RESUMEN
A neurocysticercosis-like lesion in an 11-year-old boy in the Netherlands was determined to be caused by the zoonotic Taenia martis tapeworm. Subsequent testing revealed that 15% of wild martens tested in that region were infected with T. martis tapeworms with 100% genetic similarity; thus, the infection source was most likely local.
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Neurocisticercosis , Taenia , Masculino , Niño , Animales , Humanos , Neurocisticercosis/diagnóstico por imagen , Taenia/genética , Países BajosRESUMEN
Seasonal influenza vaccination takes into account primarily hemagglutinin (HA)-specific neutralizing antibody responses. However, the accumulation of substitutions in the antigenic regions of HA (i.e., antigenic drift) occasionally results in a mismatch between the vaccine and circulating strains. To prevent poor vaccine performance, we investigated whether an antigenically matched neuraminidase (NA) may compensate for reduced vaccine efficacy due to a mismatched HA. Ferrets were vaccinated twice with adjuvanted split inactivated influenza vaccines containing homologous HA and NA (vacH3N2), only homologous HA (vacH3N1), only homologous NA (vacH1N2), heterologous HA and NA (vacH1N1), or phosphate-buffered saline (vacPBS), followed by challenge with H3N2 virus (A/Netherlands/16190/1968). Ferrets vaccinated with homologous HA (vacH3N2 and vacH3N1) displayed minimum fever and weight loss compared to vacH1N1 and vacPBS ferrets, while ferrets vaccinated with NA-matched vacH1N2 displayed intermediate fever and weight loss. Vaccination with vacH1N2 further led to a reduction in virus shedding from the nose and undetectable virus titers in the lower respiratory tract, similarly to when the homologous vacH3N2 was used. Some protection was observed upon vacH1N1 vaccination, but this was not comparable to that observed for vacH1N2, again highlighting the important role of NA in vaccine-induced protection. These results illustrate that NA antibodies can prevent severe disease caused by influenza virus infection and that an antigenically matched NA in seasonal vaccines might prevent lower respiratory tract complications. This underlines the importance of considering NA during the yearly vaccine strain selection process, which may be particularly beneficial in seasons when the HA component of the vaccine is mismatched. IMPORTANCE Despite the availability of vaccines, influenza virus infections continue to cause substantial morbidity and mortality in humans. Currently available influenza vaccines take primarily the hemagglutinin (HA) into account, but the highly variable nature of this protein as a result of antigenic drift has led to a recurrent decline in vaccine effectiveness. While the protective effect of neuraminidase (NA) antibodies has been highlighted by several studies, there are no requirements with regard to quantity or quality of NA in licensed vaccines, and NA immunity remains largely unexploited. Since antigenic changes in HA and NA are thought to occur asynchronously, NA immunity could compensate for reduced vaccine efficacy when drift in HA occurs. By matching and mismatching the HA and NA components of monovalent split inactivated vaccines, we demonstrated the potential of NA immunity to protect against disease, virus replication in the lower respiratory tract, and virus shedding in the ferret model.
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Virus de la Influenza A , Vacunas contra la Influenza , Neuraminidasa , Infecciones por Orthomyxoviridae , Animales , Anticuerpos Antivirales/inmunología , Modelos Animales de Enfermedad , Hurones , Hemaglutininas/inmunología , Subtipo H3N2 del Virus de la Influenza A , Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/normas , Neuraminidasa/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Estaciones del Año , Vacunas de Productos Inactivados/inmunologíaRESUMEN
Perineuronal or neuronal satellitosis is the term describing the presence of glial cells in the satellite space surrounding the neuronal perikaryon. Confusingly, this finding has been described both as a physiologic and pathologic condition in humans and animals. In animals, neuronal satellitosis has been described in mammals, as well as in avian species. For the latter, the authors wondered whether neuronal satellitosis is expressed in the normal telencephalon of different avian orders and families and whether this pattern in different species shows a specific brain-region association. For these aims, this study explored the presence of neuronal satellitosis in the major areas of the healthy telencephalon in wild and domestic avian species of different orders and families, evaluating its grade in different brain regions. Neuronal satellitosis was seen in the hyperpallium and mesopallium as areas with the highest grade. Passeriformes showed the highest grade of neuronal satellitosis compared to diurnal or nocturnal raptors, and Charadriiformes. To clarify the exact role of neuronal satellitosis in animals without neurological disease, further studies are needed.RESEARCH HIGHLIGHTSNeuronal satellitosis is a common finding in the healthy avian telencephalon.Neuronal satellitosis is a species- and brain-region-associated finding in birds.Passeriformes have the highest grade of neuronal satellitosis.
