Kurzgesagt – In a Nutshell
Sources – The Deadliest Virus: Rabies
We thank the following experts for their help with this script:
Dr. Sergio Rodriguez
Dr. David Lowe
Dr. James Gurney
Georgia State University
It is named after Lyssa, the ancient Greek spirit of mad rage, and has been haunting us for at least 4000 years.
Of course, a "remote diagnosis" based on 4000-year-old records is difficult, but there is evidence of the disease from the Middle East.
#Adamson, P. B. (1977): The Spread of Rabies into Europe and the Probable Origin of This Disease in Antiquity. The Journal of the Royal Asiatic Society of Great Britain and Ireland, No. 2, pp. 140-144
https://pubmed.ncbi.nlm.nih.gov/11632333/
Quote: “In the ancient Near East the earliest mention of death from dog-bite is to be found in the laws of Eshnunna from Mesopotamia, dated c. 2200 B.C. No associated symptoms are mentioned, so that rabies cannot justifiably be incriminated as the cause of death.
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The implication of the bat in the ancient Near East as a reservoir host of rabies virus was certainly not recognized. Nevertheless, the possibility of acquiring infection from these animals by susceptible animals, such as foxes and jackals, certainly was present, if they used caves and areas where infected bats congregated to rest.
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Old Babylonian lists equate šegû ("to be mad, become frenzied") with numer ous synonyms also referring to raging or madness, and the lists end with kaduhhu "with open mouth", which is a characteristic late symptom of canine rabies. These synonyms are applied to dogs. Other Old Babylonian texts mention curious and abnormal behaviour of animals in relation to other animals. Such abnormal behaviour is a characteristic early symptom of the disease, but by itself is not absolutely diagnostic of rabies.”
Viruses exist on the edge between life and death, hardly more than a few genetic instructions that need living cells to multiply.
We talked about viruses in more detail in one of our last videos:
#Kurzgesagt (2021): This Virus Shouldn't Exist (But it Does)
https://www.youtube.com/watch?v=1-NxodiGPCU&t=582s
The lyssavirus is simple even for a virus: It has only five genes, that is the instructions for five proteins that let it solve complex problems: Infect a mammal, avoid its immune system, travel to its brain, make more of itself and infect new hosts.
Keep in mind that the following explanations reflect only a fraction of the functions. We only want to give a first rough overview here. In addition, a lot of things are still unclear and discussed.
Nucleoprotein (N) encapsidates the genetic material (RNA). Together they form the ribonucleoprotein (RNP) complex that works as a template for viral transcription and replication.
Polymerase (L protein) is a multifunctional enzyme and is, to put it simply, a catalyst, a starter for the multiplication of genetic information.
Matrix protein (M) coats the virus.
Glycoprotein (G): Although the exact processes are not yet known, scientists assume that this protein is responsible, among other things, for the virus being able to enter the cell membrane and thus enter the cell. It is not entirely certain which receptors the protein docks onto in the process.
Phosphoprotein (P) may play a role in the transport of the virus. Since it attacks nerve cells, which can be very long, it uses an endogenous transport system (cytoplasmic dynein motor complex) to get into the actual cell body.
Keep in mind that these explanations reflect only a fraction of the functions. We only want to give a first rough overview here. In addition, a lot of things are still unclear and discussed.
#Fisher, C. R. et al. (2018): The spread and evolution of rabies virus: conquering new frontiers. Nature Reviews Microbiology, Vol. 16, pp. 241–255
https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6899062&blobtype=pdf
Quote: “RABV is a negative-stranded RNA virus of the Rhabdoviridae family. RABV virions [G] are enveloped by a host cell-derived membrane and take on a bullet shape of about 200 nm by 80 nm. The bullet shape is likely influenced by the constraints of budding and viral uptake. The relatively small RNA genome of the virus (~12 kb) encodes for five proteins: nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and polymerase (L, in reference to the large size of the gene).”
#Raux, H. et al. (2000): Interaction of the Rabies Virus P Protein with the LC8 Dynein Light Chain. Journal of Virology, Vol. 74, No. 21, pp. 10212–10216
https://pubmed.ncbi.nlm.nih.gov/11024151/
Quote: “Rhabdoviruses have a single-stranded negative-sense RNA genome (11 to 15 kb) that is tightly encapsidated by the viral nucleoprotein (N) to form a ribonucleoprotein (RNP). This RNP serves as the template for viral transcription and replication.
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The L protein is a multifunctional enzyme and acts as the RNA-dependent RNA polymerase. This polymerase complex carries out all the enzymatic steps of transcription, including the initiation and elongation of transcripts, and cotranscriptional modifications of RNAs, such as capping and polyadenylation.
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The N, P, and L proteins, with the viral RNA, form the ribonucleoprotein complex, which is surrounded by the lipid envelope associated with M and G proteins. The G protein forms trimers and is the primary surface antigen to which neutralising antibodies bind. The nucleoprotein protects the viral RNA from innate immune recognition but also contains several antigenic sites that act as a major target for T helper cells (adaptive immune response).”
