preprints.org > biology and life sciences > immunology and microbiology > doi: 10.20944/preprints202304.0807.v4

Preprint Review Version 4 This version is not peer-reviewed

Version 1 : Received: 21 April 2023 / Approved: 23 April 2023 / Online: 23 April 2023 (14:31:39 CEST)
Version 2 : Received: 24 April 2023 / Approved: 25 April 2023 / Online: 25 April 2023 (07:38:14 CEST)
Version 3 : Received: 7 July 2023 / Approved: 10 July 2023 / Online: 10 July 2023 (10:09:23 CEST)
Version 4 : Received: 4 November 2024 / Approved: 5 November 2024 / Online: 5 November 2024 (16:42:48 CET)

Despite being a rare disease worldwide, rabies has the highest morbidity and mortality rates, with nearly all symptomatic cases leading to coma and death. Rabies represents an infectious disease caused by the Rabies virus (RABV), which is part of the Lyssavirus group and the Rhabdoviridae family, and it mainly spreads through the bite and scratch of an infected mammal, but particularly of wild animals, such as bats, foxes, wolves and racoons, and of domestic animals, such as dogs and cats, in rabies-prone areas of the world. Airborne transmission has been deemed as extremely rare, and no clinical case as such has been recorded worldwide yet, except in the enclosed environment, such as research laboratories and caves where infected bats are present. Domestic mammals, such as dogs and ferrets, represent other important reservoirs of disease transmission, and the human cases of Asia and Africa amount approximately 95% of all human cases worldwide. Infected animals most commonly start transmitting the virus once the first symptoms have occurred, and if they experience disease aggravation and death within 10 days, a case of rabies is registered, more easily if the incidence occurred in the urban area and then, any person or animal that had been potentially exposed are strongly recommended to receive the inoculation. It is rare for asymptomatic mammals to transmit the illness. Most First-World and several Second-World countries have recently been declared dog rabies-free by the World Health Organization. The disease can only be treated prophylactically, with three doses of a vaccine containing an inactivated form of RABV, or with five doses of the vaccine and two doses of anti-RABV immunoglobulins within 28 days if the patient is believed to have been exposed to the virus beforehand. It has been projected that, once the viral load reaches elements of the central nervous system, prophylactic approaches are no longer effective, even if symptoms have not begun yet, and this highlights the urgent trait of the medical condition, strongly recommending exposed people to receive the prophylactic doses immediately after the potential exposure to the virus. The pathogen first infects the bodily fluids, before reaching the peripheral nervous system, from where it will gradually move toward the spinal cord or the encephalon, at a speed of movement ranging from 1 to 40 cm per day. It was also found, in extremely rare circumstances, to infect the nasopharyngeal cavity and the lungs. The primary cause of a successful, gradual advance of the viral load toward the point of clinical no-return for the patient - the CNS - is a complex mechanism of induced innate immune evasion, with the interferon system being heavily targeted and silenced by RABV proteins. The ‘Milwaukee’ protocol is locally believed to decrease the mortality rate of the clinical illness to approximately 80%, although significantly more research is required in this sense. First-line immune evasion represents the central mechanism developed by viruses during their evolutionary process to gain control over human immunity, so it could be the development and adjustment of a counter-offensive to this evolutionary operating system that could address the core elements of the problem. Human recombinant Type I and Type III Interferons were found to be significant vaccine adjuvants and to considerably delay the clinical onset of the disease. Despite their central role in natural immunity-based prophylaxis, vaccine support and, in often cases, vaccination per se, a local administration of IFNs as such may not be enough to tackle the core problem of the endemic disease, and a specific and systemic treatment of potential host cells with IFN I and III, as well as IFN-stimulating proteins, may constitute a major research requirement in the coming years of disease investigation, as the inoculation efforts with the inactivated virus and immunoglobulin administration continue. The administration of a relatively low dosage of somatic Natural Killer cells, gamma-interferon and perhaps, of somatic helper CD4+ and somatic cytotoxic CD8+ T-lymphocytes treated with alpha-, beta- and lambda-interferon could be merged with the administration of a similar dosage of alpha-, beta- and lambda-interferon during the efforts to develop an effective and less costly prophylactic vaccine against rabies. A combination of a nasal substance containing a low dosage of IFN I and III with a reduced concentration of neutralised RABV copies, and/or with a low dose of anti-RABV IgA antibodies, could also be tested for humans for the purposes of pre- and post-exposure prophylaxis. It is important to acknowledge that are existing clinical signs that early alpha-interferon-based therapies alone are not effective in curbing the mortality rate of the disease, which could be explained by the fact that, once symptoms begin, the virus has already reached and started distributing its load in critical areas of the host organism - the Central Nervous System (CNS) - and that the vast majority of the cases are detected after clinical symptoms start occurring. Nonetheless, researchers did find a broader window of opportunity with regards to early antiviral therapy, with methods such as RNA interference, as well as the development of the Favipiravir antiviral agent and of new targeted molecular therapies, which perhaps could be used alongside recombinant Type I, Type II and/or Type III Interferons, as well as the other mentioned innate and adaptive immune elements mentioned. Overall, there could be an application of a concept called “a United Immune System” into the practical, clinical world, that will significantly help in mounting an effective, long-term evolutionary response against advanced microbial immune evasion, changing the connection between innate and adaptive immunity from a “national road” to a “motorway”.

rabies; RABV; PRV; single-stranded RNA; RNA-dependent RNA Polymerase; viral self-camouflaging; glycoprotein; innate immunity; interferon system; natural lymphocytes; adaptive immunity; adaptive lymphocytes; dendritic cells; IgA; IgM; IgG; primary dendritic cells; macrophages; United Immune System

Biology and Life Sciences, Immunology and Microbiology

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