ArticlePDF Available

Updates on Rabies virus disease: is evolution toward "Zombie virus" a tangible threat?

Authors:

Abstract and Figures

Human rabies disease is caused by Rabies Lyssavirus, a virus belonging to Rhabdoviridae family. The more frequent means of contagion is through bites of infected mammals (especially dogs, but also bats, skunks, foxes, raccoons and wolves) which, lacerating the skin, directly inoculate virus-laden saliva into the underlying tissues. Immediately after inoculation, the Rabies virus enters neural axons and migrates along peripheral nerves towards the central nervous system, where it preferentially localizes and injuries neurons of brainstem, thalamus, basal ganglia and spinal cord. After an initial prodromic period, the infection evolves towards two distinct clinical entities, encompassing encephalitic (i.e., “furious”; ~70-80% of cases) and paralytic (i.e., “dumb”; ~20-30% of cases) rabies disease. The former subtype is characterized by fever, hyperactivity, hydrophobia, hypersalivation, deteriorated consciousness, phobic or inspiratory spasms, autonomic stimulation, irritability, up to aggressive behaviours. The current worldwide incidence and mortality of rabies disease are estimated at 0.175×100,000 and 0.153×100,000, respectively. The incidence is higher in Africa and South-East Asia, nearly double in men than in women, with a higher peak in childhood. Mortality remains as high as ~90%. Since patients with encephalitic rabies remind the traditional image of “Zombies”, we need to think out-of-the-box, in that apocalyptic epidemics of mutated Rabies virus may be seen as an imaginable menace for mankind. This would be theoretically possible by either natural or artificial virus engineering, producing viral strains characterized by facilitated human-to-human transmission, faster incubation, enhanced neurotoxicity and predisposition towards developing highly aggressive behaviours.
Content may be subject to copyright.
Updates on Rabies virus disease: is evolution toward
“Zombie virus” a tangible threat?
Giuseppe Lippi1, Gianfranco Cervellin2
1Section of Clinical Biochemistry, University of Verona, Verona, Italy; 2Academy of Emergency Medicine and Care, Pavia, Italy
Abstract
Human rabies disease is caused by Rabies Lyssavirus, a virus belonging to Rhabdoviridae family. e more
frequent means of contagion is through bites of infected mammals (especially dogs, but also bats, skunks,
foxes, raccoons and wolves) which, lacerating the skin, directly inoculate virus-laden saliva into the underly-
ing tissues. Immediately after inoculation, the Rabies virus enters neural axons and migrates along peripheral
nerves towards the central nervous system, where it preferentially localizes and injuries neurons of brainstem,
thalamus, basal ganglia and spinal cord. After an initial prodromic period, the infection evolves towards
two distinct clinical entities, encompassing encephalitic (i.e., “furious”; ~70-80% of cases) and paralytic (i.e.,
“dumb”; ~20-30% of cases) rabies disease. e former subtype is characterized by fever, hyperactivity, hydro-
phobia, hypersalivation, deteriorated consciousness, phobic or inspiratory spasms, autonomic stimulation,
irritability, up to aggressive behaviours. e current worldwide incidence and mortality of rabies disease are
estimated at 0.175×100,000 and 0.153×100,000, respectively. e incidence is higher in Africa and South-
East Asia, nearly double in men than in women, with a higher peak in childhood. Mortality remains as high
as ~90%. Since patients with encephalitic rabies remind the traditional image of “Zombies”, we need to think
out-of-the-box, in that apocalyptic epidemics of mutated Rabies virus may be seen as an imaginable menace
for mankind. is would be theoretically possible by either natural or artificial virus engineering, producing
viral strains characterized by facilitated human-to-human transmission, faster incubation, enhanced neuro-
toxicity and predisposition towards developing highly aggressive behaviours. (www.actabiomedica.it)
Key words: rabies virus; rabies disease; epidemiology; zombie
Acta Biomed 2021; Vol. 92, N. 1: e2021045 DOI: 10.23750/abm.v92i1.9153 © Mattioli 1885
Review
The Rabies virus
Rabies disease is mostly sustained in humans by
Rabies Lyssavirus, a virus belonging to the large family
of Rhabdoviridae, comprised within the Mononega-
virale order (1). It is conventionally assumed that the
original virus shall have evolved in Old World bats,
which then shifted to carnivores and spread globally.
e virus is characterized by a bullet-shaped struc-
ture, sizing approximately 75×200 nm, and is substan-
tially divided in two parts, encompassing a structural
(i.e., the viral envelope) and a functional (i.e., the
ribonucleoprotein; RNP) unit. e ~12 kd RNA of
the virus contains five major genes, encoding five cor-
responding viral proteins (1). Briefly, (i) the N gene
encodes the nucleoprotein encapsulating both viral
and unsegmented negative-stranded RNA, (ii) the P
gene encodes a phosphoprotein involved in transcrip-
tion and replication activities, as well as in mediating
interplay with cellular proteins during neural transpor-
tation (see below), (iii) the M gene encodes a matrix
protein, (iv) the G gene encodes a transmembrane
glycoprotein, which mediates binding during initial
infection and seems to be the major antigenic domain
Acta Biomed 2021; Vol. 92, N. 1: e2021045
2
follow a prevalent intra-neuronal localization, and a
clear viraemia is hence probably absent in mammals
(13). Moreover, the Rabies virus can be very rapidly
inactivated by sunlight (i.e., ultraviolet rays) and heat
exposure, so that its chances of survival outside the
host are extremely limited. It seems reasonable to con-
clude that the cumulative risk of human-to-human
infection appears definitely low, except in the case of
direct inoculation of human saliva (e.g., through vol-
untary or involuntary bite) of infected individuals (13).