#Gluska, S. et al (2014): Rabies Virus Hijacks and Accelerates the p75NTR Retrograde Axonal Transport Machinery. PLoS Pathog 10 (8)
https://www.openagrar.de/receive/openagrar_mods_00004943
Quote: “Entry of RABV into the cell requires binding of the viral glycoprotein (G) and fusion of the virus envelope with the host cell membrane.”
Fooks, A. R. et al. (2014): Current status of rabies and prospects for elimination. Lancet, Vol. 384, No. 9951, pp. 1389-1399
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62707-5/fulltext#seccestitle120
Quote: “Binding of lyssaviruses to host cells is dependent on the glycoprotein, which binds to one of several proposed receptors that facilitate virus entry. In vitro, lyssaviruses seem able to infect a diverse range of cell lines of different lineages, although the mechanisms of entry into various cells that do not express recognised receptors is unclear. However, carbohydrate moieties, phospholipids, sialylated gangliosides, and various undefined proteins associated with the membrane are thought to act as potential binding ports.”
#Schnell, M. J. et al. (2010): The cell biology of rabies virus: using stealth to reach the brain. Nature Reviews Microbiology, Vol. 8, pp. 51-61
https://www.nature.com/articles/nrmicro2260
Quote: “The transport of the rabies virus capsid would require uncoating after entry and a specific interaction of the RNP with the cellular transport machinery. Two research groups identified an interaction between rabies virus phosphoprotein and the dynein light chain 8 (LC8), which led them to propose that the virus uses the cytoplasmic dynein motor complex for intracellular transport.”
#Schnell, M. J. et al. (2010): The cell biology of rabies virus: using stealth to reach the brain. Nature Reviews Microbiology, Vol. 8, pp. 51-61
It all starts with a bite, most likely by a dog carrying millions of viruses in its saliva, pushing them deep into the tissue. The goal is your nerve cells, your neurons.
The transmitter also depends on the region. In the USA or Europe, rabies hardly occurs anymore due to vaccination programs in dogs. Here, wild animals play a bigger role in transmission.
Worldwide, however, 99% of all deaths are due to a bite from a dog.
There are other transmission routes such as organ transplants. But these account for only a tiny fraction.
CDC (2020): Rabies around the World (accessed 22.03.22)
https://www.cdc.gov/rabies/location/world/index.html
Quote: “Each year, rabies causes approximately 59,000 deaths worldwide. Despite evidence that control of dog rabies through animal vaccination programs and elimination of stray dogs can reduce the incidence of human rabies, dog rabies remains common in many countries and exposure to rabid dogs is still the cause of over 90% of human exposures to rabies and of 99% of human rabies deaths worldwide.”
CDC (2020): How is rabies transmitted? (accessed 22.03.22)
https://www.cdc.gov/rabies/transmission/index.html
Quote: “Rabies virus is transmitted through direct contact (such as through broken skin or mucous membranes in the eyes, nose, or mouth) with saliva or brain/nervous system tissue from an infected animal.
People usually get rabies from the bite of a rabid animal. It is also possible, but rare, for people to get rabies from non-bite exposures, which can include scratches, abrasions, or open wounds that are exposed to saliva or other potentially infectious material from a rabid animal. Other types of contact, such as petting a rabid animal or contact with the blood, urine or feces of a rabid animal, are not associated with risk for infection and are not considered to be exposures of concern for rabies.
Other modes of transmission—aside from bites and scratches—are uncommon. Inhalation of aerosolized rabies virus is one potential non-bite route of exposure, but except for laboratory workers, most people won’t encounter an aerosol of rabies virus. Rabies transmission through corneal and solid organ transplants have been recorded, but they are also very rare. There have only been two known solid organ donor with rabies in the United States since 2008. Many organ procurement organizations have added a screening question about rabies exposure to their procedures for evaluating the suitability of each donor.
Bite and non-bite exposures from an infected person could theoretically transmit rabies, but no such cases have been documented. Casual contact, such as touching a person with rabies or contact with non-infectious fluid or tissue (urine, blood, feces), is not associated with risk for infection. Contact with someone who is receiving rabies vaccination does not constitute rabies exposure, does not pose a risk for infection, and does not require postexposure prophylaxis.”
Lyssa probably binds to the receptors that are crucial for this process and slips inside the unsuspecting nerve cells.
Besides the nicotinic acetylcholine receptor (nAChR), there are other receptors to which the virus can dock. Which receptor exactly is responsible for the entry into the cell is still unclear.
#Fisher, C. R. et al. (2018): The spread and evolution of rabies virus: conquering new frontiers. Nature Reviews Microbiology, Vol. 16, pp. 241–255
https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6899062&blobtype=pdf
Quote: “The rabies life cycle and its resulting pathogenesis have been extensively studied and reviewed. Briefly, RABV, with its modest genome and single surface glycoprotein, can infiltrate an astonishing number of mostly neuronal tissues in almost any mammal to induce its lethal pathology. This might lead one to assume that the receptor that RABV uses to enter the cells is exceptionally conserved. However, debate surrounds RABV receptor binding (Fig. 1b). In vitro and knockout in vivo experiments have homed in on three primary candidates: the nicotinic acetylcholine receptor (nAChR), neural cell adhesion molecule (NCAM, also known as CD56), and the low-affinity neurotrophin receptor, p75NTR. Overall consensus holds that glycoprotein can bind flexibly to all three receptors, and possibly others, as needed in different stages of the life cycle or in different hosts. Recent studies on virus internalization confirm that RABV uptake is mediated by classic clathrinmediated endocytosis (Fig. 1B).
