HEMORRHAGIC FEVER VIRUSES AFFECTING HUMANS

Viral Hemorrhagic Fever Viruses

1. HEMORRHAGIC FEVER VIRUSES DR. LUMU TIMOTHY

2. Introduction Multisystem diseases affecting humans Caused mostly by RNA viruses that are in most cases enveloped Humans are accidental hosts but in some cases can transmit the viruses and disease Outbreaks are sporadic and hard to predict

3. Viral Families Arenaviridae  family (Rodent Borne Diseases) Bunyaviridae  family (Via Athropods and Rodents) Filoviridae  family (transmitted via mammals) Flaviviridae  family (transmitted via arthropods mosquitoes and ticks) Paramyxoviridae (via mammals)

4. General Pathogenesis is VHF The General Process Immune dysregulation + endothelial leak + coagulopathy + multiorgan failure = hemorrhagic fever syndrome. 1. Initial Infection & Immune Evasion Primary targets: macrophages and dendritic cells. These antigen-presenting cells become infected but fail to mature or produce cytokines resulting in weak NK and T cell activation. This leads to delayed immune responses, high viral replication, and systemic spread.

5. 2. Innate Immune Suppression Many VHFs actively block type I interferon (IFN-I) pathways. Mechanisms: Arenavirus NP and Z proteins block IRF3 and RIG-I/MDA5. Ebola VP35 and VP24 suppress dendritic cell maturation and STAT1. Dengue NS proteins block IFN signaling. The result is high viremia + impaired antiviral defense 3. Cytokine Storm & Bystander Activation Despite immune suppression, infected monocytes/macrophages release excessive cytokines (IFNs, TNF- α, IL-6, IL-8, ROS/NO). This uncontrolled inflammation → cytokine storm. Leads to bystander activation and apoptosis of lymphocytes, worsening lymphopenia and immunopathology.

6. 4. Endothelial Dysfunction & Vascular Leak Cytokines + viral glycoproteins directly activate/disrupt endothelial cells. Breakdown of tight junction proteins (e.g., VE-cadherin) and release of bradykinin increase vascular permeability. Consequences: hypotension, edema, effusions, and capillary leak syndrome. 5. Coagulopathy Platelet dysfunction + coagulation factor consumption leads to disseminated intravascular coagulation (DIC). Clinically: petechiae, mucosal bleeding, multiorgan hemorrhage. 6. Multiorgan Involvement Viral replication in liver, spleen, adrenals leads to: Hepatic injury → loss of clotting factor synthesis. Adrenal necrosis → shock. Spleen/lymphoid damage → immune collapse. Combined = multiorgan failure. 7. Immune Dysregulation Survivors mount early, robust CD4+/CD8+ T cell responses. Non-survivors show delayed or dysregulated responses, excessive apoptosis, and reduced regulatory T cells. This imbalance fuels tissue damage rather than viral clearance.

7. Filoviridae Bundibugyo ebolavirus (BDBV) - Ebola virus disease Marburg marburgvirus (MARV) - Marburg hemorrhagic fever Sudan ebolavirus (SUDV) - Ebola virus disease Taï Forest ebolavirus (TAFV) - Ebola virus disease Zaire ebolavirus (EBOV) - Ebola virus disease

8. Flaviviridae  family (transmitted via arthropods mosquitoes and ticks) Dengue virus (DENV-1-4) - Dengue fever Kyasanur forest disease virus (KFDV) - Kyasanur forest disease Omsk hemorrhagic fever virus (OHFV) - Omsk hemorrhagic fever Yellow fever virus (YFV) - Yellow fever

9. Arenaviridae Arenaviridae  family (Rodent Borne Diseases) Chapare virus (CHPV) - Chapare hemorrhagic fever Guanarito virus (GTOV) - Venezuelan hemorrhagic fever Junin virus (JUNV) - Argentine hemorrhagic fever Lassa virus (LASV) - Lassa fever Lujo virus (LUJV) - Lujo  hemorrhagic fever Lymphocytic choriomeningitis virus (LCMV) - Lymphocytic choriomeningitis Machupo virus (MACV) - Bolivian hemorrhagic fever Sabia virus (SABV) - Brazilian hemorrhagic fever

10. Arenaviridae Virions are round, ovoid or pleomorphic in shape, the surface is covered in glycoprotein spikes. They are enveloped and acquire the envelope by budding through the host plasma membrane Host cellular ribosomes are entrapped in the viral structure creating a sand-granule appearance hence their name “arena” ( latin for sand) They are - ssRNA viruses that have two distinct viral RNA segments. One is called the L segment (~7.2 kb).The other is the S segment (~3.5 kb)

11. Each segment (L and S) has two genes arranged in opposite orientations ( ambisense ). Part of the RNA encodes proteins in the negative-sense orientation (like most RNA viruses), while another part encodes proteins in the positive-sense orientation. These coding regions are separated by a non-coding intergenic region (IGR) that forms a stable stem-loop structure, acting as a transcription stop signal.

