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    Herpes Simplex Virus Evasion of Early Host Antiviral Responses. Tognarelli Eduardo I,Palomino Tomás F,Corrales Nicolás,Bueno Susan M,Kalergis Alexis M,González Pablo A Frontiers in cellular and infection microbiology Herpes simplex viruses type 1 (HSV-1) and type 2 (HSV-2) have co-evolved with humans for thousands of years and are present at a high prevalence in the population worldwide. HSV infections are responsible for several illnesses including skin and mucosal lesions, blindness and even life-threatening encephalitis in both, immunocompetent and immunocompromised individuals of all ages. Therefore, diseases caused by HSVs represent significant public health burdens. Similar to other herpesviruses, HSV-1 and HSV-2 produce lifelong infections in the host by establishing latency in neurons and sporadically reactivating from these cells, eliciting recurrences that are accompanied by viral shedding in both, symptomatic and asymptomatic individuals. The ability of HSVs to persist and recur in otherwise healthy individuals is likely given by the numerous virulence factors that these viruses have evolved to evade host antiviral responses. Here, we review and discuss molecular mechanisms used by HSVs to evade early innate antiviral responses, which are the first lines of defense against these viruses. A comprehensive understanding of how HSVs evade host early antiviral responses could contribute to the development of novel therapies and vaccines to counteract these viruses. 10.3389/fcimb.2019.00127
    Viral CNS infections in children from a malaria-endemic area of Malawi: a prospective cohort study. Mallewa Macpherson,Vallely Pam,Faragher Brian,Banda Dan,Klapper Paul,Mukaka Mavuto,Khofi Harriet,Pensulo Paul,Taylor Terrie,Molyneux Malcolm,Solomon Tom The Lancet. Global health BACKGROUND:Fever with reduced consciousness is an important cause of hospital admission of children in sub-Saharan Africa, with high mortality. Cerebral malaria, diagnosed when acute Plasmodium falciparum infection and coma are recorded with no other apparent reason, is one important cause. We investigated whether viruses could also be an important cause of CNS infection in such patients, and examined the relative contribution of viral pathogens and malaria parasitaemia. METHODS:We did a prospective cohort study in Blantyre, Malawi. From March 1, 2002, to Aug 31, 2004, we enrolled children aged between 2 months and 15 years who were admitted to hospital with suspected non-bacterial CNS infections. Children with a cerebrospinal fluid (CSF) white cell count of less than 1000 cells per μL and negative bacterial microscopy and culture were deemed to have suspected viral CNS infection. Blood was examined for asexual forms of P falciparum. PCR was done on CSF or on post-mortem brain biopsy specimens to detect 15 viruses known to cause CNS infection. FINDINGS:Full outcome data were available for 513 children with suspected viral CNS infection, of whom 94 (18%) died. 163 children (32%) had P falciparum parasitaemia, of whom 34 (21%) died. At least one virus was detected in the CNS in 133 children (26%), of whom 43 (33%) died. 12 different viruses were detected; adenovirus was the most common, affecting 42 children; mumps, human herpes virus 6, rabies, cytomegalovirus, herpes simplex virus 1, and enterovirus were also important. 45 (9%) of the 513 children had both parasitaemia and viral infection, including 27 (35%) of 78 diagnosed clinically with cerebral malaria. Children with dual infection were more likely to have seizures than were those with parasitaemia alone, viral infection only, or neither (p<0·0001). 17 (38%) of the 45 children with dual infection died, compared with 26 (30%) of 88 with viral infection only, 17 (14%) of 118 with parasitaemia only, and 34 (13%) of 262 with neither (p<0·0001). Logistic regression showed children with a viral CNS infection had a significantly higher mortality than did those who did not have a viral CNS infection (p=0·001). INTERPRETATION:Viral CNS infections are an important cause of hospital admission and death in children in Malawi, including in children whose coma might be attributed solely to cerebral malaria. Interaction between viral infection and parasitaemia could increase disease severity. FUNDING:Wellcome Trust, US National Institutes of Health, and UK Medical Research Council. 10.1016/S2214-109X(13)70060-3
    Neonatal herpes simplex virus infection following Jewish ritual circumcisions that included direct orogenital suction - New York City, 2000-2011. MMWR. Morbidity and mortality weekly report Herpes simplex virus (HSV) infection commonly causes "cold sores" (HSV type 1 [HSV-1]) and genital herpes (HSV-1 or HSV type 2 [HSV-2]); HSV infection in newborns can result in death or permanent disability. During November 2000-December 2011, a total of 11 newborn males had laboratory-confirmed HSV infection in the weeks following out-of-hospital Jewish ritual circumcision, investigators from the New York City Department of Health and Mental Hygiene (DOHMH) learned. Ten of the 11 newborns were hospitalized; two died. In six of the 11 cases, health-care providers confirmed parental reports that the ritual circumcision included an ultra-Orthodox Jewish practice known as metzitzah b'peh, in which the circumciser (mohel, plural: mohelim) places his mouth directly on the newly circumcised penis and sucks blood away from the circumcision wound (direct orogenital suction). In the remaining cases, other evidence suggested that genital infection was introduced by direct orogenital suction (probable direct orogenital suction). Based on cases reported to DOHMH during April 2006-December 2011, the risk for neonatal herpes caused by HSV-1 and untyped HSV following Jewish ritual circumcision with confirmed or probable direct orogenital suction in New York City was estimated at 1 in 4,098 or 3.4 times greater than the risk among male infants considered unlikely to have had direct orogenital suction. Oral contact with a newborn's open wound risks transmission of HSV and other pathogens. Circumcision is a surgical procedure that should be performed under sterile conditions. Health-care professionals advising parents and parents choosing Jewish ritual circumcision should inquire in advance whether direct orogenital suction will be performed, and orogenital suction should be avoided.