#Guo, Y. et al. (2019): Early events in rabies virus infection - Attachment, entry, and intracellular trafficking. Virus Research, Vol. 263, pp. 217-225
Quote: “Although the hypothesis that RABV attaches to the cell surface by direct interaction with nAChR has been proposed and validated through various methods, the exact role of nAChR during RABV uptake remains unclear. Interestingly, nAChR is located at the postsynaptic muscle membrane of NMJs, not at the presynaptic nerve membrane, suggesting that nAChR determines RABV infection in muscle cells. Since NMJs are the major sites of entry into neurons, the concentration of nAChRs at NMJs allows more amplification of virions in front of NMJs, which facilitates the subsequent uptake to nerve terminals (Lewis et al., 2015). The detailed role of nAChR and the possibility that other isoforms are involved in the process of RABV attachment still need further investigation.”
Dynein motors are actual motors that use energy and deliver packages. They are made from 50 different proteins, ten times more than the lyssavirus, and look like a little pair of shoes.
Especially in neurons, which can be very long, this "molecular freight transport" is extremely important. While dynein transports goods toward the nucleus (retrograde axonal transport), kinesin transports substances to the periphery of the cell.
#Gluska, S. et al (2014): Rabies Virus Hijacks and Accelerates the p75NTR Retrograde Axonal Transport Machinery. PLoS Pathog 10 (8)
https://www.openagrar.de/receive/openagrar_mods_00004943
Quote: “As peripheral neurons are highly polarized cells with long axons, active intracellular transport is vital to the maintenance of neuronal function and survival. Axonal transport is the cellular process of trafficking proteins, organelles, vesicles, RNA and other cellular factors to and from the neuronal cell body. The molecular motor kinesin drives transport from the cell body anterogradely, supplying proteins, lipids and other essential materials to the cell periphery. Dynein/dynactin complexes drive retrograde transport, moving damaged proteins for degradation and critical signaling molecules such as neurotrophins to the cell body.”
Lyssa uses one of its five viral proteins to hijack this amazing system and order it to head for the nucleus.
Again, the virus remains very mysterious. But it seems that the P protein (phosphoprotein) binds to a specific part of the dynein locomotor system. How important this connection really is (if it really is important) and in what form the virus travels like this is still unclear and controversial. The source gives a rough overview of the discussion.
##Schnell, M. J. et al. (2010): The cell biology of rabies virus: using stealth to reach the brain. Nature Reviews Microbiology, Vol. 8, pp. 51-61
https://www.nature.com/articles/nrmicro2260
Quote: “Because the entry site of rabies virus in axons does not provide the biochemical environment required for protein synthesis, rabies virus needs to reach the neuronal cell body for replication and transcription. Two different mechanisms have been proposed for the transport of rabies virus through the axon to the cell body: transport of either the rabies virus capsid alone or transport of the whole virion. The transport of the rabies virus capsid would require uncoating after entry and a specific interaction of the RNP with the cellular transport machinery. Two research groups identified an interaction between rabies virus phosphoprotein and the dynein light chain 8 (LC8), which led them to propose that the virus uses the cytoplasmic dynein motor complex for intracellular transport. However, deletion of the LC8-binding site in the phosphoprotein does not affect viral transport from a peripheral site to the CNS, and LC8 directly or indirectly affects primary transcription of rabies virus but not its transport.”
Usually when a virus attacks your civilian cells are crucial in activating your immune response. They notice that they have been infected and release hundreds of thousands of a special family of proteins: The interferons that, well, interfere with viruses. We’ll have to simplify a lot, but in a nutshell, Interferons alert your immune system to make antivirus weapons. But they do much more: they tell civilian cells to turn down their protein factories for a while – which means that viruses can’t replicate efficiently anymore.
They are thought to be generated by the presence of double-stranded RNA, which is not found in mammalian cells.
They dock with uninfected cells in the environment, triggering a signaling chain that suppresses replication of the virus in the cell.
#Janeway, C. A. et al. (2001): Immunobiology. 5th edition.
Quote: “Infection of cells with viruses induces the production of proteins that are known as interferons because they were found to interfere with viral replication in previously uninfected tissue culture cells. They are believed to have a similar role in vivo, blocking the spread of viruses to uninfected cells.
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Interferon synthesis is thought to occur in response to the presence of double-stranded RNA, as synthetic doublestranded RNA is a potent inducer of interferon. Double-stranded RNA, which is not found in mammalian cells, forms the genome of some viruses and might be made as part of the infectious cycle of all viruses. Therefore, doublestranded RNA might be the common element in interferon induction.”
