Interaction with the cell receptor and pathogenesis
Curated by Professor Giorgio Gallinella, U.O. microbiology virologist, S. Orsola Malpighi hospital.
of Microbiology at the university of Bologna.
Interaction with the cell receptor and pathogenesis
SARS-CoV-2 infection is possible because the virus is able to infect respiratory epithelial cells through a specific interaction between the S-viral protein and an abundantly expressed protein cell, the ACE2 (angiotensin-converting enzyme 2) receptor. The same receptor is largely used by viruses belonging to the betacoronavirus family and the specificity on receptors of different species is not absolute, thus promoting an interspecific transmissibility. ACE2 is the same receptor used by the previous SARS-CoV virus, but the binding affinity appears to be minor compared to what has been observed in the identification by SARS-CoV-2. A major efficiency in the identification of the receptor is one of the key factors which have promoted the spread of the virus on a pandemic scale. It is also a prerequisite for SARS-CoV2 to remain adapted to the human host long-term.
In addition to the contact with the receptor protein, another important step for the onset of the infection is the processing of the S-viral protein in two parts, named S1 and S2. This step also requires the intervention of proteins from the human host, proteolytic enzymes which are able to cut the S-viral protein at specific points. Even in this case there is an adaptation of the virus to the conditions provided by the host and the virus ability to infect cells is linked both to the presence of the receptor and to the abundance of these
proteolytic enzymes.
The details on attack viruses and cell receptors structure, on their interaction and dynamic are already sufficiently known in detail for the design of antiviral agents aimed to impede these initial interaction phases between cell and virus, or to assess the efficacy of protective antibodies, whether they are
natural, or induced after the immunisation of the vaccine candidate, or produced as monoclonal antibodies
for medical purposes.
Following an interaction with the cell receptor, a coordinated series of events releases the viral genome in the cell. Hence, the genome can start synthetising the different proteins, replicating and assembling them into new released viral particles, which are able to propagate the infection to other cells and other hosts. Usually the virus infects the upper airway cells, but it can spread to lower airways and to the lung, where it can cause more severe clinical situations in the alveoli. The aftermath of the infection is dual, since the virus can destroy infected cells, causing direct damage to respiratory epithelium, and can also stimulate a
highly lethal inflammatory response, both locally with pneumonia and systemically in the organism, the so
called “cytokine storm” and possible inflammatory shock syndrome with a highly lethal multiple organ failure.
Transmissibility and clinical features
The virus infects the respiratory
epithelium and it is airborne. The
infected cells release the virus in
respiratory secretions, which therefore
constitute the main source of
contagion. Secretions are usually
emitted in the form of droplets, which
can contaminate the exposed mucous
membranes, mainly the airways,
directly or indirectly through
contaminated surfaces. The virus can
also be found in smaller dispersed
suspensions, such as inhalable aerosol
and, naturally, through direct contact
with respiratory secretions. Infected
individuals represent the source of
infection and direct human-to-human
transmission is undoubtedly the
prevailing form of transmission.
Although the infective virus persistency
on inert surfaces is yet to be defined in
detail and dependently on different
situations, there is still a risk of indirect transmission of the infection.
From an epidemiological standpoint, the spread of the virus is made easier by an effective transmissibility, by a prolonged course of infection, by a wide window through which the virus can be transmitted and by a symptomatology which can be unapparent or moderate in 80% of the cases. Inapparently infected people can keep living a social life andeffectively disseminate the virus, which can reach large sections of the population. Clinical manifestations are symptomatic and progressively severe in the remaining 20% of the population, with variable mortality rates that can reach up to 10% according to the effectiveness of diagnostic procedures and which concern mainly and more severely older or comorbid people.
The main clinical pictures are borne by lungs and airways, with a series of histopathological changes of tissue damage and obstacle to normal respiratory function. Systemic manifestations are unspecified and connected to the intense inflammatory response. They can be part of the most serious symptomatological pictures. A vast series of rarer manifestations have been observed and described, mainly on an immunopathological basis.
Clearly, the problem of eventual long-term sequelae of the infection is still open.
This diversity is not exclusive to COVID-19 pathology. It is normal for the course of infectious process of the viruses, but not only, to acquire different characteristics and, moreover, the contributing factors involved in this diversity are multiple. The characteristics of the infective agent can vary according to their specificity (if, for example, there are different genetic variations). As mentioned, in the case of SARS-CoV-2, the mutations so far identified do not seem to confer different pathogenic characteristics and we still have notregistered any att enuating phenomena.
The qualities of the host play an important role, not only in general terms of age or concurrent illnesses, but also susceptibility and control capacity of the immune system.
Genetic association studies will later allow to identify predisposing or more protective factors and they could underlie the development of increasingly effective therapeutic and prophylactic protections.
Picture 5. Schematization of SARS-CoV-2 clinical course of infection in case of mild (at the top) or severe (at the bottom). After the transmission of the infection and an incubation period of the disease, localized
symptoms or systemic inflammations gradually appear. The virus is transmitted to contacts mainly in the early stages and it is traceable through molecular tests on nasopharyngeal secretion samples throughout the whole course of the active infection. Its progress and resolution depend on a set of physiological and
immunological factors of the organism, in addition to the therapeutic support capacity.
From Expasy, Viral Zone (https://viralzone.expasy.org/).
Bibliographical references
Cui, J., Li, F. & Shi, Z. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 17, 181–192 (2019). https://doi.org/10.1038/s41579-018-0118-9
Hu, B., Guo, H., Zhou, P. et al. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol (2020). https://doi.org/10.1038/s41579-020-00459-7
Vandenberg, O., Martiny, D., Rochas, O. et al. Considerations for diagnostic COVID-19 tests. Nat Rev Microbiol (2020). https://doi.org/10.1038/s41579-020-00461
Su, S., Du, L. & Jiang, S. Learning from the past: development of safe and effective COVID-19 vaccines. Nat Rev Microbiol (2020). https://doi.org/10.1038/s41579-020-00462
