RNA Viruses III Lecture Notes PDF

MICROBIOLOGY | TRANS 3C LE RNA Viruses III ABIGAIL C. RIVERA, MD, FPPS, FPIDSP | Lecture Date (09/27/2024) | Version 1...

MICROBIOLOGY | TRANS 3C LE RNA Viruses III ABIGAIL C. RIVERA, MD, FPPS, FPIDSP | Lecture Date (09/27/2024) | Version 1 02 3C OUTLINE CLASSIFICATION OF ARTHROPOD-BORNE & I. Overview III.Rodent-borne viruses RODENT-BORNE VIRUSES A. Arthropod-borne viruses A. Filoviridae All are ssRNA, EXCEPT: B. Rodent-borne viruses a. Ebola virus C. Human Arbovirus b. Marburg virus → Reoviridae: dsRNA, non-enveloped Infections B. Bunyaviridae (-) sense, enveloped: D. Togavirus and Flavivirus a. Hemorrhagic fever with → Filoviridae II. Arthropod-borne viruses renal syndrome → Bunyaviridae A. Flaviviridae b. Hantavirus pulmonary → Arenaviridae a. Dengue fever syndrome (+) sense, enveloped: b. Japanese encephalitis IV. References → Togaviridae c. Yellow Fever V. Appendix → Flaviviridae d. Zika virus B. Togaviridae Table 1. Arboviruses **See Appendix 1 a. Chikungunya Taxonomic Viruses Must Lecturer Book Previous Youtube Classification Know Trans Video Arenaviridae Genus Arenavirus New World: Chapare, SUMMARY OF ABBREVIATIONS Guanarito, Junin, Machupo, Sabia, and Whitewater Arroyo DEN Dengue serotype viruses. DENV Dengue virus Old World: Lassa, Lujo, and ELISA Enzyme-linked immunosorbent assay lymphocytic choriomeningitis HI Hemagglutination test viruses. Rodent borne HCT Hematocrit Bunyaviridae JE Japanese encephalitis Genus Anopheles A and B, NS1 Non-structural protein 1 Orthobunyavirus Bunyamwera, California RT-PCR Reverse transcriptase polymerase chain encephalitis, Guama, La Crosse, reaction Oropouche, and Turlock viruses. LEARNING OBJECTIVES Arthropod borne (mosquitoes) ✔ To identify the classification of Arboviruses and Genus Hantavirus Hantaan virus (Korean Rodent-borne viruses hemorrhagic fever), Seoul virus ✔ Recognize general features of arboviruses, alphaviruses, (hemorrhagic fever with renal and flaviviruses syndrome), Sin Nombre virus o Structure (hantavirus pulmonary o Replication syndrome). Rodent borne o Pathogenesis Filoviridae For specific Arboviruses and Rodent-borne viruses: Genus Marburgvirus Marburgvirus ✔ Identify important viral structure and general features Genus Ebolavirus Ebola viruses (shape, composition, genome, proteins or antigens, Flaviviridae envelope) Genus Flavivirus Brazilian encephalitis (Rocio ✔ Correlate the pathophysiology of specific viral diseases to virus), dengue, Japanese B its clinical manifestations encephalitis, Kyasanur Forest ✔ Select appropriate laboratory diagnostics disease, louping ill, Murray ✔ Apply appropriate available treatment options Valley encephalitis, Omsk ✔ Apply preventive measures hemorrhagic fever, Powassan virus, yellow fever, St. Louis I. OVERVIEW encephalitis, West Nile fever, A. ARTHROPOD-BORNE VIRUSES (ARBOVIRUSES) and Zika viruses. Arthropod Ecologic groupings of viruses with transmission cycles borne (mosquitoes, ticks) involving arthropods (vector) Togaviridae The virus is transmitted from one vertebrate host to Genus Alphavirus Chikungunya, Eastern, another by blood sucking arthropods such as mosquitos, Western, and Venezuelan ticks, etc. equine encephalitis viruses, Virus multiplies in the tissues of the arthropod w/o Mayaro, O’Nyong-nyong, Ross evidence of disease or damage River, Semliki Forest, and → Acquires lifelong infection Sindbis viruses. Arthropod B. RODENT-BORNE VIRUSES (ARBOVIRUSES) borne (mosquitoes) Maintained in nature by direct transmission from rodent to rodent without participation of arthropod vectors. Transmission occurs by contact with body fluids or excretions of rodents LE 2 TG 10 | R., Ibañez, G. Icasiano, W. Ico, R. TE | K. Ignaco AVPAA | K. Lazaro PAGE 1 of 15 TRANS 3C Ignacio, K. Ignaco, W. Interia, F. Isberto VPAA | P. Fabros MICROBIOLOGY | LE 2 RNA Viruses III | ABIGAIL C. RIVERA, MD, FPPS, FPIDSP C. HUMAN ARBOVIRUSES INFECTIONS Flaviviruses (Flaviviridae Family) ARBOVIRUS LIFE CYCLE Characteristics Transmitted among vertebrates by Mostly zoonotic, with humans, as accidental hosts mosquitos and ticks, some among EXCEPT urban yellow fever and dengue. rodents or bats without any known → Humans are the main host in disease transmission. insect vectors Worldwide distribution Inactivated by solvents detergents, bleach, phenol, 70% alcohol, & formaldehyde Most possess hemagglutinating ability Antigenically related (may show cross-reaction in immunodiagnostic methods) Virus 40-60 nm in diameter Properties Genome: positive-sense (can function as mRNA), single-stranded Figure 1. Arbovirus Lifecycle [Lecturer’s PPT] Small and enveloped Primary Vector: Mosquito, Tick Replication: hosts enter the cell via → Feeds on an animal host (birds, rodents) receptor-mediated endocytosis, ▪ Amplifies the virus in the population without causing replications occurs in the cytoplasm disease. Assembly: within endoplasmic Host: Reservoir of the disease reticulum → Become a blood-meal source for other mosquito REPLICATION species who themselves become infected. Bridge Vector: Other infected mosquito species → Species capable of infecting humans. Dead end or incidental hosts: Humans and other mammals infected. → Do not develop high levels of the virus in their bloodstream needed to pass the virus to other biting mosquitoes. → Humans are usually considered accidental hosts except in Urban Yellow Fever and Dengue where humans are the main hosts CLINICAL SYNDROMES 1. Fevers of an undifferentiated type Figure 2. Flavivirus life cycle[Lecturer’s PPT] → Acute febrile illness The virus binds to the host cell, and enters via 2. Encephalitis (inflammation of the brain) receptor-mediated endocytosis → Often with high mortality rates Virus fuses with endosomal membrane, where uncoating 3. Hemorrhagic fevers of the genome occurs → Highly severe and fatal Flavivirus RNA genome is positive sense, thus serves as D. TOGAVIRUS AND FLAVIVIRUS the mRNA to produce viral proteins - both structural and PROPERTIES OF TOGAVIRUSES AND FLAVIVIRUSES non-structural Viral replication occurs in the cytoplasm, and particle Table 2. Flaviviruses and Togaviruses assembly occurs in intracellular vesicles Togaviruses (Togaviridae Family) Virions are transported and released through the plasma Characteristics Establish persistent infections in membrane, to be released to the bloodstream mosquitos Transmitted between vertebrates by PATHOGENESIS mosquitoes or other blood-feeding After subcutaneous inoculation, following the bite of the arthropods insect vector, virus replication occurs in local tissues and Worldwide distribution regional lymph nodes. Inactivated by solvents detergents, Virus then enters the bloodstream and is disseminated. bleach, phenol, 70% alcohol, & → Primary Viremia formaldehyde ▪ Viruses are delivered to the monocytes and Most possess hemagglutinating ability macrophages Antigenically related (may show Cells are lysed, brand new variants are released. cross-reaction in immunodiagnostic → Secondary Viremia methods) ▪ Virus goes to its site of tropism: liver, brain, Virus 70 nm in diameter vasculature and skin Properties Genome: positive-sense (can Neuroinvasion depends on: function as mRNA), single-stranded → Level of viremia Lipid bilayer Envelope contains 8- → Genetic Background of host spikes, trimer of E1/E2 proteins → Host innate & adaptive immune responses Capsid: small, icosahedral → Virulence of the virus strain → Age (infants & elderly