And interferons tell your cells to become super transparent, which is important, because how can your immune cells notice that your civilian cells are infected when viruses hide inside them? Your body solves this by creating display windows into their insides, called MHC class I molecules. Cells constantly produce stuff to stay alive, and to showcase to your immune cells what is going on inside them, they take random samples of their products and put them into these tiny display windows to give a peek inside.
Interferon tells your cells to make WAY more display windows and become super transparent.
#Janeway, C. A. et al. (2001): Immunobiology. 5th edition.
Quote: “In all cases, T cells recognize their targets by detecting peptide fragments derived from the foreign proteins, after these peptides have been captured by specialized molecules in the host cell and displayed by them at the cell surface. The molecules that display peptide antigen to T cells are membrane glycoproteins encoded in a cluster of genes bearing the cumbersome name major histocompatibility complex, abbreviated to MHC.
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There are two types of MHC molecule, called MHC class I and MHC class II. These differ in several subtle ways but share most of their major structural features. The most important of these is formed by the two outer extracellular domains of the molecule, which combine to create a long cleft in which a single peptide fragment is trapped during the synthesis and assembly of the MHC molecule inside the cell. The MHC molecule bearing its cargo of peptide is then transported to the cell surface, where it displays the peptide to T cells (Fig. 1.27). The antigen receptors of T lymphocytes are specialized to recognize a foreign antigenic peptide fragment bound to an MHC molecule. A T cell with a receptor specific for the complex formed between that particular foreign peptide and MHC molecule can then recognize and respond to the antigen-presenting cell.”
If a cell is infected and forced to make virus parts, your immune cells will see these parts in a window and order the infected cell to kill itself – and all the viruses trapped within. This is one of the most powerful methods of wiping out a viral infection.
T cells dock at the MHC molecules and recognize the "hostile fragment" as hostile. These then send small vesicles (lysosomes) with toxic proteins (more precisely: "cytotoxic” proteins, e.g. perforin) into the infected cell.
Perforin, as the name suggests, perforates the membranes of the cell. It dies.
But there is another way.
Here, a protein (FasL) on the membrane of the immune cell docks with a specific receptor (Fas) of the infected cell. A "death program" then runs inside the cell: An inhibitory protein called I-CAD is destroyed, thereby releasing the caspase-activatable DNase (CAD), which destroys the cell nucleus. A kind of "programmed cell death", called "apoptosis".
#Janeway, C. A. et al. (2001): Immunobiology. 5th edition.
Quote: “Cytotoxic T cells kill their targets by programming them to undergo apoptosis (Fig. 8.35). When cytotoxic T cells are mixed with target cells and rapidly brought into contact by centrifugation, they can program antigen-specific target cells to die within 5 minutes, although death may take hours to become fully evident. The short period required by cytotoxic T cells to program their targets to die reflects the release of preformed effector molecules, which activate an endogenous apoptotic pathway within the target cell. As well as killing the host cell, the apoptotic mechanism may also act directly on cytosolic pathogens. For example, the nucleases that are activated in apoptosis to destroy cellular DNA can also degrade viral DNA. This prevents the assembly of virions and thus the release of infectious virus, which could otherwise infect nearby cells. Other enzymes activated in the course of apoptosis may destroy nonviral cytosolic pathogens. Apoptosis is therefore preferable to necrosis as a means of killing infected cells; in necrosis, intact pathogens are released from the dead cell and these can continue to infect healthy cells, or can parasitize the macrophages that ingest them.”
“The principal mechanism through which cytotoxic T cells act is by the calcium-dependent release of specialized lytic granules upon recognition of antigen on the surface of a target cell. These granules are modified lysosomes that contain at least two distinct classes of cytotoxic effector protein that are expressed selectively in cytotoxic T cells (Fig. 8.36). Such proteins are stored in the lytic granules in an active form, but conditions within the granules prevent them from functioning until after their release. One of these cytotoxic proteins, known as perforin, polymerizes to form transmembrane pores in target cell membranes. The other class of cytotoxic proteins comprises at least three proteases called granzymes, which belong to the same family of enzymes - the serine proteases - as the digestive enzymes trypsin and chymotrypsin. Granules that store perforin and granzymes can be seen in armed CD8 cytotoxic effector cells in tissue lesions.”
Unfortunately Lyssa blocks your neurons from making interferons and stays basically invisible to your immune system.
Since many processes have not yet been explored and the virus-host relationship is very complex, the source below can only provide a first rough insight.
Basically, the virus (RVP) with its protein P (P) prevents interferons from being produced in the cell nucleus (IFNB, left side) and interferons from other cells (Type I IFN/Type II IFN, middle and right side) from entering the cell nucleus to produce antiviral products (IFN-stimulated response element ISRE).
#Schnell, M. J. et al. (2010): The cell biology of rabies virus: using stealth to reach the brain. Nature Reviews Microbiology, Vol. 8, pp. 51-61
Your central nervous system is a very fragile part of your body and so the immune system has to be very careful. A few haywire immune cells in your brain is a quick way to die. So they aren’t free to enter your nervous system, they have to be invited in and can be kicked out.
