Receptor Variation and Susceptibility to Middle East Respiratory Syndrome Coronavirus Infection
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ABSTRACT The Middle East respiratory syndrome coronavirus (MERS-CoV) recently spread from an animal reservoir to infect humans, causing sporadic severe and frequently fatal respiratory disease. Appropriate public health and control measures will require discovery of the zoonotic MERS coronavirus reservoirs. The relevant animal hosts are liable to be those that offer optimal MERS virus cell entry. Cell entry begins with virus spike (S) protein binding to DPP4 receptors. We constructed chimeric DPP4 receptors that have the virus-binding domains of indigenous Middle Eastern animals and assessed the activities of these receptors in supporting S protein binding and virus entry. Human, camel, and horse receptors were potent and nearly equally effective MERS virus receptors, while goat and bat receptors were considerably less effective. These patterns reflected S protein affinities for the receptors. However, even the low-affinity receptors could hypersensitize cells to infection when an S-cleaving protease(s) was present, indicating that affinity thresholds for virus entry must be considered in the context of host-cell proteolytic environments. These findings suggest that virus receptors and S protein-cleaving proteases combine in a variety of animals to offer efficient virus entry and that several Middle Eastern animals are potential reservoirs for transmitting MERS-CoV to humans. IMPORTANCE MERS is a frequently fatal disease that is caused by a zoonotic CoV. The animals transmitting MERS-CoV to humans are not yet known. Infection by MERS-CoV requires receptors and proteases on host cells. We compared the receptors of humans and Middle Eastern animals and found that human, camel, and horse receptors sensitized cells to MERS-CoV infection more robustly than goat and bat receptors. Infection susceptibility correlated with affinities of the receptors for viral spike proteins. We also found that the presence of a cell surface lung protease greatly increases susceptibility to MERS-CoV, particularly in conjunction with low-affinity receptors. This cataloguing of human and animal host cell factors allows one to make inferences on the distribution of MERS-CoV in nature.Keywords:
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To the Editor: Assiri et al. (Aug. 1 issue)1 provide valuable information about a hospital outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infection. However, the authors do not describe the infection-control measures used in the hospital, and they do not discuss the possibility of aerosol transmission of MERS-CoV, a coronavirus similar to the severe acute respiratory syndrome coronavirus (SARSCoV). MERS-CoV can cause severe or fatal disease, and there is no prophylaxis or specific treatment. If the form of transmission is not understood, health care professionals should adhere to the precautionary principle that reasonable steps to reduce risk should not await scientific certainty. It is for this reason that the Centers for Disease Control and Prevention (CDC) recommended airborne precautions (the use of respirators rather than surgical masks), in addition to standard and contact precautions, for all patients with MERS-CoV. There is evidence that SARS-CoV was transmitted by respiratory aerosols,2-4 and surgical masks do not provide adequate protection against inhalation of aerosols.5 Health care workers have already been infected with MERS-CoV. It would be prudent for hospitals with the resources to do so to provide a higher level of protection (i.e., respirators) for their health care workers. Kathleen Harriman, Ph.D., M.P.H.
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Human coronaviruses (HCoVs) have long been considered in consequential pathogens, causing the -common cold‖ in otherwise healthy people.However, in the 21 st century, 2 highly pathogenic HCoVs-severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV)-emerged from animal reservoirs to cause global epidemics with alarming morbidity and mortality.In December 2019, yet another pathogenic HCoV, 2019 novel coronavirus (2019-nCoV), was recognized in Wuhan, China, and has caused serious illness and death.The ultimate cope and effect of this outbreak is unclear at present as the situation is rapidly evolving.Middle East respiratory syndrome coronavirus (MERS-CoV) is zoonotic diseases causing severe respiratory illness emerged in 2012 in Saudi Arabia.Phylogenetic studies and viral sequencing results strongly suggest that MERS-CoV originated from bat ancestors after evolutionary recombination process, primarily in dromedary camels in Africa.The prevalence of MERS-CoV antibodies, the identification of MERS-CoV RNA and viable virus from dromedary camels of Eastern Africa and the Arabian Peninsula are the suggestive evidence for inter-transmission of the virus, primarily from camels to humans and its public health risks.However, the infection in camel is mostly asymptomatic.In contrast to the camel case, the clinical signs and symptoms of MERS-CoV infection in humans ranges from an asymptomatic or mild respiratory illness to severe pneumonia and multi-organ failure with an overall mortality rate of about 35%.Though inter-human spread within health care settings is responsible for the majority of reported MERS-CoV human cases, the virus is currently incapable of causing sustained human-to-human transmission (pandemic occurrence).Currently, there is no specific drug or vaccine available for treatment and prevention of MERS-CoV.The important measures to control MERS-CoV spread are strict regulation of camel movement, regular herd screening and isolation of infected camels, use of personal protective equipment by camel handlers and awareness creation on the public where consumption of unpasteurized camel milk is common.Therefore, urgent global epidemiological studies are required, to understand the transmission patterns and the human cases of MERS-CoV and also for the proper implementation of the above-mentioned control measures.
