Marburg Virus

I. Organism Information

A. Taxonomy Information
  1. Species:
    1. Lake Victoria marburgvirus :
      1. Ontology: UMLS:C0024787
      2. GenBank Taxonomy No.: 11269
      3. Description: Filoviruses are enveloped, non-segmented, negative-stranded RNA viruses and form a separate family within the order Mononegavirales. The family Filoviridae is divided into two genera: Marburgvirus and Ebolavirus. Lake Victoria marburgvirus is the lone species in the genus Marburgvirus (Hensley et al., 2005). Synonym: Marburg virus MBG (NCBI Taxonomy).
      4. Variant(s):
        • Lake Victoria marburgvirus - Musoke :
          • GenBank Taxonomy No.: 33727
          • Parent: Lake Victoria marburgvirus
          • Description: The Musoke strain was isolated in 1980 in Kenya and subsequently purified from an infected Vero cell culture (Beer et al., 1999). Synonyms: Marburg virus (strain Musoke), Lake Victoria marburgvirus - Musoke (Kenya, 1980) (NCBI Taxonomy).
        • Lake Victoria marburgvirus - Popp :
B. Lifecycle Information :
  1. Virion :
    1. Size: While the length of the virions is variable with Marburg particles averaging close to 800 nm, and Ebola virions measuring about 1 uM, the diameter of all filovirus particles uniformly measures 80 nm (Hensley et al., 2005). Marburg and Ebola viruses are pleomorphic particles which vary greatly in length, but the unit length associated with peak infectivity is 790 nm for Marburg virus and 970 nm for Ebola virus (Beer et al., 1999).
    2. Shape: Mature filoviral particles take on a variety of forms from circular or "6"-shaped to straight filaments (Hensley et al., 2005). The virions appear as either long filamentous (and sometimes branched) forms or in shorter U-shaped, 6-shaped (mace-shaped), or circular (ring) configurations. Virions have a uniform diameter of 80 nm and a density of 1.14 g/ml (Beer et al., 1999)
    3. Picture(s):
      1. Marburg virus electronmicrograph (Centers for Disease Control):



        Description: Negative stain image of an isolate of Marburg virus, showing filamentous particles as well as the characteristic "Shepherd's Crook." Magnification approximately 100,000 times. Image courtesy of Russell Regnery, Ph.D., DVRD, NCID, CDC (Centers for Disease Control).

  2. Description: Very little is known about the natural history of any of the filoviruses. Animal reservoirs and arthropod vectors have been aggressively sought without success (Jahrling, 1997).
C. Genome Summary:
  1. Genome of Lake Victoria marburgvirus - Musoke
    1. Description: Marburg and Ebola virions contain one molecule of noninfectious, linear, negative-sense, single-stranded RNA with a Mr of 4.2x10(6), constituting about 1 percent of the virion mass (Sanchez et al., 2001). The nonsegmented negative-sense RNA genome of MARV is 19,111 bases in length and encodes seven proteins. Four of these proteins (NP, VP35, L, and VP30) constitute the nucleocapsid complex. NP, VP35, and L are sufficient to mediate viral transcription and replication in a MARV-specific minigenome system (Enterlein et al., 2006).
    2. Chromosome:
      1. GenBank Accession Number: DQ217792
      2. Size: 19111 bp (NCBI Entrez Nucleotide)
      3. Gene Count: 7 genes (NCBI Entrez Nucleotide)
      4. Description: Here we report recovery of infectious Marburg virus (MARV) from a full-length cDNA clone. Compared to the wild-type virus, recombinant MARV showed no difference in terms of morphology of virus particles, intracellular distribution in infected cells, and growth kinetics. The nucleocapsid protein VP30 of MARV and Ebola virus (EBOV) contains a Zn-binding motif which is important for the function of VP30 as a transcriptional activator in EBOV, whereas its role for MARV is unclear. It has been reported previously that MARV VP30 is able to support transcription in an EBOV-specific minigenome system. When the Zn-binding motif was destroyed, MARV VP30 was shown to be inactive in the EBOV system. While it was not possible to rescue recombinant MARV when the VP30 plasmid was omitted from transfection, MARV VP30 with a destroyed Zn-binding motif and EBOV VP30 were able to mediate virus recovery. In contrast, rescue of recombinant EBOV was not supported by EBOV VP30 containing a mutated Zn-binding domain (Enterlein et al., 2006). The complete genomic sequence of MARV strain Musoke was determined and submitted as a reference sequence to GenBank (accession number DQ217792) (Enterlein et al., 2006).

  2. Genome of Lake Victoria marburgvirus - Musoke
    1. Chromosome:
      1. GenBank Accession Number: AY430365
      2. Size: 19113 bp (NCBI Entrez Nucleotide)
      3. Gene Count: 7 genes (NCBI Entrez Nucleotide).
      4. Description: Chain PSG, Malfatti SA, Hajjaj A, Vergez LM, Do LH, Smith KL and McCready PM. Submitted (09-OCT-2003) Viral Sequencing Group, Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, CA 94550, USA (NCBI Entrez Nucleotide).

  3. Genome of Lake Victoria marburgvirus - Musoke
    1. Chromosome:
      1. GenBank Accession Number: AY430366
      2. Size: 19112 bp (NCBI Entrez Nucleotide)
      3. Gene Count: 7 genes (NCBI Entrez Nucleotide).
      4. Description: Chain PSG, Malfatti SA, Hajjaj A, Vergez LM, Do LH, Smith KL and McCready PM. Submitted (09-OCT-2003) Viral Sequencing Group, Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, CA 94550, USA (NCBI Entrez Nucleotide).

  4. Genome of Lake Victoria marburgvirus - Popp
    1. Chromosome:
      1. GenBank Accession Number: NC_001608
      2. Size: 19,112 nt (NCBI Entrez Genome)
      3. Gene Count: 7 genes. 7 proteins (NCBI Entrez Genome).
      4. Description: The nucleotide sequence of genomic RNA of Marburg virus strain Popp was determined. Strain Popp was isolated in 1967 during the first filoviral outbreak. The virus was purified from blood of infected guinea pigs in which it had been maintained. The length of the determined sequence was 19112 nucleotides. Amino acid sequences of seven known virion proteins were deduced. Nucleotide and amino acid sequences were compared with those of strain Musoke of Marburg virus isolated in 1980 in Kenya and purified from Vero cells. Homology between nucleotide sequences of two strains was 93.9%. Comparisons revealed conserved and variable regions of the nucleotide and amino acid sequences. The GP, the envelope protein of the virion, was found to be the most variable protein. The greatest differences in the protein were located in the supposedly external part of the molecule. Amino acid substitutions in the L protein, the main component of viral RNA-dependent RNA polymerase, were also distributed extremely non-randomly. It was shown that the non-coding regions of the genome were more variable than the coding ones; 37.6% of nucleotide differences corresponded to the former. 72.6% of nucleotide substitutions located in the coding regions were found to be at the third codon position (Bukreyev et al., 1995).

II. Epidemiology Information

Marburg Hemorrhagic Fever (MHF) is a rare disease that occurs naturally only in sub-Saharan Africa. Apart from the current outbreak in Angola and a smaller one (149 cases, 123 deaths) in the Congo in 1998-2000, it has been reported only sporadically (Bonn, 2005).