To protect themselves, your nerve cells can order T Cells to self-destruct, if they think they are overreacting. And Lyssa figured out a way to make infected neurons express this order. So as your powerful defense cells arrive – they are ordered to commit suicide.
The suicide of the T cells (by FasL, produced by neurons) is doubly useful for the virus: on the one hand, it protects itself from an attack of the immune system, on the other hand, less infected neurons are induced to suicide by T cells so that the virus can continue to multiply.
#Nadin‐Davis, S. A. & Fehlner‐Gardiner, C. (2008): Chapter 5 Lyssaviruses—Current Trends. Advances in virus research, Vol. (71), pp. 207-250
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7119311/
Quote: “In an exploration of the role of the death‐promoting factor Fas Ligand (FasL) and its receptor Fas in initiating apoptosis of activated lymphocytes in vivo, the virulent CVS strain, but not the attenuated PV strain, induced early production of FasL, primarily by infected neurons, which was associated with high levels of T cell apoptosis. Thus, CVS infection of mice induced only a transient migration of lymphocytes into the CNS in contrast to PV infection that permitted sustained T cell migration into the CNS and more limited CD3+ T cell apoptosis. Up‐regulation of FasL by the neurovirulent CVS strain may limit CD3+ T cell mediated apoptosis of neuronal cells and thereby preserve the integrity of the neuronal network critical to virus spread.”
But this doesn’t seem to be what happens here. Brain tissue of rabies patients shows minimal, sometimes non-existent damage. Instead of murdering everything in sight, it is currently thought that lyssa wreaks havoc by messing up the neuron communication inside your brain, so much so, that it can’t function anymore.
Some people get drowsy followed by unconsciousness and coma – in a way this is the lucky outcome. Other patients experience more weird and distressing symptoms.
The following paper provides an introduction to this topic. The authors have followed up on evidence that signs of cell death (or “apoptosis”, i.e. “programmed cell death”) have been found in the brains of deceased persons. To investigate this, they re-examined brain samples from patients who died of Rabies. Again, their results confirm that the mere damage to the brain by the virus does not play a role in lethality.
#Jackson, A. C. et al. (2008): Neuronal apoptosis does not play an important role in human rabies encephalitis. Journal of NeuroVirology, Vol. 14, pp. 368-375
Quote: “It is generally accepted that there are not prominent features of neuronal cell death in rabies encephalitis. However, Hemachudha and coworkers recently reported widespread apoptosis in the central nervous system of several human rabies cases (BMC Infect Dis 5: 104, 2005). In this study we have evaluated morphological features and markers of neuronal apoptosis in postmortem brain tissue from 12 cases of human rabies who died in four different countries. Histopathological analysis, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling) staining, and immunostaining for cleaved (activated) caspase-3 were performed on paraffin-embedded tissues from the cerebral cortex, hippocampus, and brainstem, and additional regional areas from one of the cases. We did not find morphological evidence of neuronal apoptosis or TUNEL staining in any of the cases of rabies encephalitis. Similarly, immunostained cleaved caspase-3 was not seen in neurons, but prominent staining was observed in microglial processes. We conclude that neuronal apoptosis does not play an important pathogenetic role in human rabies encephalitis.”
Abnormal behavior has been noted in communications involving neurotransmitters such as acetycholines or serotonin. However, these abnormalities are not so severe that they could clearly explain the symptoms.
#Jackson, A. (2003): Rabies Virus Infection: An Update Journal of NeuroVirology 9(2), pp. 253-258
https://www.researchgate.net/publication/10793322_Rabies_Virus_Infection_An_Update
Quote: ”Natural rabies is normally characterized by severe neurologic signs and fatal outcome with relatively mild neuropathologic changes in the CNS, supporting the idea that neuronal dysfunction, rather than Rabies virus infection AC Jackson 255 neuronal cell death, must play an important role in producing the disease. A variety of experimental studies in rabies virus infection have investigated possible abnormalities in neurotransmission involving acetylcholine, serotonin, and γ -amino-nbutyric acid (GABA). Abnormalities of uncertain significance were found, but no fundamental defect was demonstrated that explains neuronal dysfunction in rabies.”
Basically, there are two forms of the disease: a furious and paralytic.
The furious one is the "most popular" one and this type is found in 80% of patients. When you think of rabies, for example, you think of aggressive foxes foaming at the mouth, due to increased salivation, a typical characteristic of this form of the disease. Another characteristic is the alternation of phases of lucid mind with those of furious, delusional behavior.
#Fook, A. R. (2014): Current status of rabies and prospects for elimination. The Lancet Vol. 384, No. 9951, pp.1389-1399
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62707-5/fulltext
Quote: “Two clinical forms of rabies disease are typically described: encephalitic (furious) and paralytic (dumb). The earliest neurological symptom in human beings is usually pain, paraesthesia, or pruritus at the site of infection because of viral replication in local dorsal root ganglia and associated ganglionitis. After the prodrome, either the encephalitic or paralytic forms of the disease might be observed. Encephalitic rabies often presents with hypersalivation, and periods of agitation alternating with lucidity will be observed—a key feature of the so-called “furious” type of rabies. (...) The paralytic form of disease differs from the encephalitic form in that muscle weakness develops early (which is not observed in the so-called furious form of the disease), and progression to coma and death often takes longer than with the encephalitic form.”
