virus with wild-type S protein. These unexpected findings suggest that MERS-CoV adaptation during human-to-human spread may be driven by host immunological pressure such as neutralizing antibodies, resulting in reduced affinity to host receptor, and thereby impairs viral fitness and virulence, rather than positive selection for a better affinity to CD26.

Abstract. Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne viral disease. The SFTS virus (SFTSV) has been detected in the Haemaphysalis longicornis, which acts as a transmission host between animals and humans. SFTSV was first confirmed in China in 2009 and has also been circulating in Japan and South Korea. However, it is not known if a genetic connection exists between the viruses in these regions and, if so, how SFTSV is transmitted across China, South Korea, and Japan. We therefore hypothesize that the SFTSV in South Korea share common phylogenetic origins with samples from China and Japan. Further, we postulate that migratory birds, well-known carriers of the tick H. longicornis, are a potential source of SFTSV transmission across countries. Our phylogenetic analysis results show that the SFTSV isolates in South Korea were similar to isolates from Japan and China. We connect this with previous work showing that SFTSV-infected H. longicornis were found in China, South Korea, and Japan. In addition, H. longicornis were found on migratory birds. The migratory bird routes and the distribution of H. longicornis are concurrent with the occurrence of SFTSV. Therefore, we suggest that migratory birds play an important role in dispersing H. longicornis-borne SFTSV.

BackgroundScrub typhus is an endemic disease in Asia. It has been a rural disease, but indigenous urban cases have been observed in Seoul, South Korea. Urban scrub typhus may have a significant impact because of the large population.MethodsIndigenous urban scrub typhus was epidemiologically identified in Seoul, the largest metropolitan city in South Korea, using national notifiable disease data from 2010 to 2013. For detailed analysis of clinical features, patients from one hospital that reported the majority of cases were selected and compared to a historic control group. Chigger mites were prospectively collected in the city using a direct chigger mite-collecting trap, and identified using both phenotypic and 18S rDNA sequencing analyses. Their infection with Orientia tsutsugamushi was confirmed by sequencing the 56-kDa antigen gene.ResultsEighty-eight cases of urban scrub typhus were determined in Seoul. The possible sites of infection were mountainous areas (56.8%), city parks (20.5%), the vicinity of one’s own residence (17.0%), and riversides (5.7%). Eighty-seven chigger mites were collected in Gwanak mountain, one of the suspected infection sites in southern Seoul, and seventy-six (87.4%) of them were identified as Helenicula miyagawai and eight (9.2%) as Leptotrombidium scutellare. Pooled DNA extracted from H. miyagawai mites yielded O. tsutsugamushi Boryong strain. Twenty-six patients from one hospital showed low APACHE II score (3.4 ± 2.7), low complication rate (3.8%), and no hypokalemia.ConclusionsWe identified the presence of indigenous urban scrub typhus in Seoul, and a subgroup of them had mild clinical features. The chigger mite H. miyagawai infected with O. tsutsugamushi within the city was found. In endemic area, urban scrub typhus needs to be considered as one of the differential febrile diseases and a target for prevention.

BackgroundScrub typhus is a mite-borne febrile disease caused by O. tsutsugamushi infection. Recently, emergence of scrub typhus has attracted considerable attention in several endemic countries in Asia and the western Pacific. In addition, the antigenic diversity of the intracellular pathogen has been a serious obstacle for developing effective diagnostics and vaccine.Methodology/Principal findingsTo understand the evolutionary pathway of genotypic diversification of O. tsutsugamushi and the environmental factors associated with the epidemiological features of scrub typhus, we analyzed sequence data, including spatiotemporal information, of the tsa56 gene encoding a major outer membrane protein responsible for antigenic variation. A total of 324 tsa56 sequences covering more than 85% of its open reading frame were analyzed and classified into 17 genotypes based on phylogenetic relationship. Extensive sequence analysis of tsa56 genes using diverse informatics tools revealed multiple intragenic recombination events, as well as a substantially higher mutation rate than other house-keeping genes. This suggests that genetic diversification occurred via frequent point mutations and subsequent genetic recombination. Interestingly, more diverse bacterial genotypes and dominant vector species prevail in Taiwan compared to other endemic regions. Furthermore, the co-presence of identical and sub-identical clones of tsa56 gene in geographically distant areas implies potential spread of O. tsutsugamushi genotypes.Conclusions/SignificanceFluctuation and diversification of vector species harboring O. tsutsugamushi in local endemic areas may facilitate genetic recombination among diverse genotypes. Therefore, careful monitoring of dominant vector species, as well as the prevalence of O. tsutsugamushi genotypes may be advisable to enable proper anticipation of epidemiological changes of scrub typhus.