12. S segment Negative-sense → encodes NP (nucleoprotein). Positive-sense → encodes GP (glycoprotein precursor). L segment Negative-sense → encodes L (RNA-dependent RNA polymerase). Positive-sense → encodes Z (a small zinc-binding matrix protein).

13. Functions of proteins NP (Nucleoprotein) Encoded in the – sense orientation Functions: Binds viral RNA to form the ribonucleoprotein complex (RNP), protecting RNA from degradation. Essential for viral replication and transcription. Suppresses host innate immunity by interfering with RIG-I and other interferon pathways → prevents detection of viral RNA GP (Glycoprotein precursor) Encoded in the + sense orientation (so expressed later). Synthesized as a precursor (GPC), cleaved by host protease SKI-1/S1P into: GP1 → receptor-binding subunit. GP2 → fusion subunit that mediates entry. Forms spikes on the viral envelope, responsible for attachment and fusion with host cells.

14. L protein (RNA-dependent RNA polymerase) Encoded in the – sense orientation Functions: Viral polymerase: copies –RNA → +mRNA (for translation), and –RNA → +antigenome (for replication). Also adds the cap snatching feature (similar to influenza), helping viral mRNAs be efficiently translated. Z protein (matrix / zinc-binding protein) Encoded in the + sense orientation Functions: Matrix protein: links the RNP core to the glycoproteins at the membrane. Plays a major role in virion budding and assembly (via late domain motifs that hijack host ESCRT machinery). Regulates polymerase activity — acts like a switch: at high levels, it inhibits transcription, pushing the virus toward packaging instead of replication

15. Virus (Arenaviridae) Region / Epidemiology Disease in Humans Key Features / Notes Lassa virus ( Old World ) West Africa (Nigeria, Sierra Leone, Liberia, Guinea, others). Endemic with annual outbreaks; rodent reservoir ( Mastomys natalensis ). Lassa fever Often mild → severe hemorrhagic fever. Facial edema , effusions, shock. CFR: 5–10%. Major cause of morbidity & mortality. Person-to-person spread possible. Junín virus ( New World ) Argentina (endemic in Pampas region). Transmitted via rodent excreta. Argentine hemorrhagic fever (AHF) Severe VHF with neurologic sequelae in survivors. CFR: 15–30%. Controlled somewhat by Candid #1 live-attenuated vaccine . Machupo virus ( New World ) Bolivia (endemic, sporadic outbreaks). Rodent-borne. Bolivian hemorrhagic fever (BHF) Fever, petechiae, hemorrhage, pulmonary edema. CFR ~30%. No licensed vaccine. Guanarito virus ( New World ) Venezuela (endemic). Rodent-borne. Venezuelan hemorrhagic fever (VHF) Hemorrhage, pulmonary congestion, renal necrosis. CFR ~30–35%. Sabiá virus ( New World ) Brazil (rare cases, lab-acquired infections too). Brazilian hemorrhagic fever (BzHF) Severe febrile illness with hemorrhage and CNS involvement. Very rare but high fatality. Chapare virus ( New World ) Bolivia (few outbreaks, emerging pathogen). Chapare hemorrhagic fever (CHHF) Severe systemic disease with hemorrhage and high CFR (up to 60%). Lujo virus ( Old World ) Southern Africa (Zambia, South Africa). Rare but highly lethal outbreak (2008). Lujo hemorrhagic fever (LUHF) Rash, fever, shock; CFR ~80%. Person-to-person spread documented. Lymphocytic choriomeningitis virus (LCMV) ( Old World ) Worldwide, associated with house mice ( Mus musculus ). Human infection rare. Lymphocytic choriomeningitis (LCM) Usually mild febrile illness, but can cause meningitis/encephalitis. Severe in immunocompromised & congenital infections. CFR <1%.

