Discrete viral E2 lysine residues and scavenger receptor MARCO are required for clearance of circulating alphaviruses
| العنوان: | Discrete viral E2 lysine residues and scavenger receptor MARCO are required for clearance of circulating alphaviruses |
|---|---|
| المؤلفون: | Kathryn S. Carpentier, Claudia Rückert, Alexis Robison, Mary K. McCarthy, Nicholas A May, Gregory D. Ebel, Thomas E. Morrison, Bennett Davenport, Kelsey C. Haist |
| المصدر: | eLife eLife, Vol 8 (2019) |
| بيانات النشر: | eLife Sciences Publications, Ltd, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 0301 basic medicine, Mouse, viruses, medicine.disease_cause, scavenger receptor, Mice, 0302 clinical medicine, Viral Envelope Proteins, alphavirus, Chikungunya, Biology (General), Receptors, Immunologic, innate immunity, Microbiology and Infectious Disease, biology, General Neuroscience, virus diseases, General Medicine, 3. Good health, Virus, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Medicine, Chikungunya virus, Research Article, QH301-705.5, Kupffer Cells, Science, Mutation, Missense, Spleen, Alphavirus, Arbovirus, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, medicine, Animals, O'nyong-nyong Virus, Innate immune system, General Immunology and Microbiology, Alphavirus Infections, Lysine, medicine.disease, biology.organism_classification, Virology, Disease Models, Animal, 030104 developmental biology, arbovirus, Infectious disease (medical specialty) |
| الوصف: | The magnitude and duration of vertebrate viremia is a critical determinant of arbovirus transmission, geographic spread, and disease severity. We find that multiple alphaviruses, including chikungunya (CHIKV), Ross River (RRV), and o’nyong ‘nyong (ONNV) viruses, are cleared from the circulation of mice by liver Kupffer cells, impeding viral dissemination. Clearance from the circulation was independent of natural antibodies or complement factor C3, and instead relied on scavenger receptor SR-A6 (MARCO). Remarkably, lysine to arginine substitutions at distinct residues within the E2 glycoproteins of CHIKV and ONNV (E2 K200R) as well as RRV (E2 K251R) allowed for escape from clearance and enhanced viremia and dissemination. Mutational analysis revealed that viral clearance from the circulation is strictly dependent on the presence of lysine at these positions. These findings reveal a previously unrecognized innate immune pathway that controls alphavirus viremia and dissemination in vertebrate hosts, ultimately influencing disease severity and likely transmission efficiency. eLife digest Viruses transmitted by blood-feeding insects, such as mosquitoes and ticks, cause serious human diseases. In recent years these viruses (also known as arboviruses) have re-emerged at an unprecedented scale, leading to global outbreaks of diseases such as Zika or chikungunya fever. The severity of these diseases and how easily they can be transmitted depends, in part, on the level of virus in the host’s bloodstream following infection. The more viral particles present in the blood, the easier it is for other insects that bite the host to become infected and help spread the disease. Yet, the mechanisms that hosts use to control the amount of virus present in the blood and how long it persists are poorly understood. To investigate this further, Carpentier et al. used a combination of molecular and genetic techniques to study how mice clear particles of arbovirus from their bloodstream. Surgically removing the spleen from infected mice revealed that this organ, which filters out unwanted or damaged materials from blood, is not required to clear some arbovirus particles. Carpentier et al. found that removing these arboviruses from the blood instead required Kupffer cells, a type of immune cell found in the liver. Genetically manipulating mice so they no longer produced a protein on the surface of Kupffer cells known as MARCO revealed that this receptor is needed to clear chikungunya viral particles. When MARCO was genetically deleted this led to an increase in the number of viral particles in the mice’s bloodstream, and allowed the virus to spread more rapidly throughout the bodies of the mice. Further experiments on three different types of arboviruses showed that in order to be cleared by MARCO, each of these viruses needed a lysine residue – one of the building blocks that makes up proteins – at defined positions within their protein sequence. These findings reveal a previously unknown mechanism for how hosts remove arbovirus particles from their bloodstream. Future studies could use this information to identify new ways to control the transmission and reduce the severity of these viral diseases. |
| اللغة: | English |
| تدمد: | 2050-084X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8c088f92b2de53c35d26786bd8740ab3Test http://europepmc.org/articles/PMC6839921Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....8c088f92b2de53c35d26786bd8740ab3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2050084X |
|---|