most susceptible) MICROBIOLOGY RNA Viruses III PAGE 2 of 15 MICROBIOLOGY | LE 2 RNA Viruses III | ABIGAIL C. RIVERA, MD, FPPS, FPIDSP SUMMARY OF OVERVIEW 2000-2002 → DEN 1 & DEN 2 was the most common serotype Arboviruses & rodent-borne viruses have complex circulating. transmission cycles involving arthropods and rodents 2006-2008 They are classified in different viral families: → DEN 3 became the most common serotype. Flaviviridae: Togaviridae, Arenaviridae, Bunyaviridae, As of present and Reoviridae → DEN 2 & DEN 3 is the most common serotype today as Disease categories: acute febrile illness, shown by more recent surveillance. encephalitides, and hemorrhagic fevers Major mosquito-borne diseases are: yellow fever, TRANSMISSION dengue, Japanese encephalitis, Chikungunya, Zika Vector: Female Aedes mosquito (primary) (local); West Nile Fever. Eastern equine encephalitis → Only the females need to feed in order for the eggs to Humans are accidental hosts of arbovirus infections grow and are not essential for the viral life cycle Rare: → Vertical transmission II. ARTHROPOD-BORNE VIRUSES ▪ Mother to fetus A. FLAVIVIRIDAE → Blood transfusion from an infected donor DENGUE FEVER → Breast milk Also known as “Breakbone Fever” → Organ transplant Most important mosquito-borne viral disease that affects humans. PATHOPHYSIOLOGY Disease spectrum: Nonspecific viral syndrome to Dengue Fever severe and fatal hemorrhagic disease. 4 distinct serotypes: DEN-1,2,3,4 Bite of the female Aedes mosquito Family: Flaviviridae ↓ Genus: Flavivirus Subcutaneous infection of DENV Infection with a particular serotype confers lifelong (from the salivary glands of the mosquito) protection. ↓ Cross-protection between serotypes is of short duration. Replication occurs in cells (macrophages and dendritic cells) GEOGRAPHICAL DISTRIBUTION ↓ Rampant especially in subtropics and tropical countries. Spread to lymphatic system Estimated 2.5B people live in areas at risk for epidemic ↓ transmission Viremia Endemic in at least 100 countries in Africa, the ↓ Americas, parts of the Middle East, Asia, and Western Dissemination to organs Pacific. ↓ 50-100 million infections occur annually. Innate and adaptive immune response 500,000 DHF cases and 22,000 deaths, mostly among (to neutralize the virus) children ↓ DENGUE IN THE PHILIPPINES Inflammatory cytokines are released Study conducted by Bravo et al. (2000-2011) (from innate immunity) Highest Incidence ↓ → Rank 1: 5-14 y/o Increased vascular permeability - Hallmark of → Rank 2: 0-4 y/o Dengue (mainly causes the signs and symptoms) → Rank 3: 15-49 y/o Highest case fatality → 2cm ▪ May start to recover appetite and normal activity. → Severe abdominal pain RECOVERY PHASE - LABORATORY FINDINGS → Persistent vomiting (at least 3 vomiting episodes within 24 hours) Laboratory findings during this phase include the ff.: MICROBIOLOGY RNA Viruses III PAGE 5 of 15 MICROBIOLOGY | LE 2 RNA Viruses III | ABIGAIL C. RIVERA, MD, FPPS, FPIDSP → HCT stabilizes or is slightly lower due to a dilutional The serologic tests for IgM and IgG are not effect of reabsorbed plasma (hemodilution). recommended during the acute phase. → White blood count (WBC) begins rising soon after → May lead to a positive result after Day 3 of illness, or 5 defervescence. or 7 days according to different textbooks. ▪ First to recover. → For IGm: May cross-react with other flaviviruses. → Platelet count increases following WBC recovery. → If a patient presents signs and symptoms compatible DENGUE HEMORRHAGIC FEVER [Jawetz] with Dengue fever, and results in a positive IgM serologic test result, then the diagnosis would be Also known as dengue shock syndrome. Dengue virus. Severe syndrome which may occur in