Immediately after inoculation, the virus enters
neural axons of sensory and motor nerves with an
endosomal transport pathway, and then migrates
along peripheral nerves (through fast axonal trans-
port system) towards the CNS, with a speed esti-
mated at approximately 8-20 mm/day (4). According
to this velocity of propagation, the incubation period
of rabies disease depends on the site of inoculation,
whereby in patients who have been infected at distant
sites (i.e., arms or legs) the virus would need longer
time to reach the CNS than in those bitten on face or
neck. Although no clear receptor mechanism has been
elucidated so far, it seems that nicotinic acetylcholine
receptor (nAchR) and neural cell adhesion molecule
(NCAM) may play a role in concentrating virus par-
ticles at the neuromuscular junction and providing a
more efficient transportation within the intracellular
space. Once the intact virions have reached the CNS
(thus producing pathognomonic cytoplasmic inclu-
sions, known as “Negri bodies”), viral replication starts
by transcription of viral genome by P-L polymerase
and further assembly of new viruses, especially in dor-
sal-root ganglia and anterior-horn cells. e virus then
propagates throughout the CNS, principally through
plasma-membrane budding, cell-to-cell direct infec-
tion or trans-synaptic dissemination, with preferential
localization in brainstem, thalamus, basal ganglia and
spinal cord (3). Importantly, major damages to the lim-
bic system are those responsible for onsets of the typical
emotional and motivational symptoms characterizing
patients with viral encephalopathy (2). e cumulative
neurotoxicity is perhaps the result of a combination
of direct cell damage due to virus replication, as well
as to development of immune response and autoim-
mune reactions against infected neurons. Importantly,
the huge cytokines production that accompanies CNS
responsible for generation of neutralizing antibodies
and, finally, (v) the L gene encodes a RNA polymer-
ase (1). e viral capsid is typically surrounded by host
cell-originating plasma membrane, strictly interacting
with the matrix protein and the transmembrane gly-
coprotein. Overall, Rabies viruses are divided into two
major phylogroups, accounting for a total number of
up to 14 different genotypes (2). Among these, geno-
type 1 seems to be the most prevalent, and also that
causing the largest number of human infections (3).
Physiopathology of Rabies virus infection
Although all the precise mechanisms involved in
the physiopathology of Rabies virus infection have not
been thoughtfully discovered and defined so far, several
important aspects can be summarized. e more fre-
quent means of Rabies virus transmission in humans
is through bites of infected mammals which, lacerat-
ing the skin, directly inoculate virus-laden saliva into
underlying tissues. Dogs are the most frequent vehicles
of infection in poor countries, whilst virus inoculation
by other mammals such as bats, skunks, foxes, raccoons
and even wolves has been reported in developed coun-
tries (4). e risk of virus inoculation through bites
is highly variable (i.e., between 5-80%), depending
on bite severity, animal species, virus concentration,
amount of saliva inoculation and so forth, but remains
consistently higher than after simple scratchs (i.e., 0.1-
1.0%) (1). In particular, a recent study reported that
the risk of virus inoculation by animal bite exposure is
the highest for skunks, followed by bats, cats and dogs
(5). In general, bites involving the face, neck or hands
expose the patient to the highest risk of contagion,
especially when the lesion is accompanied by profuse
bleeding (1). Since Rabies virus is actively present in
many human biological fluids, especially cerebrospinal
fluid (CSF), saliva, urine and tears, as well as at the
nape of neck containing hair follicles (6), an acciden-
tal and involuntary human-to-human transmission is
theoretically possible (7,8), as also revealed by publica-
tion of a number of paradigmatic case reports (9-12).
Nonetheless, cases of rabies contamination through
direct contact with blood of infected humans have
not been described so far, whereby the virus seems to
Acta Biomed 2021; Vol. 92, N. 1: e2021045 3
nearly half of the patients few hours before death, which
can also occur for respiratory, cardiac and circulatory
arrest during severe spasm episodes (4). Taken together,
these signs and symptoms would contribute to associate
a rabid patient with the traditional image of a “Zom-
bie”, as originally depicted by George A. Romero in his
notorious 1968 movie “e Night of the Living Dead”
(17), where humans were transformed into aggressive,
flesh-eating cannibals after being exposed to radiations
of space probe which exploded in the atmosphere while
coming back from Venus.
e paralytic, and less frequent form of rabies, is
mostly characterized by weakness due to peripheral
nerve dysfunction attributable to the combined effect
of an autoimmune reaction against the infected cells
and activation of immune response against the viruses
within the axons (4). Unlike the encephalitic subtype,
where brain stem, cerebrum and limbic system are
especially affected, this form mainly involves medulla
and spinal cord (18). is mostly leads to appearance
of symptoms like muscular paralysis and facial dipare-
sis. e CNS involvement develops later in the course
of disease, evolves towards coma and is then usually
followed by death (4).
Epidemiology of rabies
e most updated statistics on rabies epidemiol-
ogy can be garnered from the database of the Global
Burden of Disease (GBD) Study 2017 (19), which is
currently considered the most comprehensive world-
wide repository of health-related information (20).
e trends of incidence and mortality of this condition
over the past 3 decades are reported in figure 1, which
clearly shows that both these epidemiologic meas-
ures have considerably declined, by approximately
80%, between the years 1990-2017. In 2017 (i.e.,
the last accessible year in the GBD database), rabies
disease has an estimated incidence and mortality of
0.175×100,000 and 0.153×100,000, respectively (i.e.,
~13200 cases and ~11500 deaths around the world).
