Arenaviruses_and_filoviruses_2023.V1 (1).pptx

ARENAVIRUSES AND FILOVIRUSES Michael E. Woods, PhD October 30, 2023 Required learning materials  Murray, Rosenthal and Pfaller, Medical Microbiology, pp. 500– 501, 527–528 Recommended learning materials LEARNING OBJECTIVES By the end of the session you should be able to:  Classify the filovi...

ARENAVIRUSES AND FILOVIRUSES Michael E. Woods, PhD October 30, 2023 Required learning materials  Murray, Rosenthal and Pfaller, Medical Microbiology, pp. 500– 501, 527–528 Recommended learning materials LEARNING OBJECTIVES By the end of the session you should be able to:  Classify the filoviruses and arenaviruses based on structure and replication, geographic origin, host reservoir, and mode of transmission  Name 2-3 virulence factors found in filoviruses and arenaviruses and discuss the potential role for each in virulence  Describe the general clinical syndromes and morphology of lesions associated with filovirus and arenavirus infection  Compare and contrast the techniques used to diagnose filovirus and arenavirus infections  Discuss the types of treatment and prevention for filovirus and arenavirus infections ARENAVIRUSES AND FILOVIRUSES OF CLINICAL SIGNIFICANCE Shape Envelope Genomic organization Lymphocytic choriomeningitis virus Pleomorphic Yes Bi-segmented, ambisense Single-strand RNA ? Lassa virus Pleomorphic Yes Bi-segmented, ambisense Single-strand RNA α-DG Pleomorphic Yes Bi-segmented, ambisense Single-strand RNA TfR1 Machupo virus Pleomorphic Yes Bi-segmented, ambisense Single-strand RNA TfR1 Guanarito virus Pleomorphic Yes Bi-segmented, ambisense Single-strand RNA TfR1 Ebola virus Filamentous Yes Non-segmented, negative sense Single-strand RNA NPC1, TIM-1 Filamentous Yes Non-segmented, negative sense Single-strand RNA NPC1, TIM-1 Virus Junin virus Family Arenaviridae Genomic composition Receptor Filoviridae Marburg virus ARENAVIRUSES AND FILOVIRUSES OF CLINICAL SIGNIFICANCE Virus Family Lymphocytic choriomeningitis virus Lassa virus Junin virus Arenaviridae Machupo virus Distribution Transmission CFR < 1% Worldwide Mus musculus (house mouse) Environmental; transplants West Africa Mastomys natalensis (multimammate rat) Environmental; nosocomial 1%–15% (drylands vesper mouse) Environmental 15%–30% Calomys callosus (large vesper mouse) Environmental; nosocomial 18%–20% Zygodontomys brevicauda (short- Environmental 23% Argentina Bolivia Guanarito virus Host/vector Venezuela Calomys musculinus tailed cane mouse) Ebola virus Filoviridae Marburg virus Sub-Saharan Africa, SE Asia (Reston) Bats Environmental; person-toperson; nosocomial 50%–90% Sub-Saharan Africa Bats Environmental; person-toperson; nosocomial 25% ARENAVIRUSES ARE DIVIDED INTO OLD WORLD AND NEW WORLD VIRUSES https://openi.nlm.nih.gov/detailedresult.php?img=PMC3509680_viruses-04-02973g001&req=4 ARENAVIRUSES INVADE A CELL BY RECEPTOR-MEDIATED ENDOCYTOSIS AND EXIT VIA MEMBRANE BUDDING J. Shao, Y. Liang and H. Ly, “Human Hemorrhagic Fever Causing Arenaviruses: Molecular Mechanisms Contributing to Virus Virulence and Disease Pathogenesis,” Pathogens, 2015, Vol. 4, No. 2, pp. 283–306 ARENAVIRUSES HAVE A BI-SEGMENTED, SINGLE-STRANDED, AMBISENSE RNA GENOME THAT ENCODES FOUR GENE PRODUCTS GPs Glycoproteins NP Nucleoprotein Z Z Protein L Forms spikes on the outer envelope of the virion; required for viral cellular entry Inhibits type I interferon responses Mediates viral budding and viral RNA synthesis; suppresses