A. Outbreak Locations:
  1. MHF was described first in 1967, when outbreaks in Germany and the former Yugoslavia were linked to African green monkeys (Cercopithecus aethiops) imported from a primate export facility in Entebbe, Uganda. A total of 37 cases, including six from secondary transmission, ultimately were reported; seven deaths occurred in primary cases. In England, an infectious agent, unlike any previously seen, was recovered from the blood and organs of these persons. Researchers called the agent Marburg virus (Ligon, 2005).
  2. Africa. The first recognized outbreak of Marburg virus in Africa occurred in February 1975, eliciting considerable press coverage. The index case was a young Australian who had been touring Rhodesia. He was admitted to the Johannesburg Hospital and died on the seventh day from hemorrhage resulting from a combination of disseminated intravascular coagulation and hepatic failure. Tests performed by the Centers for Disease Control and Prevention (CDC) confirmed that he had contracted Marburg virus. Two secondary cases, the first patient's traveling companion and a nurse, also were reported. Both of these patients survived after being given vigorous supportive treatment and prophylactic heparin (Ligon, 2005).
  3. Congo. The largest outbreak of MHF recorded to date began in late 1998 in northeastern Democratic Republic of the Congo (DRC). Although the remoteness of the area and the civil war in eastern DRC delayed access and evaluation, in May 1999 a team of international investigators identified 73 cases (8 laboratory-confirmed and 65 suspected cases retrospectively identified). Follow-up surveillance subsequently identified more than 150 cases through December 2000 (Bausch et al., 2003).
  4. Angola. On March 23, 2005, the World Health Organization (WHO) confirmed Marburg virus (family Filoviridae, which includes Ebola virus) as the causative agent of an outbreak of viral hemorrhagic fever (VHF) in Uige Province in northern Angola. Testing conducted by CDC's Special Pathogens Branch detected the presence of virus in nine of 12 clinical specimens from patients who died during the outbreak. During October 1, 2004 - March 29, 2005, a total of 124 cases were identified; of these, 117 were fatal. Approximately 75% of the reported cases occurred in children aged less than 5 years; cases also have occurred in adults, including health-care workers (CDC, 2005). As of 17 May 2005, the Ministry of Health in Angola has reported 337 cases of Marburg haemorrhagic fever. Of these cases, 311 were fatal. The vast majority of cases have occurred in Uige Province, where 326 cases and 300 deaths have been reported (WHO, 2005).
B. Transmission Information:
  1. Ontology: UMLS:C1444005 From: Human To: Human
    Mechanism: Ebola and Marburg are generally transmitted from people who are deathly ill. The people at greatest risk of contracting disease are family members, physicians, and nurses in hospitals, undertakers, and other people who come in close contact with infected individuals (Fauci, 2005). Transmission of the virus requires close personal contact with an ill or recently deceased patient (WHO, 2005).

  2. Ontology: UMLS:C1444006 From: Primate To: Human
    Mechanism: In 1967 outbreaks of hemorrhagic fever occurred simultaneously in Germany (Marburg and Frankfurt) and Yugoslavia (Belgrade) among laboratory workers having contact with tissues and blood from African green monkeys (Cercopithecus aethiops) imported from Uganda (Beer et al., 1999).

C. Environmental Reservoir:
  1. Unknown :
    1. Description: The environmental reservoir of the virus is unknown (CDC, 2005).
D. Intentional Releases:
  1. Intentional Release information :
    1. Description:
    2. Emergency contact: U.S. clinicians caring for patients with suspected Marburg virus infection should contact CDC or local public health officials for additional information about VHF infection control (CDC, 2005). If clinicians feel that VHF is a likely diagnosis, they should take two immediate steps: 1) isolate the patient, and 2) notify local and state health departments and CDC (MMWR). Report incidents to state health departments and the CDC (telephone {404} 639-1511; from 4:30 p.m. to 8 a.m., telephone {404} 639-2888). Information on investigating and managing patients with suspected viral hemorrhagic fever, collecting and shipping diagnostic specimens, and instituting control measures is available on request from the following persons at Centers for Disease Control (CDC) in Atlanta, Georgia; for all telephone numbers, dial 404-639 + extension: Epidemic Intelligence Service (EIS) Officer, Special Pathogens Branch, Division of Viral Diseases, Center for Infectious Diseases (ext. 1344); Chief, Special Pathogens Branch, Division of Viral Diseases, Center for Infectious Diseases: Joseph B. McCormick, M.D. (ext. 3308); Senior Medical Officer, Special Pathogens Branch, Division of Viral Diseases, Center for Infectious Diseases: Susan P. Fisher-Hoch, M.D. (ext. 3308); Director, Division of Viral Diseases, Center for Infectious Diseases (ext. 3574). After regular office hours and on weekends, the persons named above may be contacted through the CDC duty officer (ext. 2888) (CDC, 1988).
    3. Delivery mechanism: The viral hemorrhagic fever (VHF) agents are all highly infectious via the aerosol route, and most are quite stable as respirable aerosols. This means that they satisfy at least one criterion for being weaponized, and some clearly have the potential to be biological warfare threats (Jahrling, 1997).

III. Infected Hosts

  1. Primate:
    1. Taxonomy Information:
      1. Species:
        1. Human :
          • Ontology: UMLS:C0086418
          • GenBank Taxonomy No.: 9606
          • Scientific Name: Homo sapiens (NCBI Taxonomy)
          • Description: The Marburg virus, the natural reservoir for which remains unknown, causes MHF, thought to be of zoonotic origin, it is from the same family (Filorviridae) as the virus that causes EHF. Both viruses are among the most virulent pathogens known to infect humans, and, although both diseases have been rare occurrences, they have the capacity to cause dramatic outbreaks with high fatality rates (Ligon, 2005).
        2. African green monkey :
          • Ontology: UMLS:C0026438
          • GenBank Taxonomy No.: 9534
          • Scientific Name: Cercopithecus aethiops (NCBI Taxonomy)
          • Description: In 1967 outbreaks of hemorrhagic fever occurred simultaneously in Germany (Marburg and Frankfurt) and Yugoslavia (Belgrade) among laboratory workers having contact with tissues and blood from African green monkeys (Cercopithecus aethiops) imported from Uganda (Beer et al., 1999). Around 600 animals originating from four shipments reached Europe from Uganda over a 3-week period. Frankfurt received 50-60 animals from two shipments, Belgrade approximately 300 animals from three shipments, and the remainder went to Marburg. All spent between 60 and 87 days in a holding facility in Uganda before being shipped to London, Heathrow where they spent 6-36 hours in the animal hostel before being forwarded to Germany. Details on the Belgrade enzootic indicated that 46 of 99 animals imported from the first shipment died, and 20 and 30 from the second and third shipments, respectively. This epizootic was characterized by daily deaths of one or more animals throughout the 6-week quarantine period, suggesting ongoing transmission between animals Epidemiological evidence of the outbreak suggested that transmission between monkeys in quarantine facilities was through direct contact with contaminated equipment (Lloyd, 1998).

    2. Infection Process:
      1. Infectious Dose: 1 -10 organisms (Franz et al., 1997).
      2. Description: The virus can be spread to humans through direct contact with body fluids (e.g., blood, saliva, and urine) of an infected person or animal (CDC, 2005).