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Aves , Neuronas , Animales , Aves/anatomía & histología , Neuronas/fisiología , Telencéfalo/fisiologíaRESUMEN
Middle East respiratory syndrome coronavirus (MERS-CoV) is the cause of a severe respiratory disease with a high case fatality rate in humans. Since its emergence in mid-2012, 2578 laboratory-confirmed cases in 27 countries have been reported by the World Health Organization, leading to 888 known deaths due to the disease and related complications. Dromedary camels are considered the major reservoir host for this virus leading to zoonotic infection in humans. Dromedary camels, llamas, and alpacas are susceptible to MERS-CoV, developing a mild-to-moderate upper respiratory tract infection characterized by epithelial hyperplasia as well as infiltration of neutrophils, lymphocytes, and some macrophages within epithelium, lamina propria, in association with abundant viral antigen. The very mild lesions in the lower respiratory tract of these camelids correlate with absence of overt illness following MERS-CoV infection. Unfortunately, there is no approved antiviral treatment or vaccine for MERS-CoV infection in humans. Thus, there is an urgent need to develop intervention strategies in camelids, such as vaccination, to minimize virus spillover to humans. Therefore, the development of camelid models of MERS-CoV infection is key not only to assess vaccine prototypes but also to understand the biologic mechanisms by which the infection can be naturally controlled in these reservoir species. This review summarizes information on virus-induced pathological changes, pathogenesis, viral epidemiology, and control strategies in camelids, as the intermediate hosts and primary source of MERS-CoV infection in humans.
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Camélidos del Nuevo Mundo , Infecciones por Coronavirus , Coronavirus del Síndrome Respiratorio de Oriente Medio , Animales , Camelus , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/veterinaria , ZoonosisRESUMEN
Middle East respiratory syndrome coronavirus (MERS-CoV) uses the S1B domain of its spike protein to bind to dipeptidyl peptidase 4 (DPP4), its functional receptor, and its S1A domain to bind to sialic acids. The tissue localization of DPP4 in humans, bats, camelids, pigs, and rabbits generally correlates with MERS-CoV tropism, highlighting the role of DPP4 in virus pathogenesis and transmission. However, MERS-CoV S1A does not indiscriminately bind to all α2,3-sialic acids, and the species-specific binding and tissue distribution of these sialic acids in different MERS-CoV-susceptible species have not been investigated. We established a novel method to detect these sialic acids on tissue sections of various organs of different susceptible species by using nanoparticles displaying multivalent MERS-CoV S1A We found that the nanoparticles specifically bound to the nasal epithelial cells of dromedary camels, type II pneumocytes in human lungs, and the intestinal epithelial cells of common pipistrelle bats. Desialylation by neuraminidase abolished nanoparticle binding and significantly reduced MERS-CoV infection in primary susceptible cells. In contrast, S1A nanoparticles did not bind to the intestinal epithelium of serotine bats and frugivorous bat species, nor did they bind to the nasal epithelium of pigs and rabbits. Both pigs and rabbits have been shown to shed less infectious virus than dromedary camels and do not transmit the virus via either contact or airborne routes. Our results depict species-specific colocalization of MERS-CoV entry and attachment receptors, which may be relevant in the transmission and pathogenesis of MERS-CoV.IMPORTANCE MERS-CoV uses the S1B domain of its spike protein to attach to its host receptor, dipeptidyl peptidase 4 (DPP4). The tissue localization of DPP4 has been mapped in different susceptible species. On the other hand, the S1A domain, the N-terminal domain of this spike protein, preferentially binds to several glycotopes of α2,3-sialic acids, the attachment factor of MERS-CoV. Here we show, using a novel method, that the S1A domain specifically binds to the nasal epithelium of dromedary camels, alveolar epithelium of humans, and intestinal epithelium of common pipistrelle bats. In contrast, it does not bind to the nasal epithelium of pigs or rabbits, nor does it bind to the intestinal epithelium of serotine bats and frugivorous bat species. This finding supports the importance of the S1A domain in MERS-CoV infection and tropism, suggests its role in transmission, and highlights its potential use as a component of novel vaccine candidates.