Notably, the mortality rate has also contextually
declined during the past 30 years, from 96% to 87%,
thus mirroring the combination of improved diagnosis
and better therapeutic care.
infection generates a strong impact on hippocampus
and other limbic-system functions, thus impairing
electrical cortical activity, hypothalamo-pituitary-
adrenal axis and serotonin metabolism (4). Later in the
course of disease, Rabies virus returns to the periphery
by means of intra-axonal transport, with enhanced tro-
pism for salivary and lacrimal glands (14).
Pathology and clinics of Rabies virus infection
e so-called prodromal stage typically initiates
when the virus propagates from peripheral nerves to
dorsal-root ganglia (i.e., triggering neuropathic pain),
up to the CNS. Along with prickling or itching sensa-
tion at the site of the original bite, the initial symptoms
appear relatively non-specific, mimicking an influenza
syndrome, and thus encompassing fever, general weak-
ness and headache (1). After this initial period, whose
length is somewhat variable (i.e., between 2-10 days),
the infection can then evolve towards two distinct
clinical entities, encompassing encephalitic (i.e., “furi-
ous”; ~70-80% of cases) and paralytic (i.e., “dumb”;
~20-30% of cases) rabies (4).
e former subtype (i.e., encephalitic) of rabies is
also the most severe, whereby the vast majority of these
patients die within 1 week of onset, and display fever,
hyperactivity aggravated by thirst, fear, light, noise
and other external stimuli. Within 24 hours from the
onset of the first symptoms the patients also develop
hydrophobia, hypersalivation, fluctuating conscious-
ness, hallucinations, phobic or inspiratory spasms
(often accompanied by fearful facial expressions), along
with signs of autonomic stimulation. Importantly, the
impaired serotonin neurotransmission due to injured
brainstem cells is frequently accompanied by marked
agitation and irritability, and can occasionally evolve
toward aggressive behaviours (15). roughout this
period, patients shall be preferably isolated and sedated,
to prevent that they may involuntarily injury, or even
contaminate, relatives and/or the healthcare staff (16).
e mental status varies, characterized by almost normal
periods alternated with severe agitation or depression,
up to consciousness deterioration and coma. Seizures
are not very frequent, but can occasionally develop in
pre-terminal stage. Hematemesis may be present in
Acta Biomed 2021; Vol. 92, N. 1: e2021045
4
e geographic distribution of rabies disease in
the year 2017 is shown in figure 2. e worldwide area
with the highest incidence and mortality is Africa, fol-
lowed by South-East Asia, Eastern Mediterranean and
Western Pacific, whilst the values of both these epi-
demiologic measures is <0.01×100,000 in Europe and
Americas. e highest burden of rabies disease cases
described in Africa (i.e., 0.40×100,000) and South-
East Asia (0.34×100,000) is clearly dependent on
insufficient infrastructure for preventing, diagnosing
and rapidly establishing post-exposure prophylaxis, as
well as on ubiquity of wild and domestic animals, which
enormously magnifies the risk of human contagion (2).
Notably, the incidence of rabies disease in Romania
(which is - incidentally - the ancestral vampires’ home-
land) is over 2-fold higher than in the rest of Europe
(i.e., 0.011×100,000 vs. 0.005×100,000). e distinc-
tive geographical localization of rabies disease mirrors
that of the socio demographic index (SDI), since the
incidence in countries with low SDI (0.445×100,000)
is nearly 4-fold higher than in medium SDI countries
(0.102×100,000), being approximately 300-fold higher
than in high SDI countries (0.002×100,000).
e age and sex distribution of rabies disease is
then summarized in figure 3, showing that the overall
Figure 1. Epidemiology of Rabies virus disease during the past
three decades.
Figure 2. Geographical distribution of Rabies virus disease.
Figure 3. Sex- and age-related epidemiology of Rabies virus
disease.
incidence is nearly double in men than in women
(i.e., 0.22×100,000 vs. 0.13×100,000). e epidemi-
ology in men is characterized by an almost triphasic
curve, with peaks of incidence in the childhood (i.e.,
between 0-14 years), in the middle age (i.e., between
40-54 years) and in the elderly (i.e., after 75 years of
age), whilst the epidemiology in women seems more
homogenous, with an initial peak in childhood, a fur-
ther decline between 10-29 years and a final (virtually
stable) increase throughout adulthood.
Acta Biomed 2021; Vol. 92, N. 1: e2021045 5
Could Rabies virus become a “Zombie virus”?
e term “rabies” most likely derives from the
old Indian root word “rabh”, which stands for “mak-
ing violence” (21). It is hence not surprising that the
most devastating phenotype of encephalitic (“furi-
ous”) rabies disease is that of an individual displaying
hypersalivation, hydrophobia, paranoia, hyperactiv-
ity, hyperirritability and abnormal aggressiveness (4).