#Schnell, M. J. et al. (2010): The cell biology of rabies virus: using stealth to reach the brain. Nature Reviews Microbiology, Vol. 8, pp. 51-61
https://www.nature.com/articles/nrmicro2260
Quote: “Clinical manifestation of rabies in humans has two forms: the furious (classical) form (80% of infections), and the numb (non-classical or paralytic) form (20% of infections). The furious form of rabies “is characterized by hydrophobia: terror and excitation with spasm of inspiratory muscles, larynx and pharynx precipitated by attempts to drink”, and episodes of hallucinations and excitement are common. Animals often present with extreme aggression and randomly attack objects, other animals or humans. These behavioural changes occur simultaneously with the shedding of large amounts of rabies virus in the saliva, which facilitates the spread of the virus to a new host. The numb form of rabies is characterized by weakness and flaccid paralysis, which sometimes causes misdiagnosis at the onset of this clinical form of rabies. In both cases, survival after the onset of symptoms is rarely more than 7 days.”
In over half, one of them is hydrophobia. One of the things your brainstem controls and that gets screwed up here, are involuntary reflexes like swallowing. When you try to drink and fluid enters the mouth, your throat involuntarily closes, making it impossible to swallow. You become unable and unwilling to drink and the sight of water can make you irritated and scared, even if you’re literally dying of thirst.
Even though this diagnosis is not really reliable, it can be an indication. Practically the entire musculature of the pharynx, larynx and respiratory musculature is neurologically disturbed in phases by the virus.
#Fook, A. R. (2014): Current status of rabies and prospects for elimination. The Lancet Vol. 384, No. 9951, pp.1389-1399
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62707-5/fulltext
Quote: “Hydrophobia is also often observed, and in developing countries water might be offered to suspected patients for diagnostic purposes. As hydrophobia progresses, the offer of water leads to pharyngeal spasms and involuntarily refusal of the water with excessive gagging being noted.”
#Tongavelona, J. R. et al. (2018): Hydrophobia of human rabies. Clinical case reports vol. 6, No. 12, pp. 2519-2520.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293146/#ccr31846-sup-0001
Quote: “Hydrophobia is a clinical sign characteristic of human rabies. This sign occurs following paroxysmal contractions of pharynx responsible for hydrophobic spasms.”
Now the virus begins to leave. Still traveling through neurons, it migrates away from the brain and heads for the salivary glands. This is remarkable, because after traveling in one direction the virus reverses its course. After decades of study we don’t know how this works.
It is not only the salivary glands that are affected. In this so-called "centrifugal propagation", practically the entire body is invaded: Organs, muscles, skin, blood vessels and, of course, the salivary glands.
#Hemachudha, T. (2013): Human rabies: neuropathogenesis, diagnosis, and management. The Lancet Neurology, Vol. 12, pp. 498–513
https://pubmed.ncbi.nlm.nih.gov/23602163/
Quote: “A slow phase of centrifugal (anterograde) propagation can only begin 2 days after replication in each infected neuronal population, and leads to viral transport to the ventral and dorsal roots and centrifugal spread to extraneural organs via their sensory innervations — ie, to muscle spindles (via large dorsal root ganglia neurons), skin (via cutaneous afferents from large and small dorsal root ganglia neurons), and to immune and visceral organs, including the salivary glands, heart, and blood vessels (via small dorsal root ganglia neurons).
Now the end is near. You are rapidly developing encephalitis, a swelling of the brain with many unpleasant neurological symptoms, from lethargy to paralysis. Slowly at first, and then suddenly, organ after organ fails as you slip into a coma. Death follows soon after, ending your suffering.
Especially in the phase before the actual disease (prodome), the symptoms are very non-specific (e.g. fever). After a short time, the acute neurological phase with severe symptoms then sets in. This phase can last up to four days, after which coma follows. Within a week, the patient is dead.
#Consales C. A. & Bolzan V. L. (2007): Rabies review: Immunopathology, clinical aspects and treatment. Journal of Venomous Animals and Toxins including Tropical Diseases, Vol. 13, No.1, pp. 5-38
There is no known effective therapy, barely anyone has ever survived Lyssa once symptoms begin to show.
In 2003, U.S. physicians developed a novel treatment method which was used in 2004 while treating a 15-year-old patient who had been bitten by a bat. A kind of medicine cocktail (e.g., made of rabies immune globulin and ketamine) was combined with an artificial coma.
Several things were criticized about this treatment: the coma in particular was judged to be questionable and the effect of ketamine was called into question. Another criticism is that it has not been investigated why exactly the patient survived.
