A more detailed discussion of emerging viral diseases is
viruses belonging to other families will be described later. For
found in Chapter 8.
comparative purposes, an overview of viruses that cause res-
piratory disease is shown in Table 4.4. This table is not meant
to be comprehensive and includes only a sampling of viruses.
Genus Pneumovirus
Furthermore, some of the viruses in the table, such as measles
The genus Pneumovirus, subfamily Pneumovirinae, con-
virus, are better known for disease other than respiratory disease.
tains the respiratory syncytial viruses (RSVs). RSVs are
However, the table makes clear that a large number of diverse
known for cattle, mice, sheep, goats, and turkeys, as well
viruses can infect the respiratory tract and cause illness.
as humans. The genome of RSV is more complex than
other Paramyxoviridae, having more genes (Fig. 4.6). The
FAMILY FILOVIRIDAE
polymerase gene of RSV is more closely related to those of
the filoviruses than to those of the Paramyxovirinae, making
Table 4.5 lists the known filoviruses, which are classified
classification of these viruses problematical.
into two genera, Marburgvirus and Ebolavirus. Four species
Human RSV is the most important cause of pneumonia in
of Ebolavirus are known, three from Africa (Zaire, Sudan,
infants and children worldwide. Half of hospital admissions
and Ivory Coast ebolaviruses) and one from the Philippines
in the United States in January and February of infants less
and/or Southeast Asia (Reston ebolavirus). The filovirus
than 2 years old are due to infection by RSV. Infants are
genome is 19 kb in size and contains seven genes, which
normally infected at 6 weeks to 9 months of age. Infection
result in the production of seven or eight proteins following
begins as an upper respiratory tract infection that progresses
infection (Fig. 4.1). The biology of filoviruses has been very
to the lower respiratory tract in 2540% of primary infec-
difficult to study. Most filoviruses are severe human patho-
tions. Immunity following infection is incomplete and rein-
gens that must be handled under biosafety level 4 conditions
fection is common in children and adults, but reinfection
(BSL-4), which restricts the number of laboratories that can
tends to produce less severe disease. Symptoms can include
work with the virus and the number of experiments that can
bronchitis and pharyngitis (itis = inflammation, so inflam-
be done. Furthermore, until recently the reservoir of the
mation of the mucous membranes of the bronchi or phar-
virus in nature was unknown, limiting studies of the ecology
ynx), rhinorrhea (runny nose), cough, headache, fatigue, and
of the virus. A dendrogram showing the relationships among
fever. Pneumonia (inflammation of the lungs in which the
the filoviruses is shown in Fig. 4.11.
air sacs become filled with exudate) can result, particularly
The viruses have a genome organization similar to that
in infants or the elderly. It is estimated that 17,000 people in
of other members of the Mononegavirales. Their sequences
the United States die annually from RSV infection, and the
suggest that they are most closely related to the pneumovi-
great majority of these are people over 65 years old. RSV
ruses, and they are assumed to replicate in a manner similar
infection is particularly serious in the immunocompromised.
to that for the rhabdoviruses and paramyxoviruses. There are
As one example, individuals of any age undergoing bone
four structural protein genes, encoding the nucleoprotein NP,
marrow transplantation have a 90% mortality rate if infected
the glycoprotein GP, and two matrix proteins VP24 (M2)
by RSV.
and VP40 (M1). There are three nonstructural protein genes,
No vaccine is available at the current time for RSV.
encoding the viral polymerase and two proteins called VP30
Because of the widespread prevalence of infection by the
and VP35. The GP gene gives rise to one protein, GP, in
virus and the severity of the disease it causes, especially in
Marburg virus. In the Ebola viruses, however, a second gly-
infants, efforts are ongoing to develop a vaccine that would
coprotein, called sGP, is also produced from an edited ver-
provide protection against disease or that would at least pro-
sion of the mRNA for GP. sGP is a soluble, truncated version
tect against severe disease. A clinical trial with an inacti-
of GP whose function is unknown, but it is speculated that
vated virus vaccine in a group of children some years ago
sGP interferes with the host immune system in some way.
