Secondary hypogonadism following hand, foot, and mouth disease in an adult: a case report and review of literature

Background Previous reports have described hypogonadism associated with virus infection such as hantavirus, human immunodeficiency virus (HIV) or severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). However, to our best knowledge there has been no case report of secondary hypogonadism following hand, foot, and mouth disease (HFMD). Case presentation A previously healthy 28-year-old man with no history of major physical and psychological trauma, presented with bilateral gynecomastia and erectile dysfunction 2 weeks after HFMD. Laboratory testament showed the level of gonadotropin hormones declined. Imaging examination demonstrated no major abnormal change in pituitary or reproductive system. The diagnosis of hypogonadism was established. Then the patient was ordered to maintain mental health outward of hospital without drug intervention. One month after presentation, his gonadotropin hormone level and sexual desire had recovered, while bilateral gynecomastia and erectile dysfunction symptoms disappeared. Conclusions Physicians should notice the possibility for hypogonadism in adult patients with a recent history of HFMD.

Highly Specific Loop-Mediated Isothermal Amplification Using Graphene Oxide–Gold Nanoparticles Nanocomposite for Foot-and-Mouth Disease Virus Detection

Loop-mediated isothermal amplification (LAMP) is a molecular diagnosis technology with the advantages of rapid results, isothermal reaction conditions, and high sensitivity. However, this diagnostic system often produces false positive results due to a high rate of non-specific reactions caused by formation of hairpin structures, self-dimers, and mismatched hybridization. The non-specific signals can be due to primers used in the methods because the utilization of multiple LAMP primers increases the possibility of self-annealing of primers or mismatches between primers and templates. In this study, we report a nanomaterial-assisted LAMP method that uses a graphene oxide–gold nanoparticles (AuNPs@GO) nanocomposite to enable the detection of foot-and-mouth disease virus (FMDV) with high sensitivity and specificity. Foot-and-mouth disease (FMD) is a highly contagious and deadly disease in cloven-hoofed animals; hence, a rapid, sensitive, and specific detection method is necessary. The proposed approach exhibited high sensitivity and successful reduction of non-specific signals compared to the traditionally established LAMP assays. Additionally, a mechanism study revealed that these results arose from the adsorption of single-stranded DNA on AuNPs@GO nanocomposite. Thus, AuNPs@GO nanocomposite is demonstrated to be a promising additive in the LAMP system to achieve highly sensitive and specific detection of diverse diseases, including FMD.

Spatiotemporal Cluster Patterns of Hand, Foot, and Mouth Disease at the Province level in Mainland China, 2009-2018

BackgroundAlthough three monovalent EV-A71 vaccines have been launched in mainland China since 2016, hand, foot, and mouth disease (HFMD) still causes a considerable disease burden in China. Vaccines’ use may change the epidemiological characters of HFMD. This study aims to analyze the spatiotemporal cluster of HFMD at the province level in mainland China from 2009 to 2018 and compare the difference before and after the vaccines were launched. MethodsAll HFMD cases’ data from January 2009 to December 2018 were obtained from the public health science data center given by the Chinese Center for Diseases Control and Prevention. Spatial autocorrelation analysis and space-time scan statistics analysis were used to explore the spatiotemporal distribution pattern of this disease at the provincial level in mainland China. ResultsThe median annual incidence of HFMD was 143.22 per 100,000 (ranging from 87.01 to 205.06) in mainland China from 2009 to 2018. Two peaks of infections were observed per year. Children 5 years and under were the main morbid population. The global autocorrelation analysis showed that the spatial distribution of HFMD was presented a significant clustering pattern in each year (P<0.001), and the local autocorrelation analysis indicated that the high incidence areas were clustered in the southern and southeastern coastal provinces. The distribution of HFMD cases was clustered in time and space. The range of cluster time was between April and October. The most likely cluster appeared in the southern coastal provinces (Guangxi, Guangdong, Hainan) from 2010 to 2017 and in the southeastern coastal provinces (Shanghai, Jiangsu, Zhejiang) in 2018. ConclusionChanges in the spatiotemporal cluster of HFMD after the launch of EV-A71 vaccines were observed at the province level in mainland China in 2018. It is necessary to advance the EV-A71 vaccination plan, analyze the spatial-temporal distribution characteristics of different enterovirus pathogens of HFMD, and promote HFMD multivalent vaccines.