Interesting evidence has recently been published by a
team of scientists from the University of Alaska Fair-
banks (22), who demonstrated that a specific sequence
within the Rabies virus glycoprotein, which has partial
homology with snake toxins, is capable to inhibit the
nAchR in the CNS, thus modifying animal behaviours
and triggering high excitability and hostility.
e hypothesis of viral infection as primary cause
of a “Zombie” transformation (i.e., “zombification”) is
not new, since it has already been proposed in both the
“Resident Evil” movie series and by “Walking Dead”
comics, nearly 20 years ago (23). In the former case,
the so-called “Tyrant Virus” (also known as T-Virus”)
was originally developed by the imaginary pharma-
ceutical company “Umbrella Corporation” in the late
1970s, with the primary scope of eradicating some
genetic diseases. Nevertheless, the innate characteris-
tics of the T-Virus persuaded some scientists to pro-
mote its conversion into a biological weapon, whereby
the pathogen would have been capable to almost irre-
versibly damage the CSF (especially neurons in frontal
lobe, somatosensory cortex and hypothalamus), thus
generating a dramatic decline in intelligence and motor
functions in the host, but preserving many elementary
function, reducing pain responsiveness and amplify-
ing psychotic rage, persistent hunger, and increased
aggressiveness (i.e., “zombification”) (17).
Some intriguing cases of “pseudo-zombification
have also been reported in the scientific literature,
mostly occurring in Haiti (where the original term
“Zombie” was coined), as result of tetrodotoxin and/
or Datura stramonium intake (24), or more recently
in the US, after mass intoxication with synthetic can-
nabinoids such as AMB-FUBINACA (25). e risk
of a “Zombie emergency” has also been seriously con-
templated by the US Centers for Disease Control and
Prevention (CDC), issuing an official manual entitled
“Preparedness 101: Zombie Pandemic” (26) (Fig. 5),
which aims to prepare healthcare and civil resources to
handle epidemic threats, among which Zombie infes-
tation is perhaps the most paradigmatic example. is
document has then been followed by another guide,
endorsed by the US Government, and specifically
called “Counter-Zombie Dominance” (27). is sec-
ond document contains the thoughtful description of
how a military strategy shall be established for defend-
ing the nation against an imaginable Zombie alert,
thus encompassing detailed information on biological
characteristics of “enemy force”, on available means for
preventing pathogen transmission, as well as on con-
ceivable strategies that shall be planned for prevent-
ing collapse of civilized society (27). erefore, some
discernible questions would follow. Specifically, how
much human rabies disease overlaps with “zombifica-
tion”? And, would it be possible that a mutated Rabies
virus epidemics (or pandemic) will transform mankind
into Zombies?
e first important aspect is defining the risk of
human-to-human transmission, the mainstay of the
imaginary Zombie contagion (28). It has been previ-
ously highlighted that bloodborne transmission is very
unlikely for rabies disease, whereby viraemia does not
seemingly occur with this type of infection. e sur-
vival of Rabies virus outside the host is also frankly
poor, so that the most probable means of human-to-
human transmission would need direct inoculation of
the pathogen through bites from infected people (13).
Rabies virus detection in saliva of infected humans has
been reported as being the highest 2-3 days after the
onset of symptoms, remains apparently stable for 2-7
days afterwards, and then apparently declines (29).
roughout the contagious window, it shall hence be
assumed that patients with overt rabies disease would
be so aggressive against their own kind to feel the
uncontrollable instinct to bite them. Although there
is only sporadic evidence of rabid patients biting other
humans (e.g., a 41-year-old woman died of rabies dis-
ease after being bitten by her 5-year-old son, who in
turn had developed the pathology after being bitten
by a rabid dog) (9), this possibility cannot be straight-
forwardly excluded. e real incidence of human
bites is largely underestimated due to under-report-
ing, and also because affected people tend to avoid
Acta Biomed 2021; Vol. 92, N. 1: e2021045
6
medical care. Nevertheless, current evidence suggests
that mammalian bites would account for almost 1% of
all emergency department visits, up to 20% of which
are attributable to human bites (i.e., 0.2% of all emer-
gency department admission) (30). erefore, the
suggestion that extremely aggressive rabid patients
would suffer from an incontrollable instinct to bite
other humans, and thus transmitting the infection,
remains actual. Interestingly, the Advisory Committee
on Immunization Practices of the CDC suggests that
post-exposure prophylaxis shall be planned for all peo-
ple with mucous membranes or non-intact skin expo-
sure to potentially infectious body fluids from rabid
patients (31), thus implicitly confirming that the risk
of human-to-human transmission of rabies disease is
not irrelevant.
e comparison of the current image of a Zombie
with that of a rabid patient is a second import aspect
that needs to be accurately scrutinized. As already
emphasized, conventional Zombies, as depicted in
comics and movies (23), share some similar behaviours
with patients infected by Rabies virus. Both undergo a
variable degree of consciousness deterioration, which
tends to be almost identical in the last stages of rabies
disease. Both individuals display also fearful facial
expressions, increased hyperirritability and aggressive-
ness, which can be both substantially accentuated by
external stimuli (thirst, fear, light and noise) in rabid
patients (Figure 4), and may ultimately evolve toward
violent and ferocious behaviours.
at said, it is now widely acknowledged that
many viruses are characterized by naturally occurring
Figure 4. Clinical similarities between encephalic rabies disease and imaginary “zombification”.
Acta Biomed 2021; Vol. 92, N. 1: e2021045 7
Figure 5. e Centers for Disease Control and Prevention (CDC) manual “Preparedness 101: Zombie Pandemic”.
Acta Biomed 2021; Vol. 92, N. 1: e2021045
8
high mutation rates, which induce constant changes
as reliable means for escaping host defences or facili-
tating their transmission to other susceptible hosts.