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Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/virología , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Receptores Virales/metabolismo , Internalización del Virus , Animales , Camelus , Línea Celular , Quirópteros , Células Epiteliales/metabolismo , Células Epiteliales/virología , Especificidad del Huésped , Humanos , Membrana Mucosa/metabolismo , Membrana Mucosa/patología , Membrana Mucosa/virología , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Conejos , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/metabolismo , PorcinosRESUMEN
On 22 August, a common whitethroat in the Netherlands tested positive for West Nile virus lineage 2. The same bird had tested negative in spring. Subsequent testing of Culex mosquitoes collected in August and early September in the same location generated two of 44 positive mosquito pools, providing first evidence for enzootic transmission in the Netherlands. Sequences generated from the positive mosquito pools clustered with sequences that originate from Germany, Austria and the Czech Republic.
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Culex/virología , Fiebre del Nilo Occidental/veterinaria , Virus del Nilo Occidental/genética , Virus del Nilo Occidental/aislamiento & purificación , Animales , Aves , Culicidae/virología , Interacciones Huésped-Parásitos , Países Bajos/epidemiología , ARN Viral/genética , ARN Viral/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vigilancia de Guardia/veterinaria , Especificidad de la Especie , Fiebre del Nilo Occidental/epidemiología , Fiebre del Nilo Occidental/virología , Virus del Nilo Occidental/clasificaciónRESUMEN
We tested samples collected from camels, camel workers, and other animals in Sudan and Qatar in 2015 and 2017 for evidence of Middle East respiratory syndrome coronavirus (MERS-CoV) infection. MERS-CoV antibodies were abundant in Sudan camels, but we found no evidence of MERS-CoV infection in camel workers, other livestock, or bats.
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Camelus/virología , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Coronavirus del Síndrome Respiratorio de Oriente Medio , Zoonosis/epidemiología , Zoonosis/virología , Animales , Animales Domésticos/virología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Infecciones por Coronavirus/historia , Infecciones por Coronavirus/inmunología , Historia del Siglo XXI , Humanos , Pruebas de Neutralización , Estudios Seroepidemiológicos , Sudán/epidemiología , Zoonosis/historiaRESUMEN
Wild waterfowl form the main reservoir of influenza A viruses, from which transmission occurs directly or indirectly to various secondary hosts, including humans. Direct avian-to-human transmission has been observed for viruses of subtypes A(H5N1), A(H7N2), A(H7N3), A(H7N7), A(H9N2) and A(H10N7) upon human exposure to poultry, but a lack of sustained human-to-human transmission has prevented these viruses from causing new pandemics. Recently, avian A(H7N9) viruses were transmitted to humans, causing severe respiratory disease and deaths in China. Because transmission via respiratory droplets and aerosols (hereafter referred to as airborne transmission) is the main route for efficient transmission between humans, it is important to gain an insight into airborne transmission of the A(H7N9) virus. Here we show that although the A/Anhui/1/2013 A(H7N9) virus harbours determinants associated with human adaptation and transmissibility between mammals, its airborne transmissibility in ferrets is limited, and it is intermediate between that of typical human and avian influenza viruses. Multiple A(H7N9) virus genetic variants were transmitted. Upon ferret passage, variants with higher avian receptor binding, higher pH of fusion, and lower thermostability were selected, potentially resulting in reduced transmissibility. This A(H7N9) virus outbreak highlights the need for increased understanding of the determinants of efficient airborne transmission of avian influenza viruses between mammals.