    Impact of viral and bacterial infectious burden on long-term prognosis in patients with coronary artery disease. Rupprecht H J,Blankenberg S,Bickel C,Rippin G,Hafner G,Prellwitz W,Schlumberger W,Meyer J, Circulation BACKGROUND:The number of infectious pathogens to which an individual has been exposed (infectious burden) may correlate with coronary artery disease (CAD). In a prospective study, we evaluated the effect of 8 pathogens and the aggregate pathogen burden on the risk for future fatal cardiac events among patients with angiographically documented CAD. Methods and Results-In 1018 patients, IgG or IgA antibodies to herpes simplex virus types 1 and 2, cytomegalovirus, Epstein-Barr virus, Haemophilus influenzae, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Helicobacter pylori were determined. Moreover, highly sensitive C-reactive protein was measured. Follow-up information on cardiovascular events was obtained (mean 3.1 years, maximum 4.3 years). Seropositivities to Epstein-Barr virus (P=0.001), H pylori (P=0.002), and herpes simplex virus type 2 (P=0.045) were independently associated with the future risk of cardiovascular death. An increasing number for pathogen burden was significantly predictive of the long-term prognosis (P<0.0001). Infectious burden divided into 0 to 3, 4 or 5, and 6 to 8 seropositivities was associated with an increasing mortality of 3.7%, 7.2%, and 12.6%, respectively. Patients seropositive to >5 pathogens compared with those seropositive to <4 pathogens had a 5.1 (1.4 to 18.3) higher risk of future cardiac death. This result was mainly driven by the pathogen burden of seropositivities to Herpesviridae (P<0.0001). The prognostic impact of total or viral pathogen burden was independent of the C-reactive protein level. CONCLUSIONS:These results support the hypothesis that the number of infectious pathogens to which an individual has been exposed independently contributes to the long-term prognosis in patients with documented CAD. 10.1161/hc2601.091703
    An outbreak of herpes gladiatorum at a high-school wrestling camp. Belongia E A,Goodman J L,Holland E J,Andres C W,Homann S R,Mahanti R L,Mizener M W,Erice A,Osterholm M T The New England journal of medicine BACKGROUND AND METHODS:Herpes simplex virus type 1 (HSV-1) has been identified as a cause of cutaneous or ocular infection among athletes involved in contact sports; in this context it is known as herpes gladiatorum. In July 1989, we investigated an outbreak among 175 high-school wrestlers attending a four-week intensive-training camp. Cases of infection were identified by review of medical records, interview and examination of the wrestlers, and culture of skin lesions. Oropharyngeal swabs were obtained for HSV-1 culture, and serum samples for HSV-1 serologic studies. HSV-1 isolates were compared by restriction-endonuclease analysis. RESULTS:HSV-1 infection was diagnosed in 60 wrestlers (34 percent). The lesions were on the head in 73 percent of the wrestlers, the extremities in 42 percent, and the trunk in 28 percent. HSV-1 was isolated from 21 wrestlers (35 percent), and in 39 (65 percent) infection was identified by clinical criteria. Five had conjunctivitis or blepharitis; none had keratitis. Constitutional symptoms were common, including fever (25 percent), chills (27 percent), sore throat (40 percent), and headache (22 percent). The attack rate varied significantly among the three practice groups, ranging from 25 percent for practice group 1 (lightweights) to 67 percent for group 3 (heavyweights). Restriction-endonuclease analysis identified four strains of HSV-1 among the 21 isolates. All 10 isolates from practice group 3 were identical (strain A), and 5 of 7 isolates from practice group 2 (middleweights) were identical (strain B), which suggested concurrent transmission of different strains within different groups. HSV-1 was not isolated from any oropharyngeal swabs. CONCLUSIONS:Herpes gladiatorum may cause substantial morbidity among wrestlers, and it is primarily transmitted by direct skin-to-skin contact. Prompt identification and exclusion of wrestlers with skin lesions may reduce transmission. 10.1056/NEJM199109263251302