Rabies virus makes no exception to this rule, as
recently described by Wang et al (32), who found a vast
array (up to 100) of antigenic variants of this pathogen
in a wide range of animal hosts and geographic loca-
tions. Notably, even single amino acid mutations in the
proteins of Rabies virus can considerably alter its bio-
logical characteristics, for example increasing its path-
ogenicity and viral spread in humans, thus making the
mutated virus a tangible menace for the entire man-
kind (33). Beside the natural evolution of Rabies virus,
an equal threat may come from the science of genetic
engineering, which would reproduce the theatrical
scenario depicted in the movies of the Resident Evil
saga (23). By means of genetic engineering, scientists
have already developed innovative biological weapons,
which would appear more powerful and destructive
than their natural counterparts (34). e outbreak of
severe acute respiratory syndrome (SARS) in 2003, in
China, is perhaps the most paradigmatic example (35),
whereby many biological features of the pathogen
have led some eminent scientists to conclude that the
SARS virus might have been produced under labora-
tory conditions (36). Would a mutated Rabies virus,
bearing one or more mutations such as those described
by Hueffer et al (22), and hence characterized by facil-
itated human-to-human transmission, faster incuba-
tion, enhanced neurotoxicity and predisposing towards
aggressive highly behaviours, become the most lethal
biological agent that humans have ever faced?
Conclusions
e Rabies virus, like the vast majority of other
pathological microorganisms, attempts to perpetuate
itself with general and reservoir host-specific mecha-
nisms, which ultimately confer a considerable epide-
miological plasticity. e pace and phenotype of rabies
infection are mostly written in the virus genome,
whilst transmission is strongly favoured by aggres-
sive behaviours (i.e., a biting inclination) of rabid
hosts (37). Despite incidence and mortality of rabies
disease have both markedly declined during the past
three decades (Fig. 1), and irrespective of whether the
genetic code of Rabies virus can be naturally (i.e., by
ecological opportunities and viral adaptation) or arti-
ficially (i.e., by genetic engineering) modified, we need
to think “out-of-the-box”, in that the generation of a
“Zombie virus” cannot be firmly excluded according to
the currently available biological evidence (38). Wave-
front velocity of rabies disease propagation has been
calculated in wild animals (e.g., foxes, skunks, raccoons
and vampire bats) at around 10-40 km per year (37).
However, in densely populated towns, where natural
landscape barriers would be minimal, the human-to-
human contagion may increase by several orders of
magnitude, thus easily assuming apocalyptic propor-
tions and creating a new generation of pseudo-human
creatures, who have completely unleashed their already
existing part of zombie within (39). In keeping with
this conjecture, an interesting simulation of an imag-
inary Zombie outbreak reveals that most of the US
population would turn into Zombies within one week
from appearance of the first case, whilst only some
remotes zones in Montana and Nevada would remain
infestation-free one month afterwards (40).
In conclusion, what has become rather clear so
far is that rabies disease is entirely preventable, while
encephalomyelitis has never been described in people
who had received pre-exposure vaccination or post-
exposure booster (41). erefore, although the trans-
formation of Rabies virus into a “Zombie virus” will
always remain a tangible threat surrounding human
future (Fig. 1), further efforts shall be made for dis-
seminating a culture of widespread knowledge, preven-
tion and surveillance against this and other potentially
devastating viruses (42).
Conflict of interest: Each author declares that he or she has no
commercial associations (e.g. consultancies, stock ownership, equity
interest, patent/licensing arrangement etc.) that might pose a con-
flict of interest in connection with the submitted article.
References
1. Consales CA, Bolzan VL. Rabies review: Immunopathol-
ogy, clinical aspects and treatment. J Venom Anim Toxins
Incl Trop Dis 2007;13:5-38.
Acta Biomed 2021; Vol. 92, N. 1: e2021045 9
2. Davis BM, Rall GF, Schnell MJ. Everything You Always
Wanted to Know About Rabies Virus (But Were Afraid to
Ask). Annu Rev Virol 2015;2:451-71.
3. Schnell MJ, McGettigan JP, Wirblich C, Papaneri A. e
cell biology of rabies virus: using stealth to reach the brain.
Nat Rev Microbiol 2010;8:51-61.
4. Hemachudha T, Laothamatas J, Rupprecht CE. Human
rabies: a disease of complex neuropathogenetic mechanisms
and diagnostic challenges. Lancet Neurol 2002;1:101-9.
5. Vaidya SA, Manning SE, Dhankhar P, Meltzer MI, Rup-
precht C, Hull HF, Fishbein DB. Estimating the risk of
rabies transmission to humans in the U.S.: a Delphi analysis.
BMC Public Health 2010;10:278.
6. Wacharapluesadee S, Hemachudha T. Ante- and post-
mortem diagnosis of rabies using nucleic acid-amplification
tests. Expert Rev Mol Diagn 2010;10:207-18.
7. Helmick CG, Tauxe RV, Vernon AA. Is there a risk to con-
tacts of patients with rabies? Rev Infect Dis 1987;9:511-8.
8. Dutta JK, Dutta TK, Das AK. Human rabies: modes of
transmission. J Assoc Physicians India 1992;40:322-4.
9. Fekadu M, Endeshaw T, Alemu W, Bogale Y, Teshager T,
Olson JG. Possible human-to-human transmission of rabies
in Ethiopia. Ethiop Med J 1996;34:123-7.
10. Kolars JC. Should contacts of patients with rabies be advised
to seek postexposure prophylaxis? A survey of tropical med-
icine experts. J Travel Med 2003;10:52-4.
11. Zhu JY, Pan J, Lu YQ. A case report on indirect transmission
of human rabies. J Zhejiang Univ Sci B 2015;16:969-70.
12. Lu XX, Zhu WY, Wu GZ. Rabies virus transmission via
solid organs or tissue allotransplantation. Infect Dis Poverty
2018;7:82.