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Hurones/virología , Virus de la Influenza A/patogenicidad , Infecciones por Orthomyxoviridae/transmisión , Infecciones por Orthomyxoviridae/virología , Microbiología del Aire , Animales , Aves/virología , Chlorocebus aethiops , Perros , Genoma Viral/genética , Glicoproteínas Hemaglutininas del Virus de la Influenza/química , Humanos , Virus de la Influenza A/química , Virus de la Influenza A/clasificación , Virus de la Influenza A/genética , Gripe Aviar/transmisión , Gripe Aviar/virología , Gripe Humana/transmisión , Gripe Humana/virología , Células de Riñón Canino Madin Darby , Modelos Moleculares , Células VeroRESUMEN
Background: The 1918 Spanish H1N1 influenza pandemic was the most severe recorded influenza pandemic with an estimated 20-50 million deaths worldwide. Even though it is known that influenza viruses can cause extrarespiratory tract complications-which are often severe or even fatal-the potential contribution of extrarespiratory tissues to the pathogenesis of 1918 H1N1 virus infection has not been studied comprehensively. Methods: Here, we performed a time-course study in ferrets inoculated intranasally with 1918 H1N1 influenza virus, with special emphasis on the involvement of extrarespiratory tissues. Respiratory and extrarespiratory tissues were collected after inoculation for virological, histological, and immunological analysis. Results: Infectious virus was detected at high titers in respiratory tissues and, at lower titers in most extrarespiratory tissues. Evidence for active virus replication, as indicated by the detection of nucleoprotein by immunohistochemistry, was observed in the respiratory tract, peripheral and central nervous system, and liver. Proinflammatory cytokines were up-regulated in respiratory tissues, olfactory bulb, spinal cord, liver, heart, and pancreas. Conclusions: 1918 H1N1 virus spread to and induced cytokine responses in tissues outside the respiratory tract, which likely contributed to the severity of infection. Moreover, our data support the suggested link between 1918 H1N1 infection and central nervous system disease.
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Citocinas/metabolismo , Subtipo H1N1 del Virus de la Influenza A/inmunología , Infecciones por Orthomyxoviridae/virología , Replicación Viral/fisiología , Animales , Citocinas/genética , Hurones , Regulación de la Expresión Génica , Humanos , Inflamación/metabolismo , Pulmón/patología , Infecciones por Orthomyxoviridae/patología , Enfermedades Respiratorias/virología , Distribución Tisular , Pérdida de PesoRESUMEN
Background: Carriage of Mycoplasma pneumoniae (Mp) in the nasopharynx is considered a prerequisite for pulmonary infection. It is interesting to note that Mp carriage is also detected after infection. Although B cells are known to be involved in pulmonary Mp clearance, their role in Mp carriage is unknown. Methods: In this study, we show in a mouse model that Mp persists in the nose after pulmonary infection, similar to humans. Results: Infection of mice enhanced Mp-specific immunoglobulin (Ig) M and IgG levels in serum and bronchoalveolar lavage fluid. However, nasal washes only contained elevated Mp-specific IgA. These differences in Ig compartmentalization correlated with differences in Mp-specific B cell responses between nose- and lung-draining lymphoid tissues. Moreover, transferred Mp-specific serum Igs had no effect on nasal carriage in B cell-deficient µMT mice, whereas this enabled µMT mice to clear pulmonary Mp infection. Conclusions: We report the first evidence that humoral immunity is limited in clearing Mp from the upper respiratory tract.