16. Bunyaviridae Bunyaviridae  family (Via Athropods and Rodents) Crimean-Congo hemorrhagic virus (CCHFV) - Crimean-Congo hemorrhagic fever Dobrava -Belgrade virus (DOBV) - Hemorrhagic fever with renal syndrome Hantaan virus (HTNV) - Hemorrhagic fever with renal syndrome Puumalavirus (PUUV) - Hemorrhagic fever with renal syndrome Rift Valley fever virus (RVFV) - Rift Valley fever Saaremaa virus (SAAV) - Hemorrhagic fever with renal syndrome Seoul virus (SEOV) - Hemorrhagic fever with renal syndrome Sin Nombre virus (SNV)- Hantavirus pulmonary syndrome Severe fever and thrombocytopenia syndrome virus (SFTSV) - Severe fever and thrombocytopenia syndrome Tula virus (TULV) - Hemorrhagic fever with renal syndrome

17. Structure

18. Bunyaviruses are spherical, enveloped RNA viruses with a diameter of 90-110 nm. Possess an envelope: lipid membrane derived from the host cell and embedded with glycoproteins on its surface.  Inside, the virus contains a tripartite genome of – ve sense single-stranded RNA, divided into small, medium, and large segments, each with complementary ends (gives it a pseudocircular DNA appearance) These RNA segments are associated with nucleocapsid proteins, forming helical nucleocapsid structures within the virion. 

19. Embedded in the lipid envelope are two types of viral glycoproteins ( Gn and Gc) that form spikes on the surface for binding and entry into host cells. Within the envelope, the RNA genome is associated with the nucleocapsid protein (N), forming three distinct, helical segments.  Genome: The single-stranded RNA genome is divided into three segments:  L (Large) Segment: Encodes the viral RNA-dependent RNA polymerase, essential for viral RNA replication and mRNA synthesis.  M (Medium) Segment: Codes for the two envelope glycoproteins ( Gn and Gc).  S (Small) Segment: Encodes the viral nucleocapsid protein (N). 

20. Disease Causative virus (family) Key clinical features Epidemiology (where/when) Transmission to humans Typical severity / CFR Crimean-Congo hemorrhagic fever (CCHF) Crimean-Congo hemorrhagic fever virus ( Nairoviridae ) Sudden fever, myalgia; may progress to severe hemorrhage, shock, multi-organ failure. Endemic across Africa, Balkans, Middle East, parts of Asia south of 50°N; sporadic cases and hospital clusters/outbreaks. Tick bites (mainly Hyalomma ), crushing ticks; contact with blood/tissues of infected livestock; health-care / household exposure to patient blood/body fluids. Case-fatality up to ~40% in reported outbreaks. CDC Hantavirus Hemorrhagic Fever with Renal Syndrome (HFRS) Orthohantaviruses (e.g., Hantaan, Dobrava, Seoul, Puumala) ( Hantaviridae ) Febrile illness with capillary leak → hypotension; acute kidney injury; hemorrhagic signs vary by virus. Mostly Europe & Asia (Seoul virus is worldwide); often seasonal with rodent population surges. Inhalation of aerosolized excreta (urine/ feces /saliva) from infected rodents; no person-to-person spread for HFRS. Severity varies by virus: Hantaan / Dobrava often severe ( ~5–15% CFR ); Seoul moderate; Puumala (“ nephropathia epidemica ”) usually mild ( <1% CFR ). CDC Hantavirus Pulmonary / Cardiopulmonary Syndrome (HPS/HCPS) New World orthohantaviruses (e.g., Sin Nombre, Andes) ( Hantaviridae ) Febrile prodrome → rapid non-cardiogenic pulmonary edema/ARDS, shock; high ICU need. Americas (North, Central, South); sporadic cases and small clusters. Rodent-excreta aerosols; person-to-person transmission documented with Andes virus in South America; U.S. hantaviruses are not known to spread person-to-person. Frequently severe; ~38–40% fatal among those with respiratory involvement. CDC+1 CDC Stacks Rift Valley fever (RVF) Rift Valley fever virus ( Phenuiviridae ) Usually mild febrile illness; a small % develop severe disease: hemorrhagic fever, encephalitis, or retinitis (vision loss). Africa and Arabian Peninsula; large epizootics/epidemics linked to heavy rains/flooding and livestock amplification. Mosquito bites (Aedes, Culex); contact with blood/organs of infected animals (slaughtering, veterinary work); no confirmed human-to-human transmission. Most human infections are mild; among those with hemorrhagic disease, CFR can be ~50%; overall CFR varies by outbreak. World Health Organization