individuals (usually → For IgG: may help in determining if a patient has had children) with passively acquired (as maternal antibody) previous exposure or infection to dengue, or there is a or preexisting non neutralizing heterologous dengue history of vaccination (leads to a positive test result). antibody caused by a previous infection with a different → Most commonly used methods: serotype of virus. ▪ Envelope/membrane viral protein-specific capture Initial symptoms simulate normal dengue in which the IgM or IgG ELISA patient’s condition worsens later on. ▪ Hemagglutination Assay (HI) test Key pathological feature: Increased vascular permeability with plasma leakage into the interstitial TREATMENT spaces associated with increased levels of vasoactive No antiviral drug therapy. cytokines. Fluid replacement therapy is key to management. → Can lead to life-threatening shock in some patients. Blood transfusion No longer encouraged/recommended. DIAGNOSIS → Done as needed only. Isolation of the virus is difficult Analgesia Current favored approach: Inoculation of a mosquito cell → Acetaminophen may be used. line with patient serum coupled with nucleic acid Avoid NSAIDS. assays to identify a recovered virus. ▪ Due to risk of bleeding. Type of Recommended Timeline Remarks Therapeutic antibodies able to neutralize multiple test test genotypes of dengue are under development Molecular RT-PCR First 0-7 PREVENTION AND CONTROL test days Main method: Control vector mosquitoes Antigen NS1 → Environmental management and modification. detection → Disposing of solid waste properly and removing artificial Serologic IgM After May cross-react with man-made habitats. day 3 of other flaviviruses; Can → Covering, emptying, and cleaning of domestic water illness be detected for 3 storage containers on a weekly basis. months or longer; Change from negative → Applying insecticides to water storage containers. to positive IgM in → Personal household protection (screens, coils, paired samples (1st 7 vaporizers). days; 2nd sample → Improving community participation and mobilization. during convalescence) → Applying insecticides as space spraying during indicate current outbreaks. infection → Active monitoring and surveillance of vectors. IgG Not recommended; Immunization: Currently licensed Dengue vaccines Change from negative → CYD-TDV (Dengvaxia) to positive IgG in ▪ Used to be licensed in the Philippines but was paired samples (1st 7 withdrawn due to controversies surrounding it. days; 2nd sample ▪ Still available in some parts of Asia, North and South during convalescence) America, and in the European Union (EU) - refer to indicate current Figure X. infection ▪ Efficacious, safe in persons who have had a previous Table 1. Tests conducted to confirm Dengue fever diagnosis dengue infection. [Lecture] ▪ Increased risk of severe dengue in those who Figure 11 shows tests to help confirm a Dengue diagnosis. experienced their first natural dengue after → However, even with just clinical signs and symptoms, vaccination. and the CBC showing leukopenia (low WBC) and − Live vaccine acts as the first infection of the thrombocytopenia (low platelet count), one can patient, the natural or wild-type virus becomes the diagnose the patient without the aforementioned second infection which is of higher risk. confirmatory tests. ▪ Pre-vaccination screening is recommended for → Tests listed in Figure 11. are available for diagnosis and countries considering a vaccination program. surveillance purposes ▪ Genomic backbone is the Yellow Fever vaccine. Additional information for Figure 11. → TAK-003 (Qdenga) → The NS1 test, an antigen detection test, is readily ▪ Available in Indonesia, in countries part of the