gave disastrous results, however. Not only did the inocula-
The filovirus virion is enveloped, as is the case for all
tion with the candidate vaccine fail to protect the children
minus-strand viruses, but rather than being spherical, the
against subsequent infection by RSV, but it was found that
virion is long and thread-like (whence the name filo as in
when infected the vaccinated group suffered a much higher
filament). The infectious virion is 8001000 nm in length
proportion of serious illnesses such as viral pneumonia than
and 80 nm in diameter (Fig. 2.23E), but preparations exam-
did the control group. Thus, immunization potentiated ill-
ined in the electron microscope are pleomorphic and oddly
ness, possibly because of an unbalanced immune response.
shaped, often appearing as circles or the number 6 but some-
This result has impeded efforts to develop a vaccine and
times branched (Figs. 2.23F and G). There is one glycopro-
made it clear that a better understanding of the interaction of
tein (GP) in the envelope, present as homotrimers, that is
the virus with the immune system is important.
both N- and O-glycosylated and has a molecular weight of
Many viruses belonging to several different families have
120170 kDa.
now been described that cause respiratory disease, and more
TABLE 4.4 Viruses Causing Respiratory Disease
Virusa
Family
Nucleic acid
Host range
Disease(s)
Orthomyxoviridae
Influenza
(-)RNA
Humans, birds, horses, swine
Rhinitis, pharyngitis, croup, bronchitis,
pneumonia
Paramyxoviridae
RSV
(-) RNA
Humans, cattle
Rhinitis, pharyngitis, croup, bronchitis,
pneumonia
Canine distemper
Dogs
Bronchitis, pneumonia
NDV
Birds
Respiratory distress
Human parainfluenza
Humans
Rhinitis, pharyngitis, croup, bronchitis,
pneumonia
Measles
Humans
Pneumonia
Bunyaviridae
Sin Nombre
(-) RNA
Humans, rodents
Repiratory distress, pneumonia
Picornaviridae
Rhinoviruses
(+) RNA
Humans
Common cold (rhinitis), pharyngitis
Coxsackie A
Humans
Rhinitis, pharyngitis
Caliciviridae
Feline calicivirus
(+) RNA
Cats
Rhinitis, tracheitis, pneumonia
Coronaviridae
HCoV
(+) RNA
Humans
Rhinitis
IBV
Fowl
Bronchitis
SARS
Humans
Severe acute repiratory disease
Adenoviridae
Human Ad40,41
ds DNA
Humans
Rhinitis, pharyngitis, pneumonia
CLTV
Dogs
Pharyngitis, tracheitis, bronchitis, and
bronchopneumonia
Herpesviridae
Cytomegalovirus
ds DNA
Humans
Pharyngitis, pneumonia
Herpes simplex,
Humans
Pharyngitis, pneumonia
EBV, varicella
Various
Cattle, cats, horses, fowl
Rhinotracheitis
alphaherpesvirinae
a
Virus name abbreviations: RSV, respiratory syncytial virus; NDV, Newcastle disease virus; HCoV, human coronavirus; IBV, infectious bronchitis virus;
CLTV, canine laryngotracheitis; EBV, Epstein-Barr virus.
Adapted from Granoff and Webster (1999), pp. 1493, 1494.
TABLE 4.5 Filoviridae
Virus name
World
Usual host(s)a
Genus/members
abbreviation
Transmission
Disease
distribution
Marburgvirus
Lake Victoria
MARV
Humans
Contact with blood or
Severe hemorrhagic
Africa
marburgvirus
other body fluids
disease
Ebolavirus
Zaire ebolavirus
ZEBOV
Sudan ebolavirus
SEBOV
Humans
Contact with blood or
Severe hemorrhagic
Africa
other body fluids
disease
Cote d'Ivoire
CIEBOV
ebolavirus
Reston ebolavirus
REBOV
Cynomolgus monkeys
?