    3. Disease Information:
      1. Marburg virus disease :
        1. Pathogenesis Mechanism: After gaining access to the body, filoviruses initially infect monocytes, macrophages and other cells of the mononuclear phagocytic system (MPS), probably in regional lymph nodes. Some infected MPS cells migrate to other tissues, while virions released into the lymph or bloodstream infect fixed and mobile macrophages in the liver, spleen and other tissues throughout the body. Virions released from these MPS cells proceed to infect neighboring cells, including hepatocytes, adrenal cortical cells and fibroblasts (Bray and Paragas, 2002). Infected MPS cells become activated and release large quantities of cytokines and chemokines, including TNF-, which increases the permeability of the endothelial lining of blood vessels. Endothelial cells apparently become infected by virus only in the later stages of disease. Circulating cytokines contribute to the development of disseminated intravascular coagulation (DIC) by inducing expression of endothelial cell-surface adhesion and procoagulant molecules and tissue destruction results in the exposure of collagen in the lining of blood vessels and the release of tissue factor (Bray and Paragas, 2002). Massive lysis of lymphocytes occurs in the spleen, thymus and lymph nodes in the late stages of filovirus infection. There is no sign that the lymphocytes themselves are infected, rather they die through apoptosis, perhaps induced by cell-surface binding of chemical mediators released by MPS cells or by a viral protein. Massive cytolysis, immune dysfunction, fluid shifts, microvascular coagulation and interstitial hemorrhage all play a role in the development of shock and death (Bray and Paragas, 2002).

          • Marburg virus in the liver of an infected monkey (UCDavis School Of Veterinary Medicine Virus Images):



            Description: Marburg virus in the liver of an experimentally infected monkey. Virions bud off the surface membrane of liver cells and accumulate in the narrow spaces between cells. This infection is extremely destructive-shortly after this phase of infection the liver cells are destroyed. The uniformly cylindrical virions are sectioned in various planes-some are seen in longitudinal-section, some in cross-section, some in between. Magnification approximately x40,000. Micrograph from F. A. Murphy, School of Veterinary Medicine, University of California, Davis.


        2. Incubation Period: 5 -10 days (CDC, 2005). Symptoms normally begin after an incubation period of 4-10 days, to a maximum of three weeks (Jeffs, 2006).


        3. Prognosis: Marburg virus disease presents as an acute febrile illness and can progress within 6-8 days to severe hemorrhagic manifestations (CDC, 2005). Fatality rates for outbreaks of Marburg VHF have ranged from approximately 25% to 80%; mortality has been higher in outbreaks in which effective case management was lacking (CDC, 2005). The survivors have a prolonged convalescence with sequel including arthralgia, uveitis, psychosocial disturbances, and orchitis (Sanchez et al., 2001).


        4. Diagnosis Overview: Despite all the achievements in laboratory diagnostics in the past decades, it should be kept in mind that the diagnosis of EBOV and MARV infections will initially have to be based on clinical assessment (Grolla et al., 2005). Clinicians should consider the diagnosis of Marburg VHF among febrile patients who, within 10 days before onset of fever, have either 1) traveled in northern Angola; 2) had direct contact with blood, other body fluids, secretions, or excretions of a person or animal suspected of having VHF; or 3) worked in a laboratory or animal facility that handles hemorrhagic fever viruses. The likelihood of acquiring VHF is considered extremely low in persons who do not meet any of these criteria. The cause of fever in persons who have traveled to areas where VHF is endemic is more likely to be a different infectious disease (CDC, 2005). When the identity of a VHF agent is totally unknown, isolation in cell culture and direct visualization by electron microscopy, followed by immunological identification by immunohistochemical techniques is often successful. Immunohistochemical techniques are also useful for retrospective diagnosis using formalin-fixed tissues, where viral antigens can be detected and identified using batteries of specific immune sera and monoclonal antibodies (Jahrling, 1997). Formal laboratory diagnosis requires a laboratory with special containment facilities, which normally requires that the samples are sent outside Africa (Jahrling, 1997).


        5. Symptom Information :
          • Syndrome -- Marburg Hemorrhagic Fever:
            • Description: Marburg virus disease presents as an acute febrile illness and can progress within 6-8 days to severe hemorrhagic manifestations. After an incubation period of 5-10 days, onset of the disease is sudden and is marked by fever, chills, headache, and myalgia. Approximately the fifth day after onset of symptoms, a maculopapular rash might occur, after which nausea, vomiting, chest pain, sore throat, abdominal pain, and diarrhea might appear. Signs and symptoms become increasingly severe and can include jaundice, inflammation of the pancreas, severe weight loss, delirium, shock, liver failure, massive hemorrhaging, and multi-organ dysfunction (CDC, 2005). The target organ in the VHF syndrome is the vascular bed; correspondingly, the dominant clinical features are usually a consequence of microvascular damage and changes in vascular permeability. Common presenting complaints are fever, myalgia, and prostration; clinical examination may reveal only conjunctival injection, mild hypotension, flushing, and petechial hemorrhages. Full-blown VHF typically evolves to shock and generalized bleeding from the mucous membranes, and often is accompanied by evidence of neurological, hematopoietic, or pulmonary involvement. Hepatic involvement is common, but a clinical picture dominated by jaundice and other evidence of hepatic failure is seen in only a small percentage patients with Rift Valley fever, Crimean-Congo hemorrhagic fever, Marburg hemorrhagic fever, Ebola hemorrhagic fever, and yellow fever. Renal failure is proportional to cardiovascular compromise (Jahrling, 1997). For the diseases caused by filoviruses, little clinical data from human outbreaks exist. Although mortality is high, outbreaks are rare and sporadic. Marburg and Ebola viruses produce prominent maculopapular rashes, and disseminated intravascular coagulation (DIC) is a major factor in their pathogenesis. Therefore, treatment of the DIC should be considered, if practicable, for these patients (Jahrling, 1997). Spontaneous abortions are a recognized complication of filoviruses. The frequency of bleeding as an obstetric symptom can confuse diagnosis. A high mortality has been reported in pregnant women (Jeffs, 2006). During an epidemic, abortions in infected patients should be anticipated and planned for. Any abortions during an epidemic, especially if they have fever, should be considered at risk (Jeffs, 2006).
            • Observed: Reports of Marburg virus disease are rare, and its occurrence has been limited to countries in sub-Saharan Africa (CDC, 2005). The illness-to-infection ratio is unknown but seems to be high for primary infections, judging from the experience with the original 1967 epidemic (CDC, 1988).