13. Gongala G, Mudhusudanab SM, Sudarshanc MK, Mahen-
drad BJ, Hemachudhae T, Wildee H. What is the risk of
rabies transmission from patients to health care staff? Asian
Biomed 2012;6:937-939.
14. Mrak RE, Young L. Rabies encephalitis in humans: pathol-
ogy, pathogenesis and pathophysiology. J Neuropathol Exp
Neurol 1994;53:1-10.
15. Jackson AC. Diabolical effects of rabies encephalitis. J Neu-
rovirol 2016;22:8-13.
16. Warrell M, Warrell DA, Tarantola A. e Imperative of
Palliation in the Management of Rabies Encephalomyeli-
tis. Trop Med Infect Dis. 2017 Oct 4;2(4). pii: E52. doi:
10.3390/tropicalmed2040052.
17. Nugent C, Berdine G, Nugent K. e undead in culture and
science. Proc (Bayl Univ Med Cent) 2018;31:244-9.
18. Awasthi M, Parmar H, Patankar T, Castillo M. Imaging
findings in rabies encephalitis. AJNR Am J Neuroradiol
2001;22:677-80.
19. Global Burden of Disease Collaborative Network. Global
Burden of Disease Study 2017 (GBD 2017) Results. Seat-
tle, United States: Institute for Health Metrics and Evalu-
ation (IHME), 2018. Available at: http://ghdx.healthdata.
org/gbd-results-tool. Last accessed, January 10, 2020.
20. GBD 2017 Disease and Injury Incidence and Prevalence
Collaborators. Global, regional, and national incidence,
prevalence, and years lived with disability for 354 diseases
and injuries for 195 countries and territories, 1990-2017: a
systematic analysis for the Global Burden of Disease Study
2017. Lancet 2018;392:1789-858.
21. Dupont JR, Earle KM. Human rabies encephalitis. A study
of forty-nine fatal cases with a review of the literature. Neu-
rology 1965;15:1023-34.
22. Hueffer K, Khatri S, Rideout S, Harris MB, Papke RL,
Stokes C, Schulte MK. Rabies virus modifies host behav-
iour through a snake-toxin like region of its glycoprotein
that inhibits neurotransmitter receptors in the CNS. Sci
Rep 2017;7:12818.
23. Verran J, Reyes XA. Emerging Infectious Literatures and
the Zombie. Condition Emerg Infect Dis 2018;24:1774-8.
24. Littlewood R, Douyon C. Clinical findings in three cases of
zombification. Lancet 1997;350:1094-6.
25. Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M,
Gerona R. “Zombie” Outbreak Caused by the Synthetic
Cannabinoid AMB-FUBINACA in New York. N Engl J
Med 2017;376:235-242.
26. Centers for Disease Control and Prevention. Zombie Pre-
paredness. Available at: https://www.cdc.gov/cpr/zombie/
index.htm. Last accessed, January 10, 2020.
27. Headquarters United States Strategic Command. Coun-
ter-Zombie Dominance. Available at: https://web.archive.
org/web/20170328232114/http://www.cubadebate.cu/
wp-content/uploads/2014/05/CONPLAN-8888.pdf. Last
accessed, January 10, 2020.
28. Sartin JS. Contagious Horror: Infectious emes in Fiction
and Film. Clin Med Res 2019;17:41-46.
29. Mahadevan A, Suja MS, Mani RS, Shankar SK. Perspec-
tives in Diagnosis and Treatment of Rabies Viral Enceph-
alitis: Insights from Pathogenesis. Neurotherapeutics
2016;13:477-92.
30. Rothe K, Tsokos M, Handrick W. Animal and Human Bite
Wounds. Dtsch Arztebl Int 2015;112:433-42.
31. Manning SE, Rupprecht CE, Fishbein D, Hanlon CA,
Lumlertdacha B, Guerra M, Meltzer MI, Dhankhar P,
Vaidya SA, Jenkins SR, Sun B, Hull HF; Advisory Com-
mittee on Immunization Practices Centers for Disease
Control and Prevention (CDC). Human rabies prevention-
-United States, 2008: recommendations of the Advisory
Committee on Immunization Practices. MMWR Recomm
Rep 2008;57:1-28.
32. Wang W, Ma J, Nie J, Li J, Cao S, Wang L, Yu C, Huang
W, Li Y, Yu Y, Liang M, Zirkle B, Chen XS, Li X, Kong W,
Wang Y. Antigenic variations of recent street rabies virus.
Emerg Microbes Infect 2019;8:1584-1592.
33. Faber M, Faber ML, Papaneri A, Bette M, Weihe E,
Dietzschold B, Schnell MJ. A single amino acid change in
rabies virus glycoprotein increases virus spread and enhances
virus pathogenicity. J Virol 2005;79:14141-8.
34. van Aken J, Hammond E. Genetic engineering and bio-
logical weapons. New technologies, desires and threats from
biological research. EMBO Rep 2003;4 Spec No:S57-60.
35. Lippi G, Mattiuzzi C. Severe Acute Respiratory Sindrome
(SARS): a new and intriguing diagnostic challenge. Bio-
chim Clin 2003;27:177-85.
Acta Biomed 2021; Vol. 92, N. 1: e2021045
10
36. Boulton F. Which bio-weapons might be used by ter-
rorists against the United Kingdom? Med Confl Surviv
2003;19:326-30.
37. Fisher CR, Streicker DG, Schnell MJ. e spread and evo-
lution of rabies virus: conquering new frontiers. Nat Rev
Microbiol 2018;16:241-255.