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Linfocitos B/inmunología , Portador Sano/inmunología , Mycoplasma pneumoniae/inmunología , Nasofaringe/inmunología , Nasofaringe/microbiología , Neumonía por Mycoplasma/inmunología , Animales , Anticuerpos Antibacterianos/sangre , Inmunoglobulina A/análisis , Inmunoglobulina G/sangre , Ratones Endogámicos C57BL , Mucosa Nasal/inmunologíaRESUMEN
Hepatitis A virus (HAV) is an ancient and ubiquitous human pathogen recovered previously only from primates. The sole species of the genus Hepatovirus, existing in both enveloped and nonenveloped forms, and with a capsid structure intermediate between that of insect viruses and mammalian picornaviruses, HAV is enigmatic in its origins. We conducted a targeted search for hepatoviruses in 15,987 specimens collected from 209 small mammal species globally and discovered highly diversified viruses in bats, rodents, hedgehogs, and shrews, which by pairwise sequence distance comprise 13 novel Hepatovirus species. Near-complete genomes from nine of these species show conservation of unique hepatovirus features, including predicted internal ribosome entry site structure, a truncated VP4 capsid protein lacking N-terminal myristoylation, a carboxyl-terminal pX extension of VP1, VP2 late domains involved in membrane envelopment, and a cis-acting replication element within the 3D(pol) sequence. Antibodies in some bat sera immunoprecipitated and neutralized human HAV, suggesting conservation of critical antigenic determinants. Limited phylogenetic cosegregation among hepatoviruses and their hosts and recombination patterns are indicative of major hepatovirus host shifts in the past. Ancestral state reconstructions suggest a Hepatovirus origin in small insectivorous mammals and a rodent origin of human HAV. Patterns of infection in small mammals mimicked those of human HAV in hepatotropism, fecal shedding, acute nature, and extinction of the virus in a closed host population. The evolutionary conservation of hepatovirus structure and pathogenesis provide novel insight into the origins of HAV and highlight the utility of analyzing animal reservoirs for risk assessment of emerging viruses.
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Evolución Biológica , Virus de la Hepatitis A/genética , Mamíferos/virología , Animales , Humanos , Datos de Secuencia Molecular , FilogeniaRESUMEN
IntroductionHighly pathogenic avian influenza (HPAI) viruses of subtype H5N8 were re-introduced into the Netherlands by late 2016, after detections in south-east Asia and Russia. This second H5N8 wave resulted in a large number of outbreaks in poultry farms and the deaths of large numbers of wild birds in multiple European countries. Methods: Here we report on the detection of HPAI H5N8 virus in 57 wild birds of 12 species sampled during active (32/5,167) and passive (25/36) surveillance activities, i.e. in healthy and dead animals respectively, in the Netherlands between 8 November 2016 and 31 March 2017. Moreover, we further investigate the experimental approach of wild bird serology as a contributing tool in HPAI outbreak investigations. Results: In contrast to the first H5N8 wave, local virus amplification with associated wild bird mortality has occurred in the Netherlands in 2016/17, with evidence for occasional gene exchange with low pathogenic avian influenza (LPAI) viruses. Discussion: These apparent differences between outbreaks and the continuing detections of HPAI viruses in Europe are a cause of concern. With the current circulation of zoonotic HPAI and LPAI virus strains in Asia, increased understanding of the drivers responsible for the global spread of Asian poultry viruses via wild birds is needed.
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Animales Salvajes/virología , Aves/virología , Brotes de Enfermedades/veterinaria , Subtipo H5N8 del Virus de la Influenza A/aislamiento & purificación , Subtipo H5N8 del Virus de la Influenza A/patogenicidad , Gripe Aviar/mortalidad , Animales , Subtipo H5N8 del Virus de la Influenza A/clasificación , Subtipo H5N8 del Virus de la Influenza A/genética , Gripe Aviar/patología , Gripe Aviar/virología , Países Bajos/epidemiología , ARN Viral/genética , Vigilancia de Guardia , Análisis de Secuencia de ADNRESUMEN
Severe influenza is often associated with disease manifestations outside the respiratory tract. While proinflammatory cytokines can be detected in the lungs and blood of infected patients, the role of extra-respiratory organs in the production of proinflammatory cytokines is unknown. Here, we show that both 2009 pandemic H1N1 influenza A (H1N1) virus and highly pathogenic avian influenza A (H5N1) virus induce expression of tumor necrosis factor α, interleukin-6, and interleukin-8 in the respiratory tract and central nervous system. In addition, H5N1 virus induced cytokines in the heart, pancreas, spleen, liver, and jejunum. Together, these data suggest that extra-respiratory tissues contribute to systemic cytokine responses, which may increase the severity of influenza.