              • Symptoms Shown in the Syndrome:

            • Anorexia (Jeffs, 2006):
              • Ontology: UMLS:C0003123
              • Description: The common symptoms described include fever, profound weakness, anorexia, headache, nausea and vomiting, diarrhoea, general aches and sore throat (Jeffs, 2006).
            • Asthenia (Jeffs, 2006):
              • Ontology: UMLS:C0004093
              • Description: Fever, asthenia, and anorexia are commonly described as the most frequent symptoms (Jeffs, 2006).
            • Chest pain (Jeffs, 2006):
              • Ontology: UMLS:C0008031
              • Description: Approximately the fifth day after onset of symptoms, a maculopapular rash might occur, after which nausea, vomiting, chest pain, sore throat, abdominal pain, and diarrhea might appear (CDC, 2005).
            • Delirium (CDC, 2005):
              • Ontology: UMLS:C0011206
              • Description: Approximately the fifth day after onset of symptoms, a maculopapular rash might occur, after which nausea, vomiting, chest pain, sore throat, abdominal pain, and diarrhea might appear (CDC, 2005).
            • Diarrhea (Jeffs, 2006):
              • Ontology: UMLS:C0011991
              • Description: Approximately the fifth day after onset of symptoms, a maculopapular rash might occur, after which nausea, vomiting, chest pain, sore throat, abdominal pain, and diarrhea might appear (CDC, 2005).
            • Fever (Jeffs, 2006):
              • Ontology: UMLS:C0015967
              • Description: Fever, asthenia and anorexia are commonly described as the most frequent symptoms, although the experiences in Uige showed that not all patients had fever on presentation, and many inpatients did not have fever recorded during the advanced stages of the disease. This meant that infection could not be ruled out by absence of fever (Jeffs, 2006).
            • General aches (Jeffs, 2006):
              • Ontology: UMLS: C0281856
              • Description: The common symptoms described include fever, profound weakness, anorexia, headache, nausea and vomiting, diarrhoea, general aches and sore throat (Jeffs, 2006).
            • Headache (Jeffs, 2006):
              • Ontology: UMLS:C0018681
              • Description: The common symptoms described include fever, profound weakness, anorexia, headache, nausea and vomiting, diarrhoea, general aches and sore throat (Jeffs, 2006).
            • Inflammation of the Pancreas (CDC, 2005):
              • Description: Signs and symptoms become increasingly severe and can include jaundice, inflammation of the pancreas, severe weight loss, delirium, shock, liver failure, massive hemorrhaging, and multi-organ dysfunction (CDC, 2005).
            • Jaundice (CDC, 2005):
              • Ontology: UMLS:C0022346
              • Description: Signs and symptoms become increasingly severe and can include jaundice, inflammation of the pancreas, severe weight loss, delirium, shock, liver failure, massive hemorrhaging, and multi-organ dysfunction (CDC, 2005).
            • Liver failure (CDC, 2005):
              • Ontology: UMLS:C0085605
              • Description: Signs and symptoms become increasingly severe and can include jaundice, inflammation of the pancreas, severe weight loss, delirium, shock, liver failure, massive hemorrhaging, and multi-organ dysfunction (CDC, 2005).
            • Maculopapular rash (CDC, 2005):
              • Ontology: UMLS:C0423791
              • Description: Approximately the fifth day after onset of symptoms, a maculopapular rash might occur (CDC, 2005)


                • Maculopapular rash (Website12):



                  Description: This posterior-oblique view of a female Marburg patient's back (case #2), depicts a measles-like rash, which is a usual symptom of this viral illness. This patient was hospitalized in Johannesburg, South Africa, 1975. This type of maculopapular rash, which can appear on Marburg patients around the fifth day after the onset of symptoms, usually may be found on the patient's chest, back and stomach. This patient's skin blanched under pressure, which is a common characteristic of a Marburg virus rash. Source CDC (Website12).
            • Massive hemorrhage (CDC, 2005):
              • Ontology: UMLS:C0333279
              • Description: Signs and symptoms become increasingly severe and can include jaundice, inflammation of the pancreas, severe weight loss, delirium, shock, liver failure, massive hemorrhaging, and multi-organ dysfunction (CDC, 2005).
            • Multi-organ dysfunction (CDC, 2005):
              • Ontology: UMLS:C0026766
              • Description: Signs and symptoms become increasingly severe and can include jaundice, inflammation of the pancreas, severe weight loss, delirium, shock, liver failure, massive hemorrhaging, and multi-organ dysfunction (CDC, 2005).
            • Nausea and Vomiting (Jeffs, 2006):
              • Ontology: UMLS:C0027497 C0042963
              • Description: Approximately the fifth day after onset of symptoms, a maculopapular rash might occur, after which nausea, vomiting, chest pain, sore throat, abdominal pain, and diarrhea might appear (CDC, 2005).
            • Severe weight loss (CDC, 2005):
              • Ontology: UMLS:C0041667
              • Description: Signs and symptoms become increasingly severe and can include jaundice, inflammation of the pancreas, severe weight loss, delirium, shock, liver failure, massive hemorrhaging, and multi-organ dysfunction (CDC, 2005).
            • Shock (CDC, 2005):
              • Ontology: UMLS:C0036974
              • Description: Signs and symptoms become increasingly severe and can include jaundice, inflammation of the pancreas, severe weight loss, delirium, shock, liver failure, massive hemorrhaging, and multi-organ dysfunction (CDC, 2005).
            • Sore throat (Jeffs, 2006):
              • Ontology: UMLS:C0242429
              • Description: Approximately the fifth day after onset of symptoms, a maculopapular rash might occur, after which nausea, vomiting, chest pain, sore throat, abdominal pain, and diarrhea might appear (CDC, 2005).

        6. Treatment Information:
          • Supportive Treatment: No vaccine or curative treatment is available, and supportive treatment should be used (CDC, 2005). Restlessness, confusion, myalgia, and hyperesthesia occur frequently and should be managed by reassurance and other supportive measures, including the judicious use of sedative, pain-relieving, and amnestic medications (Jahrling, 1997).
            • Applicable: Patients with VHF syndrome generally benefit from rapid, nontraumatic hospitalization to prevent unnecessary damage to the fragile capillary bed (Jahrling, 1997).
            • Contraindicator: Transportation of these patients, especially by air, is usually contraindicated because of the effects of drastic changes in ambient pressure on lung water balance (Jahrling, 1997). Aspirin and other antiplatelet or anticlotting-factor drugs should be avoided (Jahrling, 1997).
          • Treatment of Bleeding: The management of bleeding is controversial. Uncontrolled clinical observations support vigorous administration of fresh frozen plasma, clotting factor concentrates, and platelets, as well as early use of heparin for prophylaxis of DIC. In the absence of definitive evidence, mild bleeding manifestations should not be treated at all. More severe hemorrhage indicates that appropriate replacement therapy is needed. When definite laboratory evidence of DIC becomes available, heparin therapy should be employed if appropriate laboratory support is available (Jahrling, 1997).
            • Applicable:
          • Treatment of Hypotension and Shock: Management of hypotension and shock is difficult. Patients often are modestly dehydrated from heat, fever, anorexia, vomiting, and diarrhea, in any combination. There are covert losses of intravascular volume through hemorrhage and increased vascular permeability. Nevertheless, these patients often respond poorly to fluid infusions and readily develop pulmonary edema, possibly due to myocardial impairment and increased pulmonary vascular permeability. Asanguineous fluids - either colloid or crystalloid solutions - should be given, but cautiously. Although it has never been evaluated critically for VHFs, dopamine would seem to be the agent of choice for patients with shock who are unresponsive to fluid replacement. Alpha-adrenergic vasoconstricting agents have not been clinically helpful except when emergent intervention to treat profound hypotension is necessary.Vasodilators have never been systematically evaluated. Pharmacological doses of corticosteroids (eg, methylprednisolone 30 mg/kg) provide another possible but untested therapeutic modality in treating shock (Jahrling, 1997).
            • Applicable:

    4. Prevention:
      1. Avoiding Infected People and Material:
        • Description: The best protection for persons in or traveling to the outbreak area is to avoid direct contact with body fluids from potentially infected persons. Virus transmission also might be possible through contact with objects (e.g., medical equipment) that have been contaminated with infectious material (CDC, 2005).
      2. Barrier Nursing Techniques:
        • Ontology: UMLS:C1283821
        • Description: Over-reaction on the part of medical personnel is inappropriate and detrimental to both patient and staff, but it is prudent to provide isolation measures as rigorous as feasible. At a minimum, these should include the following: stringent barrier nursing; mask, gown, glove, and needle precautions; hazard-labeling of specimens submitted to the clinical laboratory; restricted access to the patient; and autoclaving or liberal disinfection of contaminated materials, using hypochlorite or phenolic disinfectants. For more intensive care, however, increased precautions are advisable. Members of the patient care team should be limited to a small number of selected, trained individuals, and special care should be directed toward eliminating all parenteral exposures. Use of endoscopy, respirators, arterial catheters, routine blood sampling, and extensive laboratory analysis increase opportunities for aerosol dissemination of infectious blood and body fluids. For medical personnel, the wearing of flexible plastic hoods equipped with battery-powered blowers provides excellent protection of the mucous membranes and airways (Jahrling, 1997).

    5. Model System:
      1. Murine Model-Vaccines and Antiviral Drugs:
        1. Ontology: UMLS:C0025929
        2. Model Host: Mus musculus (Bray and Paragas, 2002)
        3. Model Pathogens:
        4. Description: Marburg and Ebola viruses cause fatal disease in newborn mice, but do not cause visible illness in adult immunocompetent mice. However, sequential passage of Ebola Zaire '76 virus in progressively older suckling mice resulted in the selection of a variant virus that causes rapidly lethal disease in normal adult mice when inoculated by the intraperitoneal route. The pathologic features of infection with this `mouse-adapted virus' resemble those in primates, except that coagulopathy is much less prominent. This mouse model is now in use for the preliminary testing of vaccines and antiviral drugs and for studies of filovirus pathogenesis. Immunodeficient mice, lacking either innate or antigen-specific immune responses, are susceptible to lethal infection by a variety of non-mouse-adapted Marburg and Ebola viruses. These murine models are proving to be a fruitful source of information on mechanisms of susceptibility and resistance to filovirus infection (Bray and Paragas, 2002).
      2. Guinea pig-Vaccine Testing:
        1. Ontology: UMLS:C0999699
        2. Model Host: Cavia porcellus (Bray and Paragas, 2002)
        3. Model Pathogens:
        4. Description: Guinea pigs develop a mild febrile illness after inoculation with Marburg virus or with Ebola Zaire or Sudan. Animal-to-animal transfer results in a progressive increase in virulence, resulting after a few passages in a viral stock that causes uniformly fatal disease. The major pathologic features of lethal infection in guinea pigs resemble those in mice and primates. Guinea pigs have been employed for vaccine testing, but because of their size are less useful for the initial evaluation of experimental drugs, which tend to be available in only very small quantities (Bray and Paragas, 2002)
      3. Nonhuman Primate-Model of Human Disease:
        1. Ontology: UMLS:C0237798
        2. Model Host: Several primate species have been used to model filoviral HF, including African green monkeys, cynomologus macaques, rhesus macaques (Macaca mulatta), and hamadryad baboons (Papio hamadryas) (Hensley et al., 2005).
        3. Model Pathogens:
        4. Description: Three types of laboratory animals-mice, guinea pigs, and nonhuman primates-are in use for testing antiviral drugs and vaccines and to study filovirus pathogenesis. The target cells of infection and the major pathologic features of fatal illness are similar in these diverse species. Nonhuman primates are exquisitely sensitive to all filoviruses, but guinea pigs and immunocompetent mice are inherently resistant to filovirus infection. The fundamental difference between animal models may result in divergent outcomes in tests of drug and vaccine efficacy (Bray and Paragas, 2002). All filoviruses cause severe hemorrhagic fever in nonhuman primates. Ebola Zaire virus is the most virulent, producing uniformly lethal illness in African green monkeys, cynomolgus and rhesus macaques and baboons. In cynomolgus macaques, a commonly used model, this infection is characterized by the onset of fever and diminished activity on day 3 to 4 postchallenge; a reddish-purple macular rash on the trunk beginning on day 4 to 5; obtundation by day 6 and death on day 7 to 8. Virus is initially detectable in the serum on day 3 and titers may exceed 10(7) pfu/ml by day 5. High concentrations of virus are also measured in the liver, spleen and other tissues. Changes in blood cell counts and other clinical laboratory parameters resemble those in humans. Mild hemorrhagic phenomena are common, but profuse bleeding is rare. Ebola Sudan, Ebola Reston and Marburg viruses also cause severe hemorrhagic fever in nonhuman primates, but with a more prolonged clinical course and somewhat less than 100% mortality (Bray and Paragas, 2002)