38. an K. “Zombie Virus” Possible via Rabies-Flu Hybrid?
National Geographic, 2010. Available at: https://www.
nationalgeographic.com/news/2010/10/1001027-rabies-
influenza-zombie-virus-science/: Last accessed, January 10,
2020.
39. Koch C, Crick F. e zombie within. Nature 2001;411:893.
40. Alemi AA, Bierbaum M, Myers CR, Sethna JP. You can
run, you can hide: e epidemiology and statistical mechan-
ics of zombies. Phys Rev E Stat Nonlin Soft Matter Phys
2015;92:052801.
41. Warrell MJ. Developments in human rabies prophylaxis.
Rev Sci Tech 2018;37:629-647.
42. Fisher CR, Schnell MJ. New developments in rabies vac-
cination. Rev Sci Tech 2018;37:657-672.
Correspondence:
Received: 10 January 2020
Accepted: 15 January 2020
Prof. Giuseppe Lippi. Section of Clinical Biochemistry,
University Hospital of Verona, Piazzale LA Scuro, 37134
Verona, Italy. Email: giuseppe.lippi@univr.it
... Bite location is important since bites to the face and neck are riskier than bites to the extremities. 32 Another important consideration is that many bats have tiny, sharp teeth that can pierce or scratch skin in a virtually unnoticed way. 13,33 Infected saliva contacting and entering pre-existing wounds can also lead to viral transmission. ...
Article
Full-text available
Introduction: Field work with bats is an important contribution to many areas of research in environmental biology and ecology, as well as microbiology. Work with bats poses hazards such as bites and scratches, and the potential for exposure to infectious pathogens such as rabies virus. It also exposes researchers to many other potential hazards inherent to field work, such as environmental conditions, delayed emergency responses, or challenging work conditions. Methods: This article discusses the considerations for a thorough risk assessment process around field work with bats, pre- and post-occupational health considerations, and delves into specific considerations for areas related to biosafety concerns-training, personal protective equipment, safety consideration in field methods, decontamination, and waste. It also touches on related legal and ethical issues that sit outside the realm of biosafety, but which must be addressed during the planning process. Discussion: Although the focal point of this article is bat field work located in northern and central America, the principles and practices discussed here are applicable to bat work elsewhere, as well as to field work with other animal species, and should promote careful considerations of how to safely conduct field work to protect both researchers and animals.
Article
Full-text available
The genetic and/or antigenic differences between street rabies virus (RABV) and vaccine strains could potentially affect effectiveness of rabies vaccines. As such, it is important to continue monitoring the glycoprotein (G) of the street isolates. All RABVG sequences in public database were retrieved and analysed. Using a pseudovirus system, we investigated 99 naturally occurring mutants for their reactivities to well-characterized neutralizing monoclonal antibodies (mAbs) and vaccine-induced antisera. A divergence in G sequences was found between vaccine strains and recent street isolates, with mutants demonstrating resistance to neutralizing mAbs and vaccine-induced antibodies. Moreover, antigenic variants were observed in a wide range of animal hosts and geographic locations, with most of them emerging since 2010. As the number of antigenic variants has increased in recent years, close monitoring on street isolates should be strengthened.
Article
Full-text available
Background The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. Methods We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. Findings Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1–4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0–8·4) while the total sum of global YLDs increased from 562 million (421–723) to 853 million (642–1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6–9·2) for males and 6·5% (5·4–7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782–3252] per 100 000 in males vs s1400 [1279–1524] per 100 000 in females), transport injuries (3322 [3082–3583] vs 2336 [2154–2535]), and self-harm and interpersonal violence (3265 [2943–3630] vs 5643 [5057–6302]). Interpretation Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury.
Article
Full-text available
The book club format has enabled expert and nonexpert exploration of infection and epidemiology as encountered in popular literature. This exploration reveals that fiction focusing on apocalyptic disease often uses the zombie as embodiment of infection, as well as an exemplar of current knowledge on emerging disease.
Article
Full-text available
Background: Rabies, for which the mortality rate is almost 100%, is a zoonotic viral disease that can be transmitted via solid organs or tissue allotransplantation. Dozens of deaths from rabies via solid organs or tissues allotransplantation (ROTA) have been documented during the last decades. In 2015 and 2016, two cases of rabies virus transmission via solid organs or tissue allotransplantation were reported in China, which further underscore the risk and importance of this special type of rabies for organ transplant recipients. Main text: From 1978 to 2017, at least 13 cases of ROTA, causing dozens of deaths, have been reported worldwide, whether in the high-risk or low-risk countries of rabies. The reported incubation period of ROTA ranges from 11 days to more than 17 months, while the historical incubation period of rabies is generally considered to range from ~ 1 week to several years. The pathogenesis of ROTA is not clear, but the use of post-exposure prophylaxis (PEP) can play a protective role in the transplant recipients. We also summarize reports about ROTA in China, combined with the actual situation regarding work on rabies surveillance and elimination, and suggest countermeasures for the prevention and control of ROTA in the future. Conclusions: Understanding the significance of ROTA, screening the suspected organs, assessing the risk and protecting the related population will be effective way to prevent and control further occurrence of ROTA.
