In the film Night of the Living Dead, an army of shambling, slow-witted, cannibalistic corpses reanimated by radiation attack a group of rural Pennsylvanians. We are looking for something a little in between Haiti and Hollywood: an infectious agent, a zombie virus if you will, that renders its victims half-dead but still-living shells of their former selves.
An effective agent would target, and shut down, specific parts of the brain , says Steven C. Schlozman explained to PopSci that although the walking dead have some of their motor skills intact—walking, of course, but also the ripping and tearing necessary to devour human flesh—the frontal lobe, which is responsible for morality, planning, and inhibiting impulsive actions like taking a bite out of someone , is nonexistent.
The cerebellum, which controls coordination, is probably still there but not fully functional. This makes sense, since zombies in movies are usually easy to outrun or club with a baseball bat. The most likely culprit for this partially deteriorated brain situation, according to Schlozman, is as simple as a protein.
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. 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. The incidence is higher in Africa and South-East Asia, nearly double in men than in women, with a higher peak in childhood. 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.
Rabies disease is mostly sustained in humans by Rabies Lyssavirus, a virus belonging to the large family of Rhabdoviridae, comprised within the Mononegavirale 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, more or less resambling what has more recently happened with coronavirus disease COVID 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 transcription and replication activities, as well as in mediating interplay with cellular proteins during neural transportation 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 responsible for generation of neutralizing antibodies and, finally, v the L gene encodes a RNA polymerase 1.
The viral capsid is typically surrounded by host cell-originating plasma membrane, strictly interacting with the matrix protein and the transmembrane glycoprotein. Overall, Rabies viruses are divided into two major phylogroups, accounting for a total number of up to 14 different genotypes 2. Among these, genotype 1 seems to be the most prevalent, and also that causing the largest number of human infections 3.
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.
The more frequent means of Rabies virus transmission in humans is through bites of infected mammals which, lacerating 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 countries 4. The risk of virus inoculation through bites is highly variable i. 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 accidental and involuntary human-to-human transmission is theoretically possible 7 , 8 , as also revealed by publication of a number of paradigmatic case reports 9 - Nonetheless, cases of rabies contamination through direct contact with blood of infected humans have not been described so far, whereby the virus seems to follow a prevalent intra-neuronal localization, and a clear viraemia is hence probably absent in mammals Moreover, the Rabies virus can be very rapidly inactivated by sunlight i.
It seems reasonable to conclude that the cumulative risk of human-to-human infection appears definitely low, except in the case of direct inoculation of human saliva e.
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.
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 particles at the neuromuscular junction and providing a more efficient transportation within the intracellular space. The virus then propagates throughout the CNS, principally through plasma-membrane budding, cell-to-cell direct infection or trans-synaptic dissemination, with preferential localization in brainstem, thalamus, basal ganglia and spinal cord 3.
Importantly, major damages to the limbic system are those responsible for onsets of the typical emotional and motivational symptoms characterizing patients with viral encephalopathy 2. The 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 autoimmune reactions against infected neurons.
Importantly, the huge cytokines production that accompanies CNS 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 tropism for salivary and lacrimal glands The so-called prodromal stage typically initiates when the virus propagates from peripheral nerves to dorsal-root ganglia i.
Along with prickling or itching sensation at the site of the original bite, the initial symptoms appear relatively non-specific, mimicking an influenza syndrome, and thus encompassing fever, general weakness and headache 1.
After this initial period, whose length is somewhat variable i. The former subtype i. Within 24 hours from the onset of the first symptoms the patients also develop hydrophobia, hypersalivation, fluctuating consciousness, 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 The 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 nearly half of the patients few hours before death, which can also occur for respiratory, cardiac and circulatory arrest during severe spasm episodes 4.
The 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 This mostly leads to appearance of symptoms like muscular paralysis and facial diparesis.
The CNS involvement develops later in the course of disease, evolves towards coma and is then usually followed by death 4. The most updated statistics on rabies epidemiology can be garnered from the database of the Global Burden of Disease GBD Study 19 , which is currently considered the most comprehensive worldwide repository of health-related information In i.
The geographic distribution of rabies disease in the year is shown in figure 2. The highest burden of rabies disease cases described in Africa i. The distinctive geographical localization of rabies disease mirrors that of the socio demographic index SDI , since the incidence in countries with low SDI 0. The age and sex distribution of rabies disease is then summarized in figure 3 , showing that the overall incidence is nearly double in men than in women i.
The epidemiology in men is characterized by an almost triphasic curve, with peaks of incidence in the childhood i. Interesting evidence has recently been published by a team of scientists from the University of Alaska Fairbanks 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.
Nevertheless, the innate characteristics of the T-Virus persuaded some scientists to promote its conversion into a biological weapon, whereby the pathogen would have been capable to almost irreversibly 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 amplifying psychotic rage, persistent hunger, and increased aggressiveness i.
Therefore, some discernible questions would follow. And, would it be possible that a mutated Rabies virus epidemics or pandemic will transform mankind into Zombies? The first important aspect is defining the risk of human-to-human transmission, the mainstay of the imaginary Zombie contagion It has been previously highlighted that bloodborne transmission is very unlikely for rabies disease, whereby viraemia does not seemingly occur with this type of infection.
The survival 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 Rabies virus detection in saliva of infected humans has been reported as being the highest days after the onset of symptoms, remains apparently stable for days afterwards, and then apparently declines Throughout 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. The real incidence of human bites is largely underestimated due to under-reporting, and also because affected people tend to avoid medical care.
Therefore, 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 people with mucous membranes or non-intact skin exposure 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.
The 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. In fact, the high number of domesticated species in the Old World versus the paucity of domesticated species in the Americas is the reason that the population of the Americas was devastated by human-compatible infectious diseases from the Old World during the Columbian Exchange whereas nothing similar happened to the population of the Old World because of human-compatible infectious diseases from the Americas.
On a final note, even if a zombie outbreak happened in real life, it is doubtful that it would lead to the end of the world as we know it.
In part, this is because developed countries have strong institutions in place to stop the spread of infectious diseases, as shown by the recent example of the ebola outbreak that took a horrible toll on a number of developing countries but showed no such results in their developed counterparts.
If there is anything that is common to zombie outbreaks, it is that the responsible pathogen is very, very lethal because zombies are almost always very, very dumb. Garrett by trade is a personal finance freelance writer and journalist. With over 10 years experience he's covered businesses, CEOs, and investments. However he does like to take on other topics involving some of his personal interests like automobiles, future technologies, and anything else that could change the world.
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