#Jackson, A. C. (2013): Current and future approaches to the therapy of human rabies. Antiviral Research 99, pp. 61-67
https://pubmed.ncbi.nlm.nih.gov/23369672/
Quote: “In 2003, a group of physicians and researchers with expertise in rabies published an article describing a variety of potential therapies, including rabies vaccination, rabies immune globulin, ribavirin, interferon-a and ketamine. Because combination therapies have shown success in the treatment of cancer and a variety of infectious diseases, including human immunodeficiency virus infection and chronic hepatitis C, the authors suggested a similar approach to rabies. The inclusion of ketamine as part of combination therapy was based on animal studies performed over a decade earlier at the Institut Pasteur. In the following year, a combination approach was used to treat a 15-year-old girl in Wisconsin, who had been bitten by a bat on her left hand about a month before admission, and had not received PEP. Neutralizing anti-rabies virus antibodies were demonstrated in her serum and CSF shortly after presentation. She was treated with ketamine (48 mg/kg/day as a continuous intravenous infusion) and given antiviral therapy with intravenous ribavirin and amantadine (200 mg/day given enterally). She also underwent induced therapeutic coma with intravenous midazolam and supplemental phenobarbital, to maintain a burst-suppression pattern on her electroencephalogram. This therapeutic approach has subsequently been dubbed the ‘‘Milwaukee Protocol.’’ The young patient survived with mild neurological deficits, but as stated in an editorial accompanying the case report), it is unclear why she survived. Good medical treatment in a critical care unit likely played an important role in the favorable outcome, but there is much less certainty about the benefit of any specific therapy. In particular, therapeutic coma was the most dubious and controversial component of the protocol, and the one most likely to cause harm. Therapeutic coma is effective for status epilepticus, but there is no clear scientific rationale or other evidence supporting its use for rabies or other CNS infections. The further evaluation of ketamine, including in vitro studies of virus-infected primary neurons and experimental studies in mice, has also cast doubt on its therapeutic value. Since the ‘‘Milwaukee Protocol’’ was first used in 2004, there have been at least 26 reports of the failure of similar approaches to therapy, and there have likely been additional instances of treatment failure that have not been published. Notably, the online clinical reference UpToDate does not recommend use of the Milwaukee Protocol, pending further data.”
Interestingly, however, there are some, successful methods before the onset of symptoms (postexposure prophylaxis). Methods that can prevent the actual disease such as wound cleansing or multiple administration of vaccines. Of course, this presupposes that you have noticed a bite or something similar and, above all, that you have access to appropriate treatments in the first place.
#Jackson, A. C. (2013): Current and future approaches to the therapy of human rabies. Antiviral Research 99, pp. 61-67
https://pubmed.ncbi.nlm.nih.gov/23369672/
Quote: “Rabies can be effectively prevented after a recognized exposure through postexposure prophylaxis (PEP), providing current recommendations are followed closely. PEP consists of immediate wound cleansing, active immunization with multiple doses of rabies vaccine, and passive immunization with human rabies immune globulin, injected into and around the wound and intramuscularly. The objective of PEP is to prevent rabies virus from gaining access to the nervous system. It is of no proven value after clinical signs of rabies develop.”
It is by far the deadliest virus we know.
There are, of course, viruses that are more dangerous in various characteristics (e.g., infection rate). But the combination of a fatality rate of almost 100% and the fact that it has not yet been eradicated (unlike Small Pox in the 1980s for example) plus the lack of an effective treatment, makes this virus so deadly.
#OWID (2018): Eradication of Diseases
The horrific tricks of simple Lyssa don’t work once you are vaccinated. And the vaccine is special for another reason – because Lyssa is so slow in the first few weeks, it can be given to you after you have been exposed. So you can still be vaccinated after you have been bitten by an animal.
Vaccination is combined with the administration of antibodies (rabies immune globulin, RIG) injected directly around the wound, preferably on the same day. In this way, the virus is fought with antibodies even before the body forms its own antibodies as a result of the vaccination.
Fooks, A. R. et al. (2014): Current status of rabies and prospects for elimination. Lancet, Vol. 384, No. 9951, pp. 1389-1399
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62707-5/fulltext#seccestitle120
Quote: “Every year, the application of post-exposure prophylaxis provides more than 20 million treatments and has been an effective counter-measure to rabies virus infection for more than 100 years. Rabies is preventable via several approved post-exposure prophylaxis recommendations, which consist of thorough wound-cleansing and prompt administration of rabies immune globulin (RIG), together with a full course of rabies vaccination. Wounds should be cleansed with soap or a virucidal antiseptic (eg, povidone iodine) with copious irrigation and should not be sutured unless absolutely necessary.
Post-exposure prophylaxis should be started as soon as possible after a recognised exposure and includes a series of injections of rabies vaccine. Four different post-exposure prophylaxis vaccine regimens are currently approved for individuals not previously vaccinated against rabies; three are given intramuscularly and one is given intradermally. RIG is also an important component of post-exposure prophylaxis to inhibit viral spread in the interval before sufficient immunity is developed in response to vaccination. It should be injected into and around the wound site, ideally on the day of exposure or up to 7 days after the initial dose of vaccine.”
Which is super important if you’ve had contact with a sick wild animal, say a bat, because you often don’t even notice a bite from tiny teeth.