Article
Full-text available
Rabies virus induces drastic behaviour modifications in infected hosts. The mechanisms used to achieve these changes in the host are not known. The main finding of this study is that a region in the rabies virus glycoprotein, with homologies to snake toxins, has the ability to alter behaviour in animals through inhibition of nicotinic acetylcholine receptors present in the central nervous system. This finding provides a novel aspect to virus receptor interaction and host manipulation by pathogens in general. The neurotoxin-like region of the rabies virus glycoprotein inhibited acetylcholine responses of α4β2 nicotinic receptors in vitro, as did full length ectodomain of the rabies virus glycoprotein. The same peptides significantly altered a nicotinic receptor induced behaviour in C. elegans and increased locomotor activity levels when injected into the central nervous system of mice. These results provide a mechanistic explanation for the behavioural changes in hosts infected by rabies virus.
Article
Infectious diseases have been a preeminent part of literature since the earliest human writings. In particular, they have contributed greatly to the genre of horror-written or visual art intended to startle or scare. Horror fiction has emphasized infectious themes from the earliest Babylonian and Hebrew texts. In medieval times, stories of vampires and werewolves often had a contagious component, and pivotal works of Victorian horror centered around fear of infection and contamination. As film became prominent in the 20th Century, a strong emphasis on themes of plague and apocalypse developed. An analysis of the use of infection in horror fiction and film shows that it often represents a metaphor for societal concerns, and it is extremely useful in framing challenging issues for a wide audience.
Article
Current rabies vaccines are safe and, when administered properly, they are highly effective. In addition, they elicit long-lasting immunity, with virus-neutralising antibody titres persisting for years after vaccination. However, current regimens require multiple doses to achieve high neutralising titres and they are costly, which means that it is difficult for developing countries, where rabies deaths are highest, to implement widespread vaccination. New innovations are the only way to reduce rabies disease to acceptable rates. Numerous preclinical and clinical studies are under way, testing novel vaccines, adjuvants and injection methods. Research into the use of live vaccines and alternative vaccine vectors is ongoing, while attempts to develop DNA vaccines have so far failed to match the immunogenicity and neutralising capability of traditional vaccines. The development of molecular adjuvants that induce faster, stronger immune responses with less antigen has yielded exciting preclinical results and appears to edge us closer to a better rabies vaccine. However, steep challenges remain: molecular adjuvants require administration with live vaccines, and differences in species specificity of immune molecules complicate development. Over all, the array of research undertaken over the past decade is impressive and encouraging, but most new vaccines have yet to be tested in clinical trials, and the viability of such experimental vaccines in the global market remains to be seen. Only a vaccine that outperforms currently available vaccines in every area will have a chance at widespread adoption. Nevertheless, the authors are confident that some vaccine candidates will meet these criteria.
Article
Rabies is entirely preventable. All deaths are the result of failed prophylaxis. Rabies encephalomyelitis has never been reported in anyone who received both pre-exposure vaccination and a post-exposure booster. Awareness of the risk of contact with rabid animals is crucial. A lack of basic knowledge and the inaccessibility of expensive rabies vaccines can discourage patients bitten by suspected rabid animals from seeking prompt post-exposure prophylaxis. Similarly, people working with mammals, residents of areas where dog rabies is endemic, travellers, and others at risk often fail to take advantage of pre-exposure prophylaxis. However, since human infection by a dog rabies virus has always proved fatal in unvaccinated patients, there is understandable reluctance to accept any change in vaccine protocols. The intramuscular route of delivery is wasteful and the current, low-dose intradermal (ID) regimen is not always economical or universally trusted. A new, one-week ID regimen, using less vaccine, injected at multiple sites, and involving two clinic visits, could increase the accessibility of highly immunogenic prophylaxis and reduce the prohibitive cost. The recent 2018 World Health Organization recommendations for rabies prophylaxis are included.
Article
The undead have a significant role in mythology, religion, folklore, and literature. In the 1800s, the word zombie was used to describe reanimated corpses in the Caribbean who often worked on plantations doing long, arduous field work. The movie White Zombie was released in 1932 and exploited this folklore, but it ignored the fact that zombies represent one outcome in Vodou religious beliefs regarding death and the migration of spirits following death. The interest in zombies eventually led to sociological and medical investigations into zombification. Wade Davis reported that powders used by malevolent priests (bokors) contained tetrodotoxin, which could cause the neurologic changes underlying the zombie phenotype. Recent clinical studies have indicated that synthetic cannabinoids and synthetic cathinones can cause bizarre zombie-like behavior. According to Haitian folklore, zombies can develop when bokors reanimate someone who suddenly died from an acute illness or who was purposely poisoned. Recent studies in molecular biology suggest that the sequence of programmed cell death can be reversed when the stressor is removed and that cells, tissues, and bodies (at least in Drosophila flies) can recover. These scientific studies would support the remote possibility that the near dead might recover under certain circumstances but have residual neuropsychological dysfunction. Alternatively, the bokors could maintain control of their victims using drugs with properties similar to those of synthetic cannabinoids. The concept of zombification needs to be considered in the context of culture, religion, and science.
Article
Rabies is a lethal zoonotic disease that is caused by lyssaviruses, most often rabies virus. Despite control efforts, sporadic outbreaks in wildlife populations are largely unpredictable, underscoring our incomplete knowledge of what governs viral transmission and spread in reservoir hosts. Furthermore, the evolutionary history of rabies virus and related lyssaviruses remains largely unclear. Robust surveillance efforts combined with diagnostics and disease modelling are now providing insights into the epidemiology and evolution of rabies virus. The immune status of the host, the nature of exposure and strain differences all clearly influence infection and transmission dynamics. In this Review, we focus on rabies virus infections in the wildlife and synthesize current knowledge in the rapidly advancing fields of rabies virus epidemiology and evolution, and advocate for multidisciplinary approaches to advance our understanding of this disease.