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2][3][4] The case fatality rate (CFR) in patients infected with MERS-CoV is high-estimated at 43% in 147 patients reported so far by World Health Organization (WHO). 3This rate is higher than that of SARS-estimated at 15%, and is strongly age-and sex-dependent. 4 Although the source of virus in patients with sporadic infection remains unknown, it appears likely to be some species of animal. 4,5Clear evidence of limited human-to-human transmission of MERS-CoV has now been documented in several case clusters, including particularly family members and patients in health care facilities, 6-8 but all such clusters have, at least thus far, been limited in extent.However, a real concern persists that the virus will adapt to interhuman transmission and switch from an aborted epidemic to a pandemic similar to the SARS-CoV epidemic in 2003-2004.MERS-CoV is transmitted through droplets and contact.In the case of invasive respiratory procedures, MERS-CoV is transmitted through airborne route. 2 Early diagnosis and strict implementation of the core components for infection prevention and control programs are crucial for preventing epidemic amplification. 2 In the absence of an effective vaccine and a specific antiviral treatment, there is an urgent need to rapidly identify potential therapeutics.
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There is a paucity of data regarding the differentiating characteristics of patients with laboratory-confirmed and those negative for Middle East respiratory syndrome coronavirus (MERS-CoV).This is a hospital-based case-control study comparing MERS-CoV-positive patients (cases) with MERS-CoV-negative controls.A total of 17 case patients and 82 controls with a mean age of 60.7 years and 57 years, respectively (P = .553), were included. No statistical differences were observed in relation to sex, the presence of a fever or cough, and the presence of a single or multilobar infiltrate on chest radiography. The case patients were more likely to be overweight than the control group (mean body mass index, 32 vs 27.8; P = .035), to have diabetes mellitus (87% vs 47%; odds ratio [OR], 7.24; P = .015), and to have end-stage renal disease (33% vs 7%; OR, 7; P = .012). At the time of admission, tachypnea (27% vs 60%; OR, 0.24; P = .031) and respiratory distress (15% vs 51%; OR, 0.15; P = .012) were less frequent among case patients. MERS-CoV patients were more likely to have a normal white blood cell count than the control group (82% vs 52%; OR, 4.33; P = .029). Admission chest radiography with interstitial infiltrates was more frequent in case patients than in controls (67% vs 20%; OR, 8.13; P = .001). Case patients were more likely to be admitted to the intensive care unit (53% vs 20%; OR, 4.65; P = .025) and to have a high mortality rate (76% vs 15%; OR, 18.96; P < .001).Few clinical predictors could enhance the ability to predict which patients with pneumonia would have MERS-CoV. However, further prospective analysis and matched case-control studies may shed light on other predictors of infection.