Foot-and-mouth disease virus 3A hijacks Sar1 and Sec12 for ER remodeling in a COPII-independent manner

Positive-stranded RNA viruses modify host organelles to form replication organelles (ROs) for their replication. Enteroviral 3A protein has been demonstrated to be highly associated with the COPI pathway, in which factors work on the ER-to-Golgi intermediate and the Golgi. However, Sar1, a COPII factor exerting coordinated action at endoplasmic reticulum (ER) exit sites, rather than COPI factors, is required for foot-and-mouth disease virus (FMDV) replication. Therefore, we thought that deep understanding of FMDV 3A was the key to explaining the differences and to unlocking the secret of FMDV RO formation. In this study, FMDV 3A was confirmed as a peripheral membrane protein capable of modifying the ER into vesicle-like structures, which were neither COPII vesicles nor autophagosomes. When the C-terminus of 3A was truncated, it would be located at the ER without vesicular modification. This change was revealed by mGFP and APEX2 fusion constructs observed by fluorescence microscopy and electron tomography, respectively. Referring to other 3A truncation, the minimal region for modification was aa 42–92. Furthermore, we found that the remodeling was related to two COPII factors, Sar1 and Sec12. Both interacted with 3A, but their binding domains on 3A were different. Finally, we hypothesized that the N-terminus of 3A would interact with Sar1 as its C-terminus simultaneously interacted with Sec12, which possibly would enhance Sar1 activation. On the ER membrane, two active Sar1 were connected by 3A with regions of aa 42–59 and aa 76–92, causing curvature of the membrane. This mechanism is distinct from the traditional COPII pathway and should be crucial for FMDV RO formation.

Effects and mechanisms of Portulaca oleracea L. polysaccharides on the activation of dendritic cells derived from mice immunized with FMD vaccine

Background Our previous study has showed that Portulaca oleracea L. (POL-P), as an immunoenhancer, could increase the IgG and isotypes antibody titers in mice immunized with foot and mouth disease (FMD) vaccines. However, the structural features and the mechanism of action are still unclear. Enhancing antigen presentation is one of the main ways that immunoenhancer boost immune response. Dendritic cells (DCs) are the most potent antigen presenting cell (APC), which stimulate the initial T cells directly and initiate the specific immune responses. In addition to extracellular factors and intracellular genetic factors, epigenetics plays a major role in the regulation of DCs. In this study, we obtained POL-P, and structural features and monosaccharide composition were analyzed. We evaluated the effect of POL-P on functional maturation of DCs derived from mice immunized with foot and mouth disease (FMD) vaccine and explored the related mechanism responsible for immunoenhancer. The levels of protein and gene related to IL-12p35 and IL-12p40 were determined by western blot and chromatin immunoprecipitation (ChIP) assays. The expressions of TLR2, TLR4 receptors and the downstream molecules of MyD88 and NF-κB were examined using immunohistochemistry. Results The average molecular weight (Mw) of the POL-P was 4×104 Da. The monosaccharide composition of the POL-P was mannose, rhamnose, glucuronic acid, galacturonic acid, glucose, galactose and arabinose with a relative mass of 1.2%, 13.2%, 33.5%, 1.2%, 3.3%, 32.2% and 15.4%, respectively. We concluded that co-administration of POL-P with the FMD vaccine could significantly promote DCs maturation of phenotype and the immune function. In addition, the acetylation level of histone H3 of IL-12 was closely connected with the immune activity of DCs. Moreover, POL-P induced immune response was related to up-regulating protein expression of TLR2, TLR4, MyD88 and NF-κB in DCs. Conclusions Our evidence suggested that POL-P could be a potential immunostimulant in the regulation of DCs maturation for FMD vaccine.

Membrane interactions and uncoating of Aichi virus, a picornavirus that lacks a VP4

Kobuviruses are an unusual and poorly characterised genus within the picornavirus family, and can cause gastrointestinal enteric disease in humans, livestock and pets. The human Kobuvirus, Aichi virus (AiV) can cause severe gastroenteritis and deaths in children below the age of five years, however this is a very rare occurrence. During the assembly of most picornaviruses (e.g. poliovirus, rhinovirus and foot-and-mouth disease virus), the capsid precursor protein VP0 is cleaved into VP4 and VP2. However, Kobuviruses retain an uncleaved VP0. From studies with other picornaviruses, it is known that VP4 performs the essential function of pore formation in membranes, which facilitates transfer of the viral genome across the endosomal membrane and into the cytoplasm for replication. Here, we employ genome exposure and membrane interaction assays to demonstrate that pH plays a critical role in AiV uncoating and membrane interactions. We demonstrate that incubation at low pH alters the exposure of hydrophobic residues within the capsid, enhances genome exposure and enhances permeabilisation of model membranes. Furthermore, using peptides we demonstrate that the N-terminus of VP0 mediates membrane pore formation in model membranes, indicating that this plays an analogous function to VP4. Importance: To initiate infection, viruses must enter a host cell and deliver their genome into the appropriate location. The picornavirus family of small non-enveloped RNA viruses includes significant human and animal pathogens and are also models to understand the process of cell entry. Most picornavirus capsids contain the internal protein VP4, generated from cleavage of a VP0 precursor. During entry, VP4 is released from the capsid. In enteroviruses this forms a membrane pore, which facilitates genome release into the cytoplasm. Due to high levels of sequence similarity, it is expected to play the same role for other picornaviruses. Some picornaviruses, such as Aichi virus, retain an intact VP0, and it is unknown how these viruses re-arrange their capsids and induce membrane permeability in the absence of VP4. Here we have used Aichi virus as a model VP0 virus to test for conservation of function between VP0 and VP4. This could enhance understanding of pore function and lead to development of novel therapeutic agents that block entry.