available. European Union (EU), and the UK (refer to Figure → RT-PCR for the detection of Dengue virus is not readily 12). available in hospitals. ▪ Genomic backbone is the Dengue Serotype 2 virus. MICROBIOLOGY RNA Viruses III PAGE 6 of 15 MICROBIOLOGY | LE 2 RNA Viruses III | ABIGAIL C. RIVERA, MD, FPPS, FPIDSP − Another live vaccine − Makes the immune response towards the vaccine more robust. − Higher risk for second infection from wild type does not occur as a result Table 2. Approval Status and Indications of Dengue vaccines[Lecture] CYD-TDV TAK-003 Countries ≥ 20 countries in Indonesia, EU Asia, North and countries, United South America, Kingdom European Union Dosing 0.5-mL dose; 3-dose 0.5-mL dose; regimen schedule (6 months 2-dose schedule (3 apart) months apart) Indication Prevention of dengue Prevention of in individuals 9 to 45 dengue in years of age with individuals from 4 laboratory- confirmed years of age Figure 13. Geographic distribution of JE cases by previous dengue (European Union) province.[Lopez, et al., 2015] infection and living in or from 6 years of endemic areas age (Indonesia) JE: 7-18% of meningitis & encephalitis cases. Vaccine development is difficult as one must provide JE: 16-40% of clinical encephalitis cases. protection against all four serotypes of virus. [Jawetz] JAPANESE ENCEPHALITIS VIRUS Family: Flaviviridae Genus: Flavivirus Related to Dengue, Yellow Fever and West Nile Viruses. Leading cause of viral encephalitis in Asia. Figure 14. Distribution of animal % mosquito studies.[Lopez, et al., 2015] Documented in Metro Manila & 13 provinces. 18% - 46% of pigs. 2.5% - 35% of monkeys. Figure 12. JE virus distribution Transmission primarily during irrigation periods or during → Mostly found in Southeast Asian Countries. the rainy season. ▪ 24 countries at risk. ▪ Endemic for Japanese encephalitis. ▪ 3 billion people are at risk. EPIDEMIOLOGY Transmission primarily occurs in rural agricultural areas, associated with rice production and flooding irrigation. Temperate areas: peaks in summer and fall Tropics and subtropics: Year-round, often with peaks during the rainy season. 1000,000 clinical cases every year. MICROBIOLOGY RNA Viruses III PAGE 7 of 15 MICROBIOLOGY | LE 2 RNA Viruses III | ABIGAIL C. RIVERA, MD, FPPS, FPIDSP Incidental or dead end hosts: humans and horses → Not able to transmit due to low level of viremia unlike dengue. CLINICAL MANIFESTATIONS Incubation period: 5-15 days. Clinical Spectrum: → Simple febrile illness → Aseptic meningitis → Encephalitis → Polio-like acute flaccid paralysis Case Fatality Rate: 5-30% Of those who survive, 30-50% suffer lasting damage to the central nervous system. DIAGNOSIS CSF or serum JEV-specific IGM (ELISA) If negative, a convalescent sample may be tested. Figure 15. Distribution of JE cases. [Lopez, et al., 2015] → After 10-14 days after acute illness JEV is present in all regions. → Increase in titers in IgM ELISA: recent infection of JE. 81 provinces: TREATMENT → 68 that reported suspected. No antiviral therapy. → 20 reported confirmed cases. Supportive care Management of complications PREVENTION AND CONTROL Vector control Protective measures Mass immunization of children and pigs with the JE vaccine is recommended in endemic areas. Vaccination of travelers to endemic areas. → Inactivated; live attenuated vaccine YELLOW FEVER Family: Flaviviridae Genus: Flavivirus Single serotype, with 7 genotypes Causes Yellow Fever → An acute febrile illness that occurs in the tropics and Figure 16. Age Distribution of JE Cases. Suspected cases subtropics of Africa and South America. (N=1032); Confirmed cases (N=73) [Lopez, et al., 2015] Severe cases are characterized by liver and renal Affects predominantly