Severe hemorrhagic
Philippines
disease in monkeys,
attenuated in man
a
Natural reservoirs unknown for many years, but were recently found to be bats.
Isolates
Species
Ravn 87
Musoke 80
MARV
Ratayczak 67
Ozolins 75
Mayinga 76
Kikwit 95
ZEBOV
Gabon Oct96
Gabon Feb86
Gabon 94
CIEBOV
Cote d'Ivoire 94
Boniface 76
SEBOV
Maleo 79
Gulu 00
Texas 96
Reston 89
REBOV
Philippines 92
Sienna 92
FIGURE 4.11
Phylogenetic tree of the Filoviridae, derived from nucleotide sequences for the entire coding region
of the glycoprotein genes, using the neighbor-joining method. Adapted from Fauquet et al. (2005), Figure 3 on p. 652.
Isolates are named by the location and year of isolation. Abbreviations are defined in Table 4.5.
Most of the known filoviruses cause severe hemor-
as high as 600 and the case fatality rate has varied from 50 to
rhagic fever in humans with a mortality rate as high as 90%.
90%. Asymptomatic infection during these epidemics appears
Because of the dramatic symptoms of the disease involving
to be rare. A milder strain of Ebola virus was isolated from
bleeding from multiple orifices, and the high fatality rate
the Ivory Coast in 1994 and three strains or species of African
following infection, these viruses, especially Zaire ebolavi-
ebolaviruses are now recognized which differ in their virulence
rus, have been the subject of much discussion in the popular
(Table 4.5 and Fig. 4.11). Zaire ebolavirus is the most virulent
press and have appeared in a number of works of nonfiction
with a case fatality rate approaching 90%, Sudan ebolavirus is
as well as fiction. To date, ebolaviruses have caused only
less virulent, and Ivory Coast ebolavirus is the least virulent.
a limited number of human cases, but there is always the
Human-to-human transmission of the virus requires close con-
fear that if the virus were to adapt to humans in a way that
tact with the tissues, blood, or other exudates from an infected
allowed for easier transmission, it could become a very big
person and barrier nursing is sufficient to contain the spread
problem.
of the disease. No vaccine exists for the viruses, but candidate
The filoviruses are examples of emerging viruses and a
vaccines are in an advanced stage of study.
more detailed discussion of their emergence and the epidemics
The natural reservoir of Ebola virus in Africa has recently
of disease caused by them are found in Chapter 8. Marburg
been shown to be bats. It is clear that monkeys can be infected
virus was first isolated in 1967 when it caused an outbreak
by the virus and spread it to humans, often when humans
of hemorrhagic fever in Germany and Yugoslavia, originat-
use monkeys for food. How the monkeys contract the virus
ing from African green monkeys imported from Uganda. The
or how human epidemics get started when monkeys are not
virus is native to central Africa and there have subsequently
implicated is not known.
been epidemics in Kenya, Zaire (the Democratic Republic of
A fourth strain of Ebola virus called Reston ebolavi-
Congo), Angola, and Zimbabwe involving from one or a few
rus first appeared in 1989 in a primate colony in Reston,
cases to as many as 374 cases, with an overall mortality rate
Virginia, as the causative agent of an epidemic of hemor-
of 8090%.
rhagic fever in monkeys imported from the Philippines.
Ebola virus was first isolated during a 1976 epidemic of
Although highly lethal in monkeys, the virus is not known
severe hemorrhagic fever in Zaire and Sudan and named for
to cause human disease. Nucleotide sequencing has shown
a river in the region. Subsequent epidemics in these countries
that Reston ebolavirus is closely related to the African
and in Gabon and Uganda have occurred at regular intervals
Ebola viruses, and the reason it is attenuated in humans
(see Chapter 8). The number of cases in an epidemic has been
is not known.
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