type I interferon responses Genome transcription RNA polymerase & translation Viruses 2016, 8(7), 197; doi:10.3390/v8070197 ARENAVIRUSES ARE AMBISENSE VIRUSES BOTH POSITIVE SENSE AND NEGATIVE SENSE Viruses 2016, 8(7), 197; doi: 10.3390/v8070197 LASSA FEVER—THE PROTOTYPE ARENAVIRUS —IS ENDEMIC TO WEST AFRICA  100,000–300,000 estimated Lassa fever cases each year in West Africa  5,000 estimated deaths  In 80% of cases symptoms are mild and are undiagnosed  Natural host is the Natal multimammate mouse (Mastomys natalensis)  Routes of transmission:  Exposure to contaminated rodent excreta  Direct contact with infected rodents  Nosocomial LASSA FEVER GENERALLY PROGRESSES IN FOUR STAGES Stage Symptoms 1 (days 1–3) General weakness and malaise. High fever, >39°C, constant with peaks of 40–41°C 2 (days 4–7) Sore throat (with white exudative patches) very common; headache; back, chest, side, or abdominal pain; conjunctivitis; nausea and vomiting; diarrhea; productive cough; proteinuria; low blood pressure (systolic <100 mm Hg); anemia 3 (after 7 days) Facial edema; convulsions; mucosal bleeding (mouth, nose, eyes); internal bleeding; confusion or disorientation 4 (after 14 days) Coma and death (15%–20% of hospitalized patients; 1% of all infections) LASSA VIRUS TARGETS HEPATOCYTES Other viral and infectious diseases and HIV-related liver disease Lucas, Sebastian B., MacSween’s Pathology of the Liver, 8, 403-466 Copyright © 2012 © 2012, Elsevier Limited. All rights reserved. UNIQUE FEATURES OF LASSA FEVER INCLUDE POSSIBLE NEUROLOGIC COMPLICATIONS  25% of patients exposed to Lassa virus (subclinical and survivors) will develop sensorineural hearing loss.  Possibly an immunological reaction between circulating Lassa virus antibodies and the basal cell membrane/outer cells of the cochlear  Other neurological complications in survivors include seizures, gait disturbances, tremors and encephalitis  Like most arenaviruses, Lassa readily invades the fetus; infected pregnant women often abort and have a high mortality rate https://audiology.nmsu.edu/hearing-loss-education/hearingloss-facts/snhl/ ALL FILOVIRUSES PATHOGENIC FOR PEOPLE OCCUR NATURALLY IN AFRICA  Six genera, two of clinical significance  Ebolavirus  Marburgvirus  Reston ebolavirus occurs in the Philippines, but is nonpathogenic in people  Imported to a monkey facility in Reston, VA in 1989  Topic of The Hot Zone by Richard Preston  Now the site of a daycare facility PATHOGENIC FILOVIRUSES ONLY EXIST NATURALLY IN SUB-SAHARAN AFRICA EBOLA VIRUS ECOLOGY AND TRANSMISSI ON • Natural reservoir is believed to be fruit bats in the Pteropodidae family • Humans are infected through direct contact with infected animals • Person-to-person transmission occurs among caregivers and healthcare workers http://www.cdc.gov/vhf/ebola/resources/virus-ecology.html FILOVIRUSES ARE ENVELOPED, SINGLE-STRANDED, NEGATIVESENSE RNA VIRUSES; HAVE A UNIQUE FILAMENTOUS MORPHOLOGY Ebola and Marburg haemorrhagic fever Rougeron, V., Journal of Clinical Virology, Volume 64, 111-119 Copyright © 2015 Elsevier B.V. Courtesy of the CDC Public Health Image Library FILOVIRUS LIFECYCLE AND VIRULENCE FACTORS J Infect Dis, Volume 228, Issue Supplement_6, 15 October 2023, Pages S446–S459, https://doi.org/10.1093/infdis/jiad362 L. Falasca, C. Agrati, N. Petrosillo, et al., “Molecular mechanisms of Ebola virus pathogenesis: focus on cell death,” Cell Death and Differentiation, 2015, Vol. 22, pp. 1250–1259 