We hypothesized that immune response may contribute to progression of coronavirus disease-19 at the second week of illness. Therefore, we compared cell-mediated immune (CMI) responses between severe and mild COVID-19 cases. Methods: We examined peripheral blood mononuclear cells of laboratory-confirmed COVID-19 patients from their first and third weeks of illness. Severe pneumonia was defined as an oxygen saturation 93% at room air. Expressions of molecules related to T-cell activation and functions were analyzed by flow cytometry.Results: The population dynamics of T cells at the first week were not different between the two groups. However, total numbers of CD4 + and CD8 + T cells tended to be lower in the severe group at the third week of illness. Expressions of Ki-67, PD-1, perforin, and granzyme B in CD4 + or CD8 + T cells were significantly higher in the severe group than in the mild group at the third week. In contrast to the mild group, the levels of their expression did not decrease in the severe group. Conclusions: Severe COVID-19 had a higher degree of proliferation, activation, and cytotoxicity of T-cells at the late phase of illness without cytotoxic T-cell contraction, which might contribute to the development of severe COVID-19.

BackgroundScrub typhus is an acute febrile disease caused by Orientia tsutsugamushi infection. Recently, the rapid increase of scrub typhus incidence in several countries within the endemic region has become a serious public health issue. Despite the wide range of preventative approaches that have been attempted in the past 70 years, all have failed to develop an effective prophylactic vaccine. Currently, the selection of the proper antigens is one of the critical barriers to generating cross-protective immunity against antigenically-variable strains of O. tsutsugamushi.Methodology/Principal FindingsWe examined the potential role of ScaA protein, an autotransporter protein of O. tsutsugamushi, in bacterial pathogenesis and evaluated the protective attributes of ScaA immunization in lethal O. tsutsugamushi infection in mice. Our findings demonstrate that ScaA functions as a bacterial adhesion factor, and anti-ScaA antibody significantly neutralizes bacterial infection of host cells. In addition, immunization with ScaA not only provides protective immunity against lethal challenges with the homologous strain, but also confers significant protection against heterologous strains when combined with TSA56, a major outer membrane protein of O. tsutsugamushi.Conclusions/SignificanceImmunization of ScaA proteins provides protective immunity in mice when challenged with the homologous strain and significantly enhanced protective immunity against infection with heterologous strains. To our knowledge, this is the most promising result of scrub typhus vaccination trials against infection of heterologous strains in mouse models thus far.

A new magneto-mechanical coupling model was proposed for ferromagnetic materials under applied stress and in magnetic fields. The proposed model is based on the thermodynamic theory of ferromagnetic materials and Jiles–Atherton–Sablic (J–A–S) theory with respect to the effective magnetic field. Compared with the existing models for ferromagnetic materials, the prediction results of this model are more consistent with the existing experimental results, and the prediction accuracy has been significantly improved. This model can more accurately predict the nonlinear changes in the magnetization and magnetostriction under the applied stress and magnetic field. In addition, the effects of applied stress and magnetic field on magnetization and magnetostriction of ferromagnetic materials are analyzed on the basis of magnetic domain theory. In conclusion, the proposed model can fully describe the effect of applied stress on magnetization, magnetic permeability, and magnetostrictive strain, and the effects of applied stress and magnetic field on total magnetostrictive strain (i.e., the ΔE effect); furthermore, it sufficiently reflect the nonlinear coupling properties of the magnetic field, magnetization, and magnetostriction for ferromagnetic materials under applied stress and in magnetic fields.

Background Understanding the memory T-cell response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is crucial for assessing the longevity of protective immunity after SARS-CoV-2 infection or coronavirus disease-2019 (COVID-19) vaccination. However, the longitudinal memory T-cell response up to 8 months post-symptom onset (PSO) according to the severity of illness is unknown. Methods We analyzed peripheral blood mononuclear cells (PBMCs) from healthy volunteers or patients with COVID-19 who experienced asymptomatic, mild, or severe illness at 2, 5, and 8 months PSO. SARS-CoV-2 spike, nucleocapsid, and membrane protein-stimulated PBMCs were subjected to flow cytometry analysis Results A total of 24 patients—seven asymptomatic and nine with mild and eight with severe disease—as well as six healthy volunteers were analyzed. SARS-CoV-2-specific OX40 +CD137 + CD4 + T cells and CD69 +CD137 + CD8 + T cells persisted at 8 months PSO. Also, antigen-specific cytokine-producing or polyfunctional CD4 + T cells were maintained for up to 8 months PSO. Memory CD4 + T-cell responses tended to be greater in patients who had severe illness than in those with mild or asymptomatic disease. Conclusions Memory response to SARS-CoV-2, based on the frequency and functionality, persists for 8 months PSO. Further investigations involving its longevity and protective effect from reinfection are warranted.