    Herpesvirus Infections and Childhood Arterial Ischemic Stroke: Results of the VIPS Study. Elkind Mitchell S V,Hills Nancy K,Glaser Carol A,Lo Warren D,Amlie-Lefond Catherine,Dlamini Nomazulu,Kneen Rachel,Hod Eldad A,Wintermark Max,deVeber Gabrielle A,Fullerton Heather J, Circulation BACKGROUND:Epidemiological studies demonstrate that childhood infections, including varicella zoster virus, are associated with an increased risk of arterial ischemic stroke (AIS). Other herpesviruses have been linked to childhood AIS in case reports. We sought to determine whether herpesvirus infections, which are potentially treatable, increase the risk of childhood AIS. METHODS AND RESULTS:We enrolled 326 centrally confirmed cases of AIS and 115 stroke-free controls with trauma (29 days to 18 years of age) with acute blood samples (≤3 weeks after stroke/trauma); cases had convalescent samples (7-28 days later) when feasible. Samples were tested by commercial enzyme-linked immunosorbent assay kits for immunoglobulin M/immunoglobulin G antibodies to herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus, and varicella zoster virus. An algorithm developed a priori classified serological evidence of past and acute herpesvirus infection as dichotomous variables. The median (quartiles) age was 7.7 (3.1-14.3) years for cases and 10.7 (6.9-13.2) years for controls (P=0.03). Serological evidence of past infection did not differ between cases and controls. However, serological evidence of acute herpesvirus infection doubled the odds of childhood AIS, even after adjusting for age, race, and socioeconomic status (odds ratio, 2.2; 95% confidence interval, 1.2-4.0; P=0.007). Among 187 cases with acute and convalescent blood samples, 85 (45%) showed evidence of acute herpesvirus infection; herpes simplex virus 1 was found most often. Most infections were asymptomatic. CONCLUSIONS:Herpesviruses may act as a trigger for childhood AIS, even if the infection is subclinical. Antivirals like acyclovir might have a role in the prevention of recurrent stroke if further studies confirm a causal relationship. 10.1161/CIRCULATIONAHA.115.018595
    Congenital viral infections in England over five decades: a population-based observational study. The Lancet. Infectious diseases BACKGROUND:Congenital viral infections cause substantial long-term morbidity but population-based data about diagnosis rates are scarce. The aim of this study was to assess the long-term trends in congenital viral infections in England and to report on how the rates of these infections might have changed with improved methods for detection, the introduction of the two-dose measles-mumps-rubella (MMR) vaccine in 1996, and the implementation of the Newborn Hearing Screening Programme (NHSP) in 2006. METHODS:For this population-based, observational cohort study, we used national and regional hospitalisation data from 1968 to 2016 in England (Hospital In-Patient Enquiry, Hospital Episode Statistics, and Oxford Record Linkage Study) to calculate annual rates of hospital discharges coded with-and individuals aged younger than 1 month diagnosed with-congenital cytomegalovirus, herpes simplex virus (HSV), varicella zoster virus (VZV), and rubella. We investigated associations of congenital cytomegalovirus, HSV, and VZV with perinatal and maternal factors (sex, mother's ethnicity, mode of delivery, gestational age, birthweight, mother's age, mother's index of multiple deprivation, and number of previous pregnancies). FINDINGS:In 2016, discharge rates per 100 000 infant population were 22·3 (95% CI 18·8-26·1) for congenital cytomegalovirus, 17·6 (14·6-21·1) for HSV, 32·6 (28·4-37·2) for VZV, and 0·15 (0·0-0·8) for rubella. Compared with earlier years of the study, the discharge rate in 2016 was higher for congenital cytomegalovirus, HSV, and VZV, whereas it was lower for rubella. For congenital cytomegalovirus, there was a significant step-increase between 2006 and 2007 following implementation of the NHSP (rate ratio comparing the trend line post-NHSP with that pre-NHSP 1·55 [95% CI 1·12-2·14], p=0·0072). Congenital cytomegalovirus infection was associated with birthweight less than 1 kg, maternal age younger than 25 years, socioeconomically deprived households, casearean section, and mothers of black ethnicity. Congenital HSV infection was associated with maternal age younger than 20 years, gestational age less than 32 weeks, and vaginal and emergency caesarean section deliveries, while VZV infection was associated with increased parity and black and south Asian ethnicities. INTERPRETATION:The increase in hospital discharges coded with congenital cytomegalovirus is most likely due to the introduction of sensitive diagnostic techniques and retrospective diagnoses made in infants after implementation of the NHSP. Public health strategies to improve prevention and treatment of congenital viral infections are urgently warranted. The decrease in discharges for rubella is most likely due to the MMR vaccine. FUNDING:None. 10.1016/S1473-3099(19)30416-5