IV. Labwork Information

A. Biosafety Information:
  1. General biosafety information :
    • Biosafety Level: Level 4 (Beer et al., 1999).
    • Applicable: Because of their aerosol infectivity, high mortality rate, potential for person-to-person transmission, and the lack of commercially available vaccines and chemotherapy, Marburg and Ebola viruses are classified as biosafety level four pathogens (Beer et al., 1999).
    • Precautions:
      • The virus has been reported to survive for as long as several days on contaminated surfaces (CDC, 2005). The patient should be isolated in a single room with an adjoining anteroom serving as its only entrance. The anteroom should contain supplies for routine patient care, as well as gloves, gowns, and masks for the staff (CDC, 1988). Hand-washing facilities should be available in the anteroom, as well as containers of decontaminating solutions. If possible, the patient's room should be at negative air pressure compared with the anteroom and the outside hall, and the air should not be recirculated. However, this is not absolutely required, and does not constitute a reason to transfer the patient. If a room such as described is not available, use adjacent rooms to provide safe and adequate space (CDC, 1988). Strict barrier-nursing techniques should be enforced: all persons entering the patient's room should wear disposable gloves, gowns, masks, and shoe covers. Protective eye wear should be worn by persons dealing with disoriented or uncooperative patients or performing procedures that might involve the patient's vomiting or bleeding (for example, inserting a nasogastric tube or an intravenous or arterial line). Protective clothing should be donned and removed in the anteroom. Only essential medical and nursing personnel should enter the patient's room and anteroom. Isolation signs listing necessary precautions should be posted outside the anteroom (CDC, 1988). Lipid-containing viruses, including the enveloped viruses, are among the most readily inactivated of all viral agents. Suitable disinfectant solutions include 0.5% sodium hypochlorite (10% aqueous solution of household bleach), as well as fresh, correctly prepared solutions of gluteraldehyde (2% or as recommended by the manufacturer) and phenolic disinfectants (0.5%-3%). Soaps and detergents can also inactivate these viruses and should be used liberally (CDC, 1988). Laboratory personnel accidentally exposed to potentially-infected material (for example, through injections or cuts or abrasions on the hands) should immediately wash the infected part, apply a disinfectant solution such as hypochlorite solution, and notify the patient's physician. The person should then be considered as a high-risk contact and placed under surveillance. Accidental spills of potentially contaminated material should be liberally covered with disinfectant solution, left to soak for 30 minutes, and wiped up with absorbent material soaked in disinfectant (CDC, 1988).
    • Disposal:
      • The patient should use a chemical toilet. All secretions, excretions, and other body fluids (other than laboratory specimens) should be treated with disinfectant solution. All material used for patients, such as disposable linen and pajamas, should be double-bagged in airtight bags. The outside bags should be sponged with disinfectant solution and later incinerated or autoclaved. Disposable items worn by staff, such as gowns, gloves, etc., should be similarly treated. Disposable items used in patient care (suction catheters, dressings, etc.) should be placed in a rigid plastic container of disinfectant solution. The outside of the container should be sponged with disinfectant, and the container should be autoclaved, incinerated, or otherwise safely discarded (CDC, 1988). All unnecessary handling of the body, including embalming, should be avoided. Persons who dispose of the corpse must take the same precautions outlined for medical and laboratory staff. The corpse should be placed in an airtight bag and cremated or buried immediately (CDC, 1988). Disposable items, such as pipette tips, specimen containers, swabs, etc., should be placed in a container filled with disinfectant solution and incinerated. Clothes and blankets that were used by the patient should be washed in a disinfectant, such as hypochlorite solution. Nondisposable items such as endoscopes used in patient care must be cleaned with decontaminating fluids (for example, gluteraldehyde or hypochlorite). Laboratory equipment must be treated similarly. All non-disposable materials that withstand autoclaving should be autoclaved, after they have been soaked in disinfectant solution. The patient's bed and other exposed surfaces in the hospital room, or in vehicles used to transport the patient, should be decontaminated with disinfectant solution (CDC, 1988).
B. Culturing Information:
  1. Virus Isolation by Cell Culture :
    1. Description: Although high-level containment is warranted because of the extreme hazard associated with handling the viruses, virus isolation remains relatively simple and sensitive: The virus grows well in a large variety of cell lines, although Vero or Vero E6 cells have been most used. The virus is relatively stable and some infectious virus may survive less than favorable handling and shipping; care should be taken to ensure the physical integrity for biosafety reasons and to maintain an adequate refrigerated or frozen state of biologic integrity of the sample to maximize diagnostic success (Sanchez et al., 2001). Diagnosis by viral cultivation and identification requires 3 to 10 days (Jahrling, 1997). Viral isolation should not be attempted without BL-4 containment (Jahrling, 1997).

    2. Medium:
      1. Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal calf serum), penicillin (100 U/ml), streptomycin (100 ug/ml), and L-glutamine (2 mM) (Stroher et al., 2001) (Stroher et al., 2001).
    3. Optimal Temperature: 37 C (Stroher et al., 2001)
    4. Optimal Humidity: humidity 95% (Stroher et al., 2001)
C. Diagnostic Tests :
  1. Organism Detection Tests:
    1. Electron microscopy:
      1. Ontology: UMLS:C0026019
      2. Time to Perform: unknown
      3. Description: Electron microscopy has been particularly useful in the diagnosis of filovirus infections. Negative-contrast electron microsopic examination of initial-passage cell culture supernates can be performed with safety after prefixation. Although the fine structure of virions is distorted, resolution of nucleocapsid structures within virions can establish the diagnosis. A similar approach may be tried on patient serum or plasma. For thin-section electron microscopic examination of patient tissues, any standard fixation (e.g., 1% gluteraldehyde in phosphate buffer), embedding (usually a rapid polymerization method), and staining system can be used. Most experience has been gained with examination of liver tissue, obtained at autopsy or agonal biopsy. In several cases of Marburg and Ebola hemorrhagic fever, virions and uniquely structured inclusion bodies have been identified in liver tissue. Direct examination of body fluids has been valuable, but in inexperienced hands this can lead to a mistaken diagnosis if confirmatory methods are not available (Sanchez et al., 2001). Due to relatively high viremia levels in humans, electron microscopy has been particularly useful in diagnosis of Filovirus infections (Grolla et al., 2005).
      4. Picture(s):
        • Electron micrograph of the Marburg virus (Website12):



          Description: Electron micrograph of the Marburg virus. Marburg virus, first recognized in 1967, causes a severe type of hemorrhagic fever, which affects humans, as well as non-human primates. Source CDC (Website12).

  2. Immunoassay Tests:
    1. Antigen-capture ELISA:
      1. Ontology: UMLS:C1553127
      2. Time to Perform: 1-hour-to-1-day
      3. Description: Testing for Marburg-specific immunoglobulin (Ig) M and IgG antibodies by the enzyme-linked immunosorbent assay (ELISA) was conducted with a technique analogous to that reported for detecting antibody to Ebola virus, except for the substitution of an antigen made from the Musoke strain of Marburg virus. The cut-off value for a positive ELISA result was set to 3 standard deviations from the mean control-adjusted optical density (OD) of 410 nm found on a panel of normal serum samples. This value generally corresponds to an OD of approximately 0.1 at a dilution of 1:100 for the IgM assay, and 0.2 at 1:400 for the IgG assay, which generally has a higher background. Positive and negative controls were included with each run and consisted of serum from African patients with and without a laboratory-confirmed history of MHF. Because the rarity of MHF has precluded rigorous field testing of the ELISA for Marburg antibody, all ELISA-positive serum samples were also examined by the immunofluorescent antibody assay (IFA) (Bausch et al., 2003) The assay time is approximately 3 to 4 hours (Sanchez et al., 2001). This assay was also useful in detection of virus antigen in frozen tissues (Sanchez et al., 2001). Serology can be useful for confirmation but it should be kept in mind that negative serology is not exclusive since filovirus-infected individuals often die without a proper humoral immune response (Grolla et al., 2005).
    2. Nucleoprotein-capture ELISA:
      1. Ontology: UMLS:C1553127
      2. Time to Perform: unknown
      3. Description: In order to establish a diagnostic system for Marburg hemorrhagic fever by the detection of Marburg virus nucleoprotein, monoclonal antibodies to the recombinant nucleoprotein were produced. Two clones of monoclonal antibodies, MAb2A7 and MAb2H6, were efficacious in the antigen-capture enzyme-linked immunosorbent assay (ELISA). At least 40 ng/ml of the recombinant nucleoprotein of Marburg virus was detected by the antigen-capture ELISA format. The epitope of the monoclonal antibody (MAb2A7) was located in the carboxy-terminus of nucleoprotein from amino acid position 634 to 647, while that of the MAb2H6 was located on the extreme region of the carboxy-terminus of the Marburg virus nucleoprotein (amino acid position 643-695). These monoclonal antibodies strongly interacted with the conformational epitopes on the carboxy-terminus of the nucleoprotein. Furthermore, these two monoclonal antibodies were reacted with the authentic Marburg virus antigens by indirect immunofluorescence assay. These data suggest that the Marburg virus nucleoprotein-capture ELISA system using the monoclonal antibodies is a promising technique for rapid diagnosis of Marburg hemorrhagic fever (Saijo et al., 2005).
    3. ELISA using Recombinant Nucleoproteins:
      1. Ontology: UMLS:C0014441
      2. Time to Perform: unknown
      3. Description: The full-length nucleoprotein (NP) of Ebola virus (EBO) was expressed as a His-tagged recombinant protein (His-EBO-NP) by a baculovirus system. Carboxy-terminal halves of NPs of EBO and Marburg virus (MBG) were expressed as glutathione S-transferase-tagged recombinant proteins in an Escherichia coli system. The antigenic regions on the NPs of EBO and MBG were determined by both Western blotting and enzyme-linked immunosorbent assay (ELISA) to be located on the C-terminal halves. The C-terminal 110 and 102 amino acids of the NPs of EBO and MBG, respectively, possess strong antigenicity. The full-length NP of EBO was strongly expressed in insect cells upon infection with the recombinant baculovirus, while expression of the full-length NP of MBG was weak. We developed an immunoglobulin G (IgG) ELISA using His-EBO-NP and the C-terminal halves of the NPs of EBO and MBG as antigens. We evaluated the IgG ELISA for the ability to detect IgG antibodies to EBO and MBG, using human sera collected from EBO and MBG patients. The IgG ELISA with the recombinant NPs showed high sensitivity and specificity in detecting EBO and MBG antibodies. The results indicate that ELISA systems prepared with the recombinant NPs of EBO and MBG are valuable tools for the diagnosis of EBO and MBG infections and for seroepidemiological field studies (Saijo et al., 2001).