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Citocinas/metabolismo , Subtipo H1N1 del Virus de la Influenza A , Subtipo H5N1 del Virus de la Influenza A , Infecciones por Orthomyxoviridae/veterinaria , Animales , Citocinas/biosíntesis , Citocinas/genética , Hurones , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/virologíaRESUMEN
Middle East respiratory syndrome (MERS) cases continue to be reported, predominantly in Saudi Arabia and occasionally other countries. Although dromedaries are the main reservoir, other animal species might be susceptible to MERS coronavirus (MERS-CoV) infection and potentially serve as reservoirs. To determine whether other animals are potential reservoirs, we inoculated MERS-CoV into llamas, pigs, sheep, and horses and collected nasal and rectal swab samples at various times. The presence of MERS-CoV in the nose of pigs and llamas was confirmed by PCR, titration of infectious virus, immunohistochemistry, and in situ hybridization; seroconversion was detected in animals of both species. Conversely, in sheep and horses, virus-specific antibodies did not develop and no evidence of viral replication in the upper respiratory tract was found. These results prove the susceptibility of llamas and pigs to MERS-CoV infection. Thus, the possibility of MERS-CoV circulation in animals other than dromedaries, such as llamas and pigs, is not negligible.
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Enfermedades de los Animales/epidemiología , Infecciones por Coronavirus/veterinaria , Susceptibilidad a Enfermedades , Ganado/virología , Coronavirus del Síndrome Respiratorio de Oriente Medio , Enfermedades de los Animales/diagnóstico , Enfermedades de los Animales/virología , Animales , Chlorocebus aethiops , Reservorios de Enfermedades , Ensayo de Inmunoadsorción Enzimática , Caballos , Inmunidad Humoral , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Pruebas de Neutralización , Vigilancia en Salud Pública , ARN Viral , Ovinos , Porcinos , Células VeroRESUMEN
A norovirus was detected in harbor porpoises, a previously unknown host for norovirus. This norovirus had low similarity to any known norovirus. Viral RNA was detected primarily in intestinal tissue, and specific serum antibodies were detected in 8 (24%) of 34 harbor porpoises from the North Sea.
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Infecciones por Caliciviridae/epidemiología , Infecciones por Caliciviridae/veterinaria , Genoma Viral , Norovirus/genética , Filogenia , Animales , Infecciones por Caliciviridae/virología , Intestinos/patología , Intestinos/virología , Norovirus/clasificación , Mar del Norte/epidemiología , Phocoena/virología , ARN Polimerasa Dependiente del ARN/genética , Proteínas Virales/genéticaRESUMEN
We screened squirrels in Germany and the Netherlands for the novel zoonotic variegated squirrel bornavirus 1 (VSBV-1). The detection of VSBV-1 in 11 squirrels indicates a considerable risk for transmission to humans handling those animals. Therefore, squirrels in contact with humans should routinely be tested for VSBV-1.
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Bornaviridae/clasificación , Bornaviridae/aislamiento & purificación , Infecciones por Mononegavirales/veterinaria , Sciuridae/virología , Animales , Alemania/epidemiología , Humanos , Infecciones por Mononegavirales/epidemiología , Infecciones por Mononegavirales/virología , Países Bajos/epidemiología , Factores de Riesgo , ZoonosisRESUMEN
UNLABELLED: Cleavage of influenza virus hemagglutinin (HA) by host cell proteases is necessary for viral activation and infectivity. In humans and mice, members of the type II transmembrane protease family (TTSP), e.g., TMPRSS2, TMPRSS4, and TMPRSS11d (HAT), have been shown to cleave influenza virus HA for viral activation and infectivity in vitro Recently, we reported that inactivation of a single HA-activating protease gene,Tmprss2, in knockout mice inhibits the spread of H1N1 influenza viruses. However, after infection of Tmprss2 knockout mice with an H3N2 influenza virus, only a slight increase in survival was observed, and mice still lost body weight. In this study, we investigated an additional trypsin-like protease, TMPRSS4. Both TMPRSS2 and TMPRSS4 are expressed in the same cell types of the mouse lung. Deletion of Tmprss4 alone in knockout mice does not protect them from body weight loss and death upon infection with H3N2 influenza virus. In contrast,Tmprss2(-/-)Tmprss4(-/-)double-knockout mice showed a remarkably reduced virus spread and lung pathology, in addition to reduced body weight loss and mortality. Thus, our results identified TMPRSS4 as a second host cell protease that, in addition to TMPRSS2, is able to activate the HA of H3N2 influenza virus in vivo IMPORTANCE: Influenza epidemics and recurring pandemics are responsible for significant global morbidity and mortality. Due to high variability of the virus genome, resistance to available antiviral drugs is frequently observed, and new targets for treatment of influenza are needed. Host cell factors essential for processing of the virus hemagglutinin represent very suitable drug targets because the virus is dependent on these host factors for replication. We reported previously that Tmprss2-deficient mice are protected against H1N1 virus infections, but only marginal protection against H3N2 virus infections was observed. Here we show that deletion of two host protease genes,Tmprss2 and Tmprss4, strongly reduced viral spread as well as lung pathology and resulted in increased survival after H3N2 virus infection. Thus, TMPRSS4 represents another host cell factor that is involved in cleavage activation of H3N2 influenza viruses in vivo.