EBOLA VIRUS DISEASE Jacob, S.T., Crozier, I., Fischer, W.A. et al. Ebola virus disease. Nat Rev Dis Primers 6, 13 (2020). https://doi.org/10.103 8/s41572-020-0147-3 EBOLA VIRUS DISEASE PROGRESSES IN STAGES • Formerly Ebola hemorrhagic fever • Incubation period ranges from 2 to 21 days • May present similar to flu, malaria or typhoid fever • Recovery depends on good supportive clinical care and the patient’s immune response • Recovery is associated with protective antibody response for at least 10 years FILOVIRUSES CAUSE EXTENSIVE TISSUE DAMAGE Infection/death of Infection of spleen/lymph Infection of adrenal cortical hepatocytes: nodes: cells: Dysfunction, decreased production Lymphoid depletion and necrosis Impaired synthesis of steroid- of clotting factors and albumin through bystander killing; synthesizing enzymes = defective adaptive immunity hypotension Viral hemorrhagic fevers Hensley, Lisa E., Infectious Diseases, Chapter 126, 12471252 LABORATORY DIAGNOSIS FOR FILOVIRUSES DEPENDS ON THE STAGE OF THE INFECTION Key considerations:  Timing  Complexity  Containment  PCR effective when the virus is present in blood or other body fluids  IgM ELISA during first 1-2 months  IgG ELISA from 1 month to years Denis Malvy Prof, Anita K McElroy PhD, Hilde de Clerck MD, Stephan Günther Prof and Johan van Griensven Prof TREATMENT AND PREVENTION OF ARENAVIRUS AND FILOVIRUS DISEASE Virus Primary treatment Antiviral treatment Effectiveness of convalescent plasma Vaccine available Lassa virus Supportive care Ribavirin Not effective No Patient isolation Ebola virus Supportive care Inmazeb and Ebanga May be effective Yes Patient isolation Marburg virus Supportive care None approved May be effective No Patient isolation Primary control measures * Candid 1 vaccine strain is not licensed in the United States; available in Argentina. Candid 1 vaccination may also be effective at preventing Machupo virus infection, based on RIBAVIRIN MAY BE EFFECTIVE AGAINST ARENAVIRUSES, BASED ON LIMITED DATA; NOT EFFECTIVE FOR FILOVIRUS INFECTION  Oral ribavirin post-exposure prophylaxis is recommended for high-risk exposures to Lassa virus  Appears to be effective for treating South American hemorrhagic fever, based on limited data  Not recommended for treatment of LCMV aseptic meningitis  Mode of action depends on level of phosphorylation  Ribavirin monophosphate  Inhibits inosine monophosphate dehydrogenase, which results in depletion of guanine  Ribavirin triphosphate  Inhibits viral RNA polymerases  Promotes hyper-mutation of the viral genome EBOLA VACCINES – WE NOW HAVE THEM!! ERVEBO® (Ebola Zaire Vaccine, Live also known as V920, rVSVΔG-ZEBOVGP or rVSV-ZEBOV) is approved by the U.S. Food and Drug Administration (FDA) for the prevention of disease caused by Zaire ebolavirus in individuals 18 years of age and older as a single dose administration. Clinical efficacy of the vaccine was supported by a randomized cluster (ring) vaccination study during the 2014–2016 outbreak in Guinea. In this study, 3,775 people in close contact with diagnosed EVD cases (contacts) and their close contacts (contacts of contacts) received immediate vaccination. No one who was vaccinated immediately developed EVD 10 or more days after vaccination. Woolsey C, Geisbert TW (2021) Current state of Ebola virus vaccines: A snapshot. PLoS Pathog 17(12): e1010078. https://doi.org/10.1371/journal.ppat.1010078 

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