  3. Nucleic Acid Detection Tests: :
    1. Real-time Reverse transcription-PCR assays for VHFs:
      1. Ontology: UMLS:C0032520
      2. Time to Perform: 1-hour-to-1-day
      3. Description: Viral hemorrhagic fevers (VHFs) are acute infections with high case fatality rates. Important VHF agents are Ebola and Marburg viruses (MBGV/EBOV), Lassa virus (LASV), Crimean-Congo hemorrhagic fever virus (CCHFV), Rift Valley fever virus (RVFV), dengue virus (DENV), and yellow fever virus (YFV). VHFs are clinically difficult to diagnose and to distinguish; a rapid and reliable laboratory diagnosis is required in suspected cases. We have established six one-step, real-time reverse transcription-PCR assays for these pathogens based on the Superscript reverse transcriptase-Platinum Taq polymerase enzyme mixture. Novel primers and/or 5'-nuclease detection probes were designed for RVFV, DENV, YFV, and CCHFV by using the latest DNA database entries. PCR products were detected in real time on a LightCycler instrument by using 5'-nuclease technology (RVFV, DENV, and YFV) or SybrGreen dye intercalation (MBGV/EBOV, LASV, and CCHFV). The inhibitory effect of SybrGreen on reverse transcription was overcome by initial immobilization of the dye in the reaction capillaries. Universal cycling conditions for SybrGreen and 5'-nuclease probe detection were established. Thus, up to three assays could be performed in parallel, facilitating rapid testing for several pathogens. All assays were thoroughly optimized and validated in terms of analytical sensitivity by using in vitro-transcribed RNA. The greater than or equal to 95% detection limits as determined by probit regression analysis ranged from 1,545 to 2,835 viral genome equivalents/ml of serum (8.6 to 16 RNA copies per assay). The suitability of the assays was exemplified by detection and quantification of viral RNA in serum samples of VHF patients (Drosten et al., 2002). RT-PCR assays seem to be favored by many investigators since BSL-4 biocontainment is not necessary after proper inactivation as well as the sensitivity/specificity of the technique (Grolla et al., 2005).
      4. Primers:
        • FiloA and FiloB
    2. One-tube Fluorogenic RT-PCR assay:
      1. Ontology: UMLS:C0599161
      2. Time to Perform: 1-hour-to-1-day
      3. Description: A rapid, sensitive, and specific laboratory diagnostic test is necessary to confirm outbreaks of Marburg virus and to distinguish it from other diseases that can present with similar clinical symptoms. A one-tube reverse transcriptase-polymerase chain reaction (RT-PCR) assay for the identification of Marburg virus was developed and evaluated using the ABI PRISM 7700 Sequence Detection System and TaqMan chemistry. The sensitivity and specificity of the newly designed primer/probe set (MBGGP3) was evaluated. MBGGP3 was equivalent to or 10-100-fold more sensitive than previously designed primer sets as determined by limit of detection experiments. In addition, the MBGGP3 assay was able to detect all strains of Marburg virus tested, but gave negative results with other haemorrhagic fever and genetically related viruses. The results of this study indicate that the MBGGP3 primer/probe set is both sensitive and specific. In addition, this assay is compatible with emerging rapid nucleic acid analysis platforms and therefore may prove to be a useful diagnostic tool for the control and management of future outbreaks (Gibb et al., 2001). The MBGGP3 primer/probe set was specific for all Marburg strains tested in a blinded cross-reactivity panel and showed an estimated clinical specificity of 100% when tested against a blind tissue panel (Gibb et al., 2001) (Gibb et al., 2001).
      4. Primers:
        • MBGGP3 forward and reverse primers
    3. PCR to Identify Filoviruses:
      1. Ontology: UMLS:xxx, GO:xxx, SNOMED:xxx, otherStd:xxx
      2. Time to Perform: 1-hour-to-1-day
      3. Description: Our approach is using two primers directed against well-conserved regions of the Filovirus genome and monitoring the accumularion of amplification products using SYBR Green 1, a dye which upon binding non-specifically to double-straned DNA, results in an increase in fluorescence at 530 nm. As this dye will non-specifically bind to all double-stranded DNA produced during the amplification process, the presense of specific Filovirus product must be determined by the melt point analysis of the products carried out at the end of the amplification. The primers EBsp5 5'-TTYCCTAGCAAYATGATGG, EBsp3 5'-TATAATAATCACTGACATGCAT) detect an approximately 250 bp region of the glycoprotein gene of EBOV species (Grolla et al., 2005).
      4. Primers:

  4. Other Types of Diagnostic Tests:

    No other tests available here.