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Background:
The hypothesis that initiation of DMARD-treatment before arthritis becomes apparent could permanently modulate the disease process, such that persistent RA is prevented, is being studied in several ongoing trials. Essential for such studies is the ability to accurately predict clinically apparent inflammatory arthritis (IA). However there are two hurdles: first, it is insufficiently known whether it is possible to obtain high positive predictive values (PPV) in patients presenting with clinically suspect arthralgia (CSA). Second, none of current predictive models is validated in independent cohorts. We here aimed to evaluate the first question, incorporating improved markers of MRI-detected subclinical inflammation that were recently identified but have not yet been combined with other known predictors.[1]Objectives:
To assess the feasibility of achieving high PPVs in prediction of IA-development in patients with CSA by combining clinical, laboratory and imaging parameters.Methods:
580 patients with CSA were consecutively included in the Clinically Suspect Arthralgia (CSA)-cohort and followed on the development of IA, determined by physical examination of joints. Unilateral contrast-enhanced 1.5 Tesla MRIs were made of MCP(2-5), wrist and MTP(1-5)-joints at baseline and scored in line with the RAMRIS. The number of locations with subclinical inflammation (0/1-2/≥3) and the presence of MCP peritendinitis were defined as described previously.[1] Other studied clinical and laboratory variables were based on the literature: initial localisation of complaints (small/large joints), functional disability (health assessment questionnaire (HAQ) ≥1), ACPA-positivity (Anti-CCP2), RF-positivity (IgM-RF) and elevated CRP.[2,3] LASSO Cox regression with a 10-fold cross-validated shrinkage parameter was used for predictor selection. Regression coefficients were rounded to the nearest number ending in .5 or .0 and multiplied by two, resulting in a weighted score. Kaplan Meijer curves were used to obtain PPVs of this weighted score and the area under the curve (AUC) was determined at 2-year follow-up.Results:
Mean age was 44, 78% was female, and 18% progressed to IA within 2 years. The following parameters were selected with LASSO: RF-positivity, ACPA-positivity, HAQ≥1, >2 locations of subclinical inflammation and presence of MCP-extensor peritendinitis. Based on the beta of LASSO-regression, patients were assigned 2 points for the risk-factors ACPA-positivity and >2 locations of subclinical inflammation, 1 point for RF-positivity and presence of MCP-extensor peritendinitis and 0 points for HAQ≥1. Kaplan Meijer curves show PPVs of 8%, 9%, 30%, 54%, 73%, 79% and 86% at two years (Figure 1). This model yielded an AUC of 0.79.Conclusion:
High PPVs for IA-development can be achieved in patients with CSA by weighting a combination of known predictors. Although encouraging, these data are based on one observational cohort study and have not been validated in independent cohorts, limiting the relevance. To support future research in the field of arthralgia, it is needed that different research groups work together to come to risk estimations that are validated and accepted.References:
[1] Matthijssen XME et al. ART 2019;21(1):249-. [2] van Steenbergen HW et al. ART 2014;16(2):R92. [3] ten Brinck RM et al. RMD Open 2017;3(1):e000419.Disclosure of Interests:
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Currently, the expansion of the novel human respiratory coronavirus (known as SARS-CoV-2 [severe acute respiratory syndrome coronavirus 2], COVID-2019 [coronavirus disease 2019], or 2019-nCoV [2019 novel coronavirus]) has stressed the need for therapeutic alternatives to alleviate and stop this new epidemic. The previous epidemics of infections by high-morbidity human coronaviruses, such as SARS-CoV in 2003 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, prompted the characterization of compounds that could be potentially active against the currently emerging novel coronavirus, SARS-CoV-2.
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During the summer of 2012, in Jeddah, Saudi Arabia, a hitherto unknown coronavirus (CoV) was isolated from the sputum of a patient with acute pneumonia and renal failure (1, 2). The isolate was provisionally called human coronavirus Erasmus Medical Center (EMC) (3). Shortly thereafter, in September 2012, the same type of virus, named human coronavirus England 1, was recovered from a patient with severe respiratory illness who had been transferred from the Gulf region of the Middle East to London, United Kingdom (4) (GenBank accession no. KC164505.2). The onset of the new disease was traced back to an even earlier time point. Already in April 2012, a cluster of pneumonia cases in health care workers had occurred in an intensive care unit of a hospital in Zarqa, Jordan (5). Two persons died, both of whom were confirmed to have been infected with the novel coronavirus through a retrospective analysis of stored samples (6). These findings met with considerable concern. Although the number of laboratory-confirmed cases is limited (34 as of 12 May 2013), the morbidity and mortality of the infection is alarming, as is its uncanny resemblance—at least in its clinical features—to severe acute respiratory syndrome (SARS). While in a small minority of the known cases the patients developed mild disease, most patients presented with a severe acute respiratory condition requiring hospitalization; the mortality rate is approximately 60% (7).
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