If you have had contact with a wild animal, especially if you have been bitten or scratched, talk to a doctor. The general recommendation according to the CDC is to consider the incident not as an emergency, but as urgent, and to wash the wound carefully and thoroughly.
#CDC (2022): When should I seek medical attention?
https://www.cdc.gov/rabies/exposure/index.html
Quote: “If you’ve been in contact with any wildlife or unfamiliar animals, particularly if you’ve been bitten or scratched, you should talk with a healthcare or public health professional to determine your risk for rabies or other illnesses. Wash any wounds immediately with soap and water and then plan to see a healthcare provider. (It’s important to know that, unlike most other animals that carry rabies, many types of bats have very small teeth which may leave marks that disappear quickly. If you are unsure, seek medical advice to be safe.)
Remember that rabies is a medical urgency but not an emergency. Decisions should not be delayed.
See your doctor for attention for any trauma due to an animal attack before considering the need for rabies vaccination. After any wounds have been addressed, your doctor – possibly in consultation with your state or local health department – will help you decide if you need treatment known as rabies postexposure prophylaxis (PEP). Decisions to start PEP will be based on your type of exposure, the animal you were exposed to, whether the animal is available for testing, and laboratory and surveillance information for the geographic area where the exposure occurred.
In the United States, PEP consists of a regimen of one dose of immune globulin and four doses of rabies vaccine over a 14-day period. Rabies immune globulin and the first dose of rabies vaccine should be given by your health care provider as soon as possible after exposure. Current vaccines are relatively painless and are given in your arm like a flu or tetanus vaccine; rabies vaccines are not given in the stomach.”
It still kills around 60,000 people each year, almost half of them children.
96% of all cases worldwide are in Africa and Asia, 35% in India alone. The reasons for this include lack of access to post-exposure prophylaxis (PEP) or to appropriate centers and a general lack of health care infrastructure, personnel and rabies surveillance or management.
#Hampson, K. et al.(2015): Estimating the Global Burden of Endemic Canine Rabies. PLOS Neglected Tropical Diseases, Vol. 9, No. 4
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400070/
Quote: “We estimated that around 59,000 [95% CIs: 25,000–159,200] human rabies deaths occur annually globally, with the vast majority of these in Africa (36.4%) and Asia (59.6%). Less than 0.05% of estimated deaths occurred in the Americas [182, 95% CIs: 84–428], of which over 70% were from Haiti. India, with 35% of human rabies deaths, accounted for more deaths than any other country, but the estimated per-person death rate was highest in the poorest countries in sub-Saharan Africa.
(...)
The human and economic costs of canine rabies are poorly known. A major challenge to estimating the burden of rabies is the absence of reliable surveillance data for countries where the disease is most prevalent. Basic information on how many lives are lost to rabies and the economic costs of preventing disease amongst those exposed are needed to advocate for sustainable control programmes. Official reporting of incidence data on rabies and rabies exposures remains desperately poor in most canine rabies-endemic countries, and is increasingly recognized to grossly underestimate the true number of cases. Active surveillance studies highlight the disparities between officially recorded and likely occurring rabies deaths. These include recent studies from both Asia and Africa based on probability decision tree modelling; extensive verbal autopsy surveys; community surveys and contact tracing, which all show much higher mortality than officially reported. Specific features of rabies contribute to the problem of underreporting. Death is inevitable following clinical onset and therefore a large number of rabies victims never report to health facilities and are never diagnosed. Misdiagnosis to other neurological syndromes is frequent, especially in malaria endemic regions. Shortages of life-saving PEP and centres that provide PEP for bite victims and poorly monitored sales of PEP to private suppliers all complicate counting the number of rabies diagnoses made and the number of treatments given. These problems of PEP provision particularly increase the risks of disease among the rural poor, an already marginalized sector of society. Moreover, poor infrastructure and a lack of personnel and facilities for rabies surveillance and diagnosis in most developing countries means that only very limited data of questionable reliability are available.”
There are several studies in which the group of patients receiving post-exposure treatment was analyzed and the result was 30-50% children.
Other studies, e.g. from India, which deal with deaths, come to similar rates with 50%.
#Knobel, D. L. et al. (2005): Re-evaluating the burden of rabies in Africa and Asia. Bulletin of the World Health Organization, 83 (5), pp. 360–68.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2626230/
Quote: “The results of our study predict that there will be five times more rabies deaths in rural areas than in urban areas. Children in particular are at a higher risk of exposure to rabid dogs. Typically, 30-50% of those receiving post-exposure treatment are children aged < 16 years. Children are also more likely to suffer multiple bites and bites to the face and head, both of which carry a higher risk of contracting rabies.”
#Suraweera, W. et al. (2012): Deaths from Symptomatically Identifiable Furious Rabies in India: A Nationally Representative Mortality Survey. PLOS Neglected Tropical Diseases, Vol. 6, No. 10
Quote: “Approximately 62% of all rabies deaths in India in 2005 were in males and 50% were in children under 15 years. The overall rabies mortality rate was 1.1 deaths per 100,000 population (99% CI 0.9 to 1.4), with the highest rates being in children under 5 years and in the elderly age 70 years or older.”