V. References

A. Journal References:
Bausch et al., 2003: Bausch DG, Borchert M, Grein T, Roth C, Swanepoel R, Libande ML, Talarmin A, Bertherat E, Muyembe-Tamfum JJ, Tugume B, Colebunders R, Konde KM, Pirad P, Olinda LL, Rodier GR, Campbell P, Tomori O, Ksiazek TG, Rollin PE. Risk factors for Marburg hemorrhagic fever, Democratic Republic of the Congo. Emerg Infect Dis. 2003; 9(12): 1531 - 1537. [PubMed: 14720391].
Beer et al., 1999: Beer B, Kurth R, Bukreyev A. Characteristics of Filoviridae: Marburg and Ebola viruses. Naturwissenschaften. 1999; 86(1): 8 - 17. [PubMed: 10024977].
Bonn, 2005: Bonn D. Marburg fever in Angola: still a mystery disease. Lancet Infect Dis. 2005; 5(6): 331 - 331. [PubMed: 15948310].
Bray and Paragas, 2002: Bray M, Paragas, J. Experimental therapy of filovirus infections. Antiviral Research. 2002; 54(1): 1 - 17. [PubMed: 11888653].
Bukreyev et al., 1995: Bukreyev AA, AA, Volchkov VE, Blinov VM, Dryga SA, Netesov SV. The complete nucleotide sequence of the Popp (1967) strain of Marburg virus: a comparison with the Musoke (1980) strain. Arch Virol. 1995; 140(9): 1589 - 1600. [PubMed: 7487490].
CDC, 1988: Center for Disease Control and Prevention Management of Patients with Suspected Viral Hemorrhagic Fever. Morb Mortal Weekly Report. 1988; 37(Supplemental 3): 1 - 16. [PubMed: 3126390].
CDC, 2005: Centers for Disease Control and Prevention (CDC). Outbreak of Marburg virus hemorrhagic fever--Angola, October 1, 2004-March 29, 2005. MMWR Morb Mortal Wkly Rep. 2005; 54(12): 308 - 309. [PubMed: 15800477].
Drosten et al., 2002: Drosten C, Gottig S, Schilling S, Asper M, Panning M, Schmitz H, Gunther S. Rapid detection and quantification of RNA of Ebola and Marburg viruses, Lassa virus, Crimean-Congo hemorrhagic fever virus, Rift Valley fever virus, dengue virus, and yellow fever virus by real-time reverse transcription-PCR. J Clin Microbiol. 2002; 40(7): 2323 - 2330. [PubMed: 12089242].
Enterlein et al., 2006: Enterlein S, Volchkov V, Weik M, Kolesnikova L, Volchkova V, Klenk HD, Muhlberger E. Rescue of recombinant Marburg virus from cDNA is dependent on nucleocapsid protein VP30. J Virol. 2006; 80(2): 1038 - 1043. [PubMed: 16379005].
Fauci, 2005: Fauci AS. Emerging and reemerging infectious diseases: the perpetual challenge. Acad Med. 2005; 80(12): 1079 - 1085. [PubMed: 16306276].
Franz et al., 1997: Franz DR, Jahrling, PB, Friedlander, AM, McClain DJ, Hoover DL, Bryne WR, Pavlin JA, Christopher GW, Eitzen EM Jr. Clinical recognition and management of patients exposed to biological warfare agents. JAMA. 1997; 278(5): 399 - 411. [PubMed: 9244332].
Gibb et al., 2001: Gibb T.R, Norwood DA Jr, Woollen N, Henchal EA. Development and evaluation of a fluorogenic 5'-nuclease assay to identify Marburg virus. Mol Cell Probes. 2001; 15(5): 259 - 266. [PubMed: 11735297].
Grolla et al., 2005: Grolla A, Lucht A, Dick D, Strong JE, Feldmann H. Laboratory diagnosis of Ebola and Marburg hemorrhagic fever. Bull Soc Pathol Exot. 2005; 98(3): 205 - 209. [PubMed: 16267962].
Hensley et al., 2005: Hensley LE, Jones SM, Feldmann H, Jahrling PB, Geisbert TW. Ebola and Marburg viruses: pathogenesis and development of countermeasures. Curr Mol Med. 2005; 5(8): 761 - 772. [PubMed: 16375711].
Jeffs, 2006: Jeffs B. A clinical guide to viral haemorrhagic fevers: Ebola, Marburg and Lassa. Trop Doct. 2006; 36(1): 1 - 4. [PubMed: 16483416].
Ligon, 2005: Ligon BL Outbreak of Marburg hemorrhagic fever in Angola: a review of the history of the disease and its biological aspects. Semin Pediatr Infect Dis. 2005; 16(3): 219 - 224. [PubMed: 16044395].
Saijo et al., 2001: Saijo M, Niikura M, Morikawa S, Ksiazek TG, Meyer RF, Peters CJ, Kurane I. Enzyme-linked immunosorbent assays for detection of antibodies to Ebola and Marburg viruses using recombinant nucleoproteins. J Clin Microbiol. 2001; 39(1): 1 - 7. [PubMed: 11136739].
Saijo et al., 2005: Saijo M, Niikura M, Maeda A, Sata T, Kurata T, Kurane I, Morikawa S. Characterization of monoclonal antibodies to Marburg virus nucleoprotein (NP) that can be used for NP-capture enzyme-linked immunosorbent assay. J Med Virol. 2005; 76(1): 111 - 118. [PubMed: 15778962].
Stroher et al., 2001: Stroher U, West E, Bugany H, Klenk HD, Schnittler HJ, Feldmann H. Infection and Activation of Monocytes by Marburg and Ebola Viruses. Journal of Virology. 2001; 75(22): 11025 - 11033. [PubMed: 11602743].
WHO, 2005: World Health Organization Marburg haemorrhagic fever, Angola. Wkly Epidemiol Rec. 2005; 80(18): 158 - 159. [PubMed: 15898301].
B. Book References:
Jahrling, 1997: Jahrling PB Viral Hemorrhagic Fevers. 591 - 602. In: Zajtchuk R, Bellamy RF. Textbook of Military Medicine: Medical aspects of chemical and biological warfare1997. Office of The Surgeon General at TMM Publications, Borden Institute, Walter Reed Army Medical Center, Washington ,DC 20307-5001.
Lloyd, 1998: Lloyd G. Marburg and Ebola viruses. 387 - 399. In: Palmer SR, Simpson DIH. Zoonoses1998. Oxford University Press, New York, New York, USA.
Sanchez et al., 2001: Sanchez A, Khan AS, Zaki SR, Nabel GJ, Ksiazek TG, Peters CJ. Filoviridae: Marburg and Ebola viruses. 1279 - 1304. In: Knipe DM., Howley PM. Field's Virology Fourth Edition Volume 12001. Lippincott Williams and Wilkins, Philadelphia Pa.
C. Website References:
Website12: Medical Pictures from CDC [ http://www.lib.uiowa.edu/hardin/md/cdc/index.html ].
Centers for Disease Control: Questions and Answers About Marburg Hemorrhagic Fever [ http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/marburg/qa.htm ].
NCBI Taxonomy: Lake Victoria marburgvirus [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?lvl=0&id=11269 ].
NCBI Taxonomy: Lake Victoria marburgvirus - Musoke [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?lvl=0&id=33727 ].
NCBI Taxonomy: Lake Victoria marburgvirus - Popp [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?lvl=0&id=33728 ].
NCBI Entrez Genome: Lake Victoria marburgvirus, complete genome [ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genome&cmd=Retrieve&dopt=Overview&list_uids=10467 ].
NCBI Entrez Nucleotide: Lake Victoria marburgvirus - Musoke from Kenya, complete genome. [ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=nucleotide&cmd=retrieve&dopt=genbank&list_uids=77543426 ].
NCBI Entrez Nucleotide: Lake Victoria marburgvirus strain pp3 guinea pig lethal variant, complete genome. [ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=nucleotide&cmd=retrieve&dopt=genbank&list_uids=40388387 ].
NCBI Entrez Nucleotide: Lake Victoria marburgvirus strain pp4 guinea pig nonlethal variant, complete genome. [ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=nucleotide&cmd=retrieve&dopt=genbank&list_uids=40388379 ].
NCBI Taxonomy: Homo sapiens [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?lvl=0&id= 9606 ].
NCBI Taxonomy: Cercopithecus aethiops [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?lvl=0&id= 9534 ].
UCDavis School Of Veterinary Medicine Virus Images: UCDavis School Of Veterinary Medicine Virus Images [ http://www.vetmed.ucdavis.edu/viruses/download.html ].
D. Thesis References:

No thesis or dissertation references used.

VI. Curation Information