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Glicoproteínas Hemaglutininas del Virus de la Influenza/metabolismo , Subtipo H3N2 del Virus de la Influenza A/fisiología , Proteínas de la Membrana/metabolismo , Infecciones por Orthomyxoviridae/metabolismo , Infecciones por Orthomyxoviridae/virología , Serina Endopeptidasas/metabolismo , Animales , Bronquios/metabolismo , Bronquios/virología , Quimiocinas/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Activación Enzimática , Femenino , Eliminación de Gen , Expresión Génica , Interacciones Huésped-Patógeno , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Infecciones por Orthomyxoviridae/genética , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/mortalidad , Proteolisis , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/virología , Serina Endopeptidasas/genética , Carga Viral , Replicación ViralRESUMEN
Middle East respiratory syndrome coronavirus (MERS-CoV) is not efficiently transmitted between humans, but it is highly prevalent in dromedary camels. Here we report that the MERS-CoV receptor--dipeptidyl peptidase 4 (DPP4)--is expressed in the upper respiratory tract epithelium of camels but not in that of humans. Lack of DPP4 expression may be the primary cause of limited MERS-CoV replication in the human upper respiratory tract and hence restrict transmission.
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Infecciones por Coronavirus/virología , Dipeptidil Peptidasa 4/genética , Regulación de la Expresión Génica , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Receptores Virales/genética , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/virología , Animales , Camelus , Infecciones por Coronavirus/transmisión , Dipeptidil Peptidasa 4/metabolismo , Humanos , Inmunohistoquímica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Virales/metabolismo , Replicación ViralRESUMEN
BACKGROUND: Influenza A viruses can replicate in the olfactory mucosa and subsequently use the olfactory nerve to enter the central nervous system (CNS). It is currently unknown whether intervention strategies are able to reduce or prevent influenza virus replication within the olfactory mucosa and subsequent spread to the CNS. Therefore, we tested the efficacy of homologous vaccination and prophylactic oseltamivir to prevent H5N1 virus CNS invasion via the olfactory nerve in our ferret model. METHODS: Ferrets were vaccinated intramuscularly or received oseltamivir (5 mg/kg twice daily) prophylactically before intranasal inoculation of highly pathogenic H5N1 virus (A/Indonesia/05/2005) and were examined using virology and pathology. RESULTS: Homologous vaccination reduced H5N1 virus replication in the olfactory mucosa and prevented subsequent virus spread to the CNS. However, prophylactic oseltamivir did not prevent H5N1 virus replication in the olfactory mucosa sufficiently, resulting in CNS invasion via the olfactory nerve causing a severe meningoencephalitis. CONCLUSIONS: Within our ferret model, vaccination is more effective than prophylactic oseltamivir in preventing CNS invasion by H5N1 virus via the olfactory nerve. This study highlights the importance of including the olfactory mucosa, olfactory nerve, and CNS tissues in future vaccine and antiviral studies, especially for viruses with a known neurotropic potential.