    Herpes simplex virus type 2 in the United States, 1976 to 1994. Fleming D T,McQuillan G M,Johnson R E,Nahmias A J,Aral S O,Lee F K,St Louis M E The New England journal of medicine BACKGROUND:Herpes simplex virus type 2 (HSV-2) infection is usually transmitted sexually and can cause recurrent, painful genital ulcers. In neonates the infection is potentially lethal. We investigated the seroprevalence and correlates of HSV-2 infection in the United States and identified changes in HSV-2 seroprevalence since the late 1970s. METHODS:Serum samples and questionnaire data were collected during the National Health and Nutrition Examination Surveys (NHANES) II (1976 to 1980) and III (1988 to 1994). HSV-2 antibody was assessed with an immunodot assay specific for glycoprotein gG-2 of HSV-2. RESULTS:From 1988 to 1994, the seroprevalence of HSV-2 in persons 12 years of age or older in the United States was 21.9 percent (95 percent confidence interval, 20.2 to 23.6 percent), corresponding to 45 million infected people in the noninstitutionalized civilian population. The seroprevalence was higher among women (25.6 percent) than men (17.8 percent) and higher among blacks (45.9 percent) than whites (17.6 percent). Less than 10 percent of all those who were seropositive reported a history of genital herpes infection. In a multivariate model, the independent predictors of HSV-2 seropositivity were female sex, black race or Mexican-American ethnic background, older age, less education, poverty, cocaine use, and a greater lifetime number of sexual partners. As compared with the period from 1976 to 1980, the age-adjusted seroprevalence of HSV-2 rose 30 percent (95 percent confidence interval, 15.8 to 45.8 percent). The seroprevalence quintupled among white teenagers and doubled among whites in their twenties. Among blacks and older whites, the increases were smaller. CONCLUSIONS:Since the late 1970s, the prevalence of HSV-2 infection has increased by 30 percent, and HSV-2 is now detectable in roughly one of five persons 12 years of age or older nationwide. Improvements in the prevention of HSV-2 infection are needed, particularly since genital ulcers may facilitate the transmission of the human immunodeficiency virus. 10.1056/NEJM199710163371601
    Chlamydia pneumoniae, cytomegalovirus, and herpes simplex virus in atherosclerosis of the carotid artery. Chiu B,Viira E,Tucker W,Fong I W Circulation BACKGROUND:Chlamydia pneumoniae and the herpes viruses cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1) have been associated with human atherosclerosis in seroepidemiological and separate histopathological studies. We investigated the concurrent presence of these microorganisms in patients undergoing carotid endarterectomy. METHODS AND RESULTS:Endarterectomy specimens from 76 patients with carotid artery stenosis were stained for C. pneumoniae, CMV, and HSV-1 particles with specific IgG monoclonal antibodies by the avidin-biotin-peroxidase method. IgG antibodies to CMV and C. pneumoniae were also measured in the serum. These were correlated with plaque morphology and the presence of the microorganisms in the atherosclerotic plaques. C. pneumoniae was detected in 54 (71%) (95% confidence interval [CI], 59.5% to 80.9%), CMV was detected in 27 (35.5%) (CI, 24.9% to 47.3%), and HSV-1 was detected in 8 (10.5%) (CI, 4.7% to 19.7%) versus none of 20 (0%) control normal carotid artery and aortic tissue (autopsy) specimens (CI, 0% to 16.8%) (P<.001 for CMV and C. pneumoniae). At least one microorganism was detected in 59 of the specimens (77.6%) (CI, 66.6% to 86.4%), with a single microorganism present only in 35 (46%), two microorganisms present in 18 (23.7%) (CI, 14.7% to 34.8%), and all three present in 6 (7.9%) (CI, 3.0% to 16.4%). Atherosclerotic plaques with thrombosis were more likely to have C. pneumoniae (80.4%) or CMV (57.8%) than were plaques without thrombosis (56.7% and 16.7%, respectively; P=.04 and .007). There was no correlation between the presence of CMV and C. pneumoniae in the atherosclerotic vessels and serum antibody titers. CONCLUSIONS:C. pneumoniae and CMV are commonly detected in atherosclerotic plaques of the carotid arteries, but their presence cannot be predicted by measuring serum antibodies. The presence of these microorganisms may predispose to a greater risk of thrombosis in the plaques, but further studies are needed to confirm this observation. 10.1161/01.cir.96.7.2144
    Medical and legal implications of testing for sexually transmitted infections in children. Hammerschlag Margaret R,Guillén Christina D Clinical microbiology reviews Testing for sexually transmitted infections (STIs) in children presents a number of problems for the practitioner that are not usually faced when testing adults for the same infections. The identification of an STI in a child can have, in addition to medical implications, serious legal implications. The presence of an STI is often used to support the presence or allegations of sexual abuse, and conversely, the identification of an STI in a child will prompt an investigation of possible abuse. The purpose of this paper is to review the epidemiology of child sexual abuse, including the epidemiology of major STIs including Neisseria gonorrhoeae, Chlamydia trachomatis, syphilis, herpes simplex virus (HSV), Trichomonas vaginalis, and human papillomavirus, and the current recommendations for diagnostic testing in this population. 10.1128/CMR.00024-09
    Interaction between APOE4 and herpes simplex virus type 1 in Alzheimer's disease. Linard Morgane,Letenneur Luc,Garrigue Isabelle,Doize Angélique,Dartigues Jean-François,Helmer Catherine Alzheimer's & dementia : the journal of the Alzheimer's Association INTRODUCTION:Numerous results suggest the implication of infectious agents in the onset of Alzheimer's disease (AD). METHODS:In the Bordeaux-3C prospective cohort, we assessed the impact of herpes simplex virus type 1 (HSV-1) infection on the incidence of AD according to apolipoprotein E (APOE) status, a genetic susceptibility factor. Cox models were performed to estimate the 10-year risk of AD associated with anti-HSV antibodies in 1037 participants according to APOE4 status. RESULTS:Among APOE4 carriers, subjects for whom the frequency of HSV-1 reactivation is supposed to be high, that is, immunoglobulin M (IgM) positive or elevated levels of IgG, had an increased risk of AD with adjusted hazard ratios (HRs) of 3.68 (1.08-12.55) and 3.28 (1.19-9.03), respectively. No significant association was found in APOE4-negative subjects. DISCUSSION:These results, in accordance with a solid pathophysiological rationale, suggest a role for HSV-1 in AD development among subjects with a genetic susceptibility factor, the APOE4 allele. 10.1002/alz.12008
    Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. The Lancet. Infectious diseases BACKGROUND:Encephalitis has many causes, but for most patients the cause is unknown. We aimed to establish the cause and identify the clinical differences between causes in patients with encephalitis in England. METHODS:Patients of all ages and with symptoms suggestive of encephalitis were actively recruited for 2 years (staged start between October, 2005, and November, 2006) from 24 hospitals by clinical staff. Systematic laboratory testing included PCR and antibody assays for all commonly recognised causes of infectious encephalitis, investigation for less commonly recognised causes in immunocompromised patients, and testing for travel-related causes if indicated. We also tested for non-infectious causes for acute encephalitis including autoimmunity. A multidisciplinary expert team reviewed clinical presentation and hospital tests and directed further investigations. Patients were followed up for 6 months after discharge from hospital. FINDINGS:We identified 203 patients with encephalitis. Median age was 30 years (range 0-87). 86 patients (42%, 95% CI 35-49) had infectious causes, including 38 (19%, 14-25) herpes simplex virus, ten (5%, 2-9) varicella zoster virus, and ten (5%, 2-9) Mycobacterium tuberculosis; 75 (37%, 30-44) had unknown causes. 42 patients (21%, 15-27) had acute immune-mediated encephalitis. 24 patients (12%, 8-17) died, with higher case fatality for infections from M tuberculosis (three patients; 30%, 7-65) and varicella zoster virus (two patients; 20%, 2-56). The 16 patients with antibody-associated encephalitis had the worst outcome of all groups-nine (56%, 30-80) either died or had severe disabilities. Patients who died were more likely to be immunocompromised than were those who survived (OR = 3·44). INTERPRETATION:Early diagnosis of encephalitis is crucial to ensure that the right treatment is given on time. Extensive testing substantially reduced the proportion with unknown cause, but the proportion of cases with unknown cause was higher than that for any specific identified cause. FUNDING:The Policy Research Programme, Department of Health, UK. 10.1016/S1473-3099(10)70222-X