Coronavirus in animals: What contribution for research?
Coronaviruses are ubiquitous pathogens responsible up to third of a mm on colds. In addition, circumstantial evidence has linked them to certain diarrhea and neurological disorders. disorders such as multiple sclerosis.
This family of enveloped RNA viruses has so far received little attention from the medical community, reflecting the lack of knowledge about their biology and the lack of widely used diagnostic tests.
Fortunately, animal models of coronavirus infections have begun to reveal important information about viral and pathogenesis. interaction with the immune system. For example, acute encephalitis caused by murine neurotropic coronaviruses can be prevented by vaccination with a purified viral surface protein or a synthetic peptide homologous to an important determinant of this molecule.
Prevention is also possible by passive transfer of monoclonal antibodies against this protein, by active immunization with anti-idiotypic antibodies repaired against a monoclonal antibody, or by the use of iral mutants who have lost these determinants of pathogenesis. Interestingly, animals infected with this virus are immunologically sensitized to the basic protein myelin, a major component of myelin sheath surrounding the nerve fibers. Immuhosuppressed animais do not develop demyelinating disease.
Neurological diseases induced by coronaviruses can therefore be immune mediated. A recently observed sequence homology between a human coronavirus protein and a region of myelin basic protein located near an immunodominant site recognized by the lymphocytes of patients with multiple sclerosis can provide an ink between the animal madel and the possible neurological implication of human coronaviruses.
Advanced diagnostic technologies such as nucleic acid hybridization and polymerase chain reaction are beginning to be applied to coronaviruses and should provide important information about the suspected medical importance of these insidious viruses. Knowledge acquired from animal models could then serve as a basis for the development of preventive and curative measures.
The basic protein myelin and the proteolipid protein are the most abundant proteins in the central nervous system. In several animal species, the injection of these proteins causes experimental allergic encephalomyelitis, an autoimmune neurological disease, involving T lymphocytes specific to the target tissue, and whose clinical and histopathological characteristics are very similar to MS, the most demyelinating disease. widespread in humans. The primary sequence of PBM is highly conserved in several animal species and some of its encephalitogenic determinants, which vary according to the inoculated species, have been identified.
Although encephalitogenic sites in humans cannot be directly characterized, the study of the molecular specificity of lymphocytes isolated from patients allow them to be identified. An immunodominant region for recognition of PBM by T lymphocytes of MS patients is now known.
One of the possible induction mechanisms of an autoimmune disease of viral origin consists in the sharing of protein sequences between the virus and the host organism, a relatively frequent phenomenon. This molecular mimicry can be fortuitous. We have noticed that antisera specific to the murine coronavirus recognize keyhole limpet hemocyanin, a protein extracted from a mollusc which is used as a carrier molecule to make synthetic peptides immunogenic.
This could explain the partial protection against coronaviral encephalitis which is conferred by this molecule. However, the Molecular mimicry could also be acquired by the virus during evolution in order to contribute to its pathogenic potential. Thus, when the immune response targets regions shared between viral and cellular proteins, the induced autoimmunity can have unfortunate pathological consequences, as is the case when the encephalitogenic site of PBM constitutes the target of this immune attack.
We noticed a homology of five amino acids (minimum size of epitopes recognized by T lymphocytes and antibodies) between a non-structural protein of a human coronaviral strain and the human PBM. A mathematical calculation indicates that the chances that this homology is the result of pure chance are one in more than three million.
This conserved region is associated with encephalitogenic sites of PBM identified after the injection of the corresponding peptides in laboratory animals. It is located a few residues downstream from the region preferentially recognized by the immune system of patients suffering from MS, and is the target of lymphocytes found in some of these patients. Finally, it may be noted that the susceptibility of nerve cells to coronaviral infection in vitro has already been reported for a serotype.
Although the medical importance of coronaviruses remains to be established, such observations show the validity of the study of the neurotropism of these viruses.
Diagnostic laboratories do not include coronaviruses in their panoply of tests. In retrospect, some epidemiological studies on the prevalence of respiratory infections have been carried out using an ELISA-type immunoenzymatic test.
Only, however, antibodies to the two known serotypes are detectable, and the presence of other serotypes remains a very real possibility. The direct isolation of coronavirus after inoculation of cultured cells, although very difficult given their high tissue and species specificity, has also been the subject of some work.
Currently, the diagnosis of enteric infections involving coronaviruses is limited to the observation of characteristic particles under the electron microscope, which makes the results uncertain. Finally, only a few isolated works have concentrated on the neurological implication of coronaviruses, bringing still controversial results. Fortunately, efforts are starting to be made to develop rapid and sensitive diagnostic methods by molecular hybridization and amplification by chain polymerization (PCR).
These developments will accelerate research on the epidemiology and pathogenesis of human coronaviruses.
At present, the recognized medical importance of coronaviruses is limited to mild respiratory infections which, although widespread, have not yet received the attention of medical authorities.
Despite some indications regarding their involvement in gastrointestinal and neurological infections, research efforts on enteric and neurotropic coronaviruses remain very weak. No sooner have we lifted the veil on the medical importance of coronaviruses than the need to develop new molecular tools that will verify the suspected medical implication of these insidious viruses, then consider prevention and treatment. We must explore the research avenues provided by animal coronaviruses, in order to verify